EAS Nelson, WK Ko, E Kwan, SF Leung, KH Poon, CB Chow, WK Sin, YK Wong, CY Yeung

These guidelines are not intended for the management of acute diarrhoea in neonates.

Explanatory Notes on Level of Evidence and Grading System on Recommendation

The definition of types of evidence and grading recommendations originate from the US Agency for Health Care Policy and Research (AHCPR) and are also recommended and used by the Royal College of Paediatrics and Child Health.

Evidence is graded upon the methodological qualities. Guidelines normally contain many different recommendation based upon different levels of evidence. It is important that users are aware of the level of evidence on which each guideline recommendation is based. The link between guideline recommendation and the supporting evidence should be made explicit. Separating the strength of the recommendation from the level of evidence helps in situations where extrapolation is required to take the evidence of a methodologically strong study and apply it to the target population. Gradings of recommendation in addition to level of evidence allow more flexibility for future revision. Currently, there are discussions on taking account of relevant high quality non-RCTs and qualitative research and to incorporate them into appropriate grading system.

Key Recommendations

Assessment

• Signs for assessment of dehydration should be used collectively.

• Children with diarrhoea who have signs of dehydration, signs of toxaemia, young age of less than 3 months, or blood in the stool should be considered for hospital admission.

Oral Rehydration Therapy

• Oral Rehydration Therapy (ORT) is the preferred treatment of mild to moderate dehydration in children with acute diarrhoea.

• Hypotonic ORS is preferred in developed countries.

• ORT should be under medical supervision and can usually be completed over four hours.

• ORT can successfully rehydrate most children even with vomiting.

• In hypernatraemic dehydration, ORT is safer than intravenous rehydration provided child is able to drink.

Nutrition Therapy

• Breastfeeding should continue through rehydration and maintenance phases of treatment.

• Dehydrated infants and children should be fed age-appropriate diets as soon as they are rehydrated.

• Gradual reintroduction of milk-based formulas or cow's milk is not routinely required.

• Lactose free or lactose-reduced formulas are not routinely required.

Drug Therapy

• Antibiotics are not recommended for uncomplicated diarrhoea.

• Probiotics (Lactobacillus) are safe and effective and can be recommended for the treatment of children with acute infectious diarrhoea.

• Antidiarrhoeal drugs are not routinely recommended for acute diarrhoea in children.

Recommendations for Management of Acute Diarrhoea in Young Children

• Assessment determines treatment modality and monitors treatment response. (Level IIa Evidence, Grade B Recommendation)

• Reliable signs for assessment of dehydration include: (Level IIa Evidence, Grade B Recommendation)

• Conventional clinical signs of dehydration are valid and reliable when used collectively, but individually lack sensitivity and specificity. (Level IIa Evidence, Grade B Recommendation)

• Children with diarrhoea who have signs of dehydration, signs of toxaemia, young age of less than 3 months, or blood in the stool should be considered for hospital admission. (Level IV Evidence, Grade C Recommendation)

• Plasma or serum biochemistry tests are indicated for patients with severe dehydration and probably also for those patients with some signs of dehydration who require intravenous fluid replacement. (Level IV Evidence, Grade C Recommendation)

• Stool culture should be considered for patients who have blood in the diarrhoeal stool, persistent fever or signs of toxicity. (Level IV Evidence, Grade C Recommendation)

• Stool for rotavirus antigen testing is not routinely required as it should not alter management. However it is useful for diagnostic purposes. (Level IV Evidence, Grade C Recommendation)

• Oral Rehydration Therapy (ORT) is the preferred treatment of mild to moderate dehydration in children with acute diarrhoea. (Level Ia Evidence, Grade A Recommendation) Children who are very ill, lethargic, drink poorly, with shock or near shock should be treated initially with IV solutions, details of which are not discussed in this guideline. When the child's condition has stabilised and mental status is satisfactory, ORT

• may be instituted. (Level IV Evidence, Grade C Recommendation) ORT should not be given to children with intestinal ileus until bowel sounds are audible, (Level IV Evidence, Grade C Recommendation) or in the presence of glucose malabsorption i.e. patients with dramatic increase in stool output with ORT and glucose or reducing substances in the stool. (Level IV Evidence, Grade C Recommendation)

• Standard WHO-ORS, hypotonic ORS and rice-based ORS are all effective for the treatment of dehydration. (Level Ia Evidence, Grade A Recommendation) However hypotonic ORS with reduced sodium (50-75 mmol/L) and glucose (75-111 mmol/L) concentration and low osmolarity (200-250 mmol/L) is preferred in developed countries where mainly non-cholera diarrhoea occurs. (Level IV Evidence, Grade C Recommendation) Compared to WHO-ORS, hypotonic ORS may decrease stool output and shorten duration of diarrhoea, without increased risk of hyponatraemia. (Level Ia Evidence, Grade A Recommendation) Rice-based ORS does not have beneficial effects over the WHO-ORS in the treatment of dehydration due to non-cholera diarrhoea, especially when food is given immediately after rehydration. (Level Ia Evidence, Grade A Recommendation)

• Oral rehydration can usually be completed over four hours. (Level IV Evidence, Grade C Recommendation)
  

  - NO signs of dehydration give maintenance therapy - Mild-moderate dehydration give 50-75 ml/kg ORS

  Rehydration should be carried out under medical supervision and regular and frequent assessment of hydration status is essential. (Level IV Evidence, Grade C Recommendation) ORT may fail in children with continuing rapid stool loss (>10-20 ml/kg/hour), insufficient intake of ORS or frequent, severe vomiting. (Level IV Evidence, Grade C Recommendation) If the child still has signs of dehydration at the end of four hours, appropriate rehydration therapy should be instituted accordingly.

• Maintenance fluids can be given as breast milk, formula, or other fluids appropriate for age, offered ad libitum. (Level IV Evidence, Grade C Recommendation) More fluids than usual should be offered to prevent dehydration. (Level IV Evidence, Grade C Recommendation) Drinks sweetened with sugar (e.g. soft drinks, sweetened juices) should be avoided as they may cause osmotic diarrhoea and hypernatraemia. (Level IV Evidence, Grade C Recommendation)

• Ongoing losses can be replaced by normal diets given ad libitum in children with mild diarrhoea and NO signs of dehydration. (Level IV Evidence, Grade C Recommendation) In high risk cases with persistent profuse diarrhoea or vomiting, ongoing losses should be replaced with extra feeds of low-sodium ORS (40-60 mmol/L of sodium). (Level IV Evidence, Grade C Recommendation) When high-sodium ORS (>60 mmol/L) is used to replace ongoing losses after rehydration, other low-sodium fluids (e.g. breast milk, formula, or water) should be given in alternate feeds. (Level IV Evidence, Grade C Recommendation) The following guide may be useful for caregivers to replace ongoing losses (stool and vomitus) during both rehydration and maintenance therapy: (Level IV Evidence, Grade C Recommendation)
  

  Each watery or loose stool:
  <2 years of age:	50-100 ml (1/4 to 1/2 a large cup)
  2-10 years:	100-200 ml (1/2 to 1 large cup)
  OR	10 ml/kg
  Each episode of emesis:	2 ml/kg

  
  

• Families should be advised to seek further medical advice should the child: (Level IV Evidence, Grade C Recommendation)

• Starts to pass many watery stools
• Has repeated vomiting
• Becomes very thirsty
• Is eating or drinking poorly
• Develops a fever
• Has blood in the stool
• Deteriorates in any other way

 

• ORT can successfully rehydrate most children even with vomiting. (Level Ia Evidence, Grade A Recommendation) Small volumes of ORS (5-10 ml) should be administered every 1-2 minutes, with a gradual increase in the amount consumed. (Level IV Evidence, Grade C Recommendation) Continuous, slow infusion of ORS via a nasogastric tube may be an alternative in non-comatose patients and those without ileus. (Level III Evidence, Grade B Recommendation)

• In hypernatraemic dehydration ORT is safer than intravenous rehydration. (Level Ib Evidence, Grade A Recommendation) Provided the child's neurological status is stable and the child is able to drink, use "Slow ORT", aiming to complete rehydration over 12 hours and monitoring serum sodium to avoid a rapid reduction. (Level III Evidence, Grade B Recommendation)

Nutrition Therapy

• Breastfeeding should continue through rehydration and maintenance phases of treatment. (Level Ib Evidence, Grade A Recommendation)

• Exclusive breastfeeding should be promoted to reduce the severity of acute diarrhoea in infants during the first six months of life. (Level IIa Evidence, Grade B Recommendation)

• Children who are not dehydrated should continue to be fed age-appropriate diets. (Level Ia Evidence, Grade A Recommendation)

• Dehydrated infants and children should be fed age-appropriate diets as soon as they are rehydrated (usually within 4 hours). (Level Ia Evidence, Grade A Recommendation)

• Gradual reintroduction of milk-based formulas or cow's milk is not routinely required. (Level Ia Evidence, Grade A Recommendation)

• Lactose free or lactose-reduced formulas are not routinely required. (Level Ia Evidence, Grade A Recommendation) These formulas may be considered if there is no improvement in the stool consistency after several days or if reducing substances are identified in the stool. (Level IV Evidence, Grade C Recommendation)

• Complex carbohydrates (e.g. rice, wheat, potatoes, bread and cereals), lean meat, yoghurt, fruits, and vegetables are better tolerated and more preferred than foods which are sugary (e.g. tea, juices and soft drinks) or fatty. (Level IV Evidence, Grade C Recommendation)

Drug Therapy

Antibiotics

• Antibiotics are not recommended for uncomplicated diarrhoea. (Level III Evidence, Grade B Recommendation)

• Most cases of Salmonella gastroenteritis do not require antibiotic therapy as symptoms are not improved by antibiotics (Level Ib Evidence, Grade A Recommendation)

• Parenteral antibiotics, e.g. third generation cephalosporins may be required for young infants (<3 months), any ill or septic looking patient and immunocompromised children with Salmonella gastroenteritis who have a higher risk of complications. (Level IV Evidence, Grade C Recommendation)

• Campylobacter gastroenteritis is usually self-limiting and antibiotic may only be of value if given early. Antibiotic may be indicated for children in institutional settings to shorten bacterial excretion. (Level IV Evidence, Grade C Recommendation)

• Shigellosis is highly infectious and notifiable. Antibiotic may shorten the infectious period but the disease is often self-limiting and hence antibiotic is used in ill patients or those who are still symptomatic when the pathogen is detected. (Level IV Evidence, Grade C Recommendation)

• Antibiotics are not usually required for diarrhoeagenic E. Coli, Yersinia enterocolitica, Vibrio parahaemolyticus, Aeromonas spp., Plesiomonas spp. Oral metronidazole or vancomycin is indicated for severe Clostridium difficile associated diarrhoea. Metronidazole is helpful for giardia lamblia. (Level IV Evidence, Grade C Recommendation)

Probiotics

• Probiotics (Lactobacillus) are safe and effective and can be recommended for the treatment of children with acute infectious diarrhoea. (Level Ia Evidence, Grade A Recommendation)

Antidiarrhoeal agents

• Antidiarrhoeal agents are not routinely recommended for acute diarrhoea in children. (Level IV Evidence, Grade C Recommendation)

• These agents should not be used in children with fever, toxaemia or blood in the stool. (Level IV Evidence, Grade C Recommendation)

• Users of these agents as adjunctive therapy should pay attention to precautions and possible risks. Attention to the appropriate dosage and proper education of parents are prudent. (Level IV Evidence, Grade C Recommendation)

Background

Acute diarrhoea is a very significant cause of morbidity amongst hospitalised children in Hong Kong. Less data is available for ambulatory children. Approximately 12% of all paediatric medical admissions to Hospital Authority Hospitals for the two-year period July 1997 to June 1999 were due to acute diarrhoea (Table 1). Approximately 10% of these admissions were due to rotavirus and 11% to Salmonella. However these percentages are believed to underestimate the true burden of these pathogens.¹ A prospective study over a one year period at one hospital in Hong Kong showed that approximately one third of diarrhoeal admissions were due to rotavirus, one third to bacteria (majority Salmonella) and the remaining one third had no specific organism identified.² Pathogenic E. Coli were not a common cause of acute diarrhoea in this population.² Shigella was uncommon and tended to cause disease in older children, whereas Salmonella mainly affected the younger infants. The economic importance of rotavirus infection in Hong Kong has been highlighted, although the impact of other causes of viral diarrhoea are less well quantified.^1,3 A number of Hong Kong studies have looked at rotavirus gastroenteritis in hospital and community settings (Table 2). In community settings rotavirus is responsible for a smaller proportion of children assessed with diarrhoea.

Evidence for Recommendations

Recommendation:

• Assessment determines treatment modality and monitors treatment response. (Level IIa Evidence, Grade B Recommendation)
• Reliable signs for assessment of dehydration include: (Level IIa Evidence, Grade B Recommendation)

• Conventional clinical signs of dehydration are valid and reliable when used collectively, but individually lack sensitivity and specificity. (Level IIa Evidence, Grade B Recommendation)

• Children with diarrhoea who have signs of dehydration, signs of toxaemia, young age of <3 months, or blood in the stool should be considered for hospital admission. (Level IV Evidence, Grade C Recommendation)

Evidence:

A number of guidelines for the clinical assessment of dehydration have been proposed (Tables 3a-3d). The gold standard for diagnosis of dehydration is measurement of acute weight loss. However as the patient's true pre-illness weight is rarely known in the acute care setting, an estimate of the fluid deficit is mainly based on clinical assessment. Assessment of dehydration is used to determine the treatment modality and to monitor the response to treatment.⁹ (Level IIa Evidence, Grade B Recommendation) Weight after rehydration was found to be similar to pre-illness weight and the clinical signs used to assess dehydration were correlated with the actual dehydration.⁹ (Level IIa Evidence, Grade B Recommendation) 3-4% is the level at which dehydration becomes clinically apparent, rather than 5% as is normally stated. Decreased peripheral perfusion, deep acidotic breathing and decreased skin turgor were found to be reliable signs,¹⁰ together with circulatory collapse and capillary refill time >= 2 seconds showing severe dehydration >= 9%.¹¹ (Level IIa Evidence, Grade B Recommendation) Although actual weight losses of <3%, 3-8% and >= 9% better reflects the clinical findings of no signs of dehydration, mild to moderate dehydration and severe dehydration respectively, the weight loss classification of <5%, 5-10% and >10% is still widely used in clinical practice.

Conventionally used clinical signs of dehydration are valid and reliable when used collectively. However, when used individually parameters lack sensitivity and specificity (Table 4). (Level IIb Evidence, Grade B Recommendation)

The sensitivity of individual conventional clinical signs of dehydration ranged from 0.35 to 0.85. The specificity of these signs ranged from 0.53 to 0.97.⁹

Suggestions for Admission

Delphi consensus agreement was used to determine the recommendations for admission of children who present to hospital with diarrhoea in the United Kingdom.¹³ Factors considered included level of hydration, presence of risk factors and assessment of the caregiver. However the extent to which these recommendations can be applied to children managed in community settings is less clear.

Investigations

Recommendation:

• Plasma or serum biochemistry tests are indicated for patients with severe dehydration and probably also for those patients with some signs of dehydration who require intravenous fluid replacement. (Level IV Evidence, Grade C Recommendation)

• Stool culture should be considered for patients who have blood in the diarrhoeal stool, persistent fever or signs of toxicity. (Level IV Evidence, Grade C Recommendation)

• Stool for rotavirus antigen testing is not routinely required, as it should not alter management. However it is useful for diagnostic purposes. (Level IV Evidence, Grade C Recommendation)

Evidence:

There is limited evidence for cost-effectiveness of investigations in acute diarrhoea, especially for the local setting. Recommendations are based on consensus. The following investigations may be useful in patients with acute diarrhoea:

• Plasma/serum biochemistry
  (e.g. Na, K, HCO₃, urea, pH)
• Full blood counts
• Blood culture
• Stool bacterial culture
• Stool lactoferrin, occult blood and leucocytes
• Stool viral antigens, viral EM, viral culture
• Stool parasites
• Stool biochemistry for carbohydrate intolerance (pH, reducing substance and osmotic gap)

The value of plasma/serum electrolytes and urea level is obvious in the situation of severe dehydration. For lesser degrees of dehydration, the need for investigations is less clear cut and should be individualised. It has been suggested that electrolyte, urea/creatinine and bicarbonate levels should be checked in moderately dehydrated children whose histories or physical findings (e.g. "doughy" feel to skin) are inconsistent with straight-forward diarrhoeal episodes and in all severely dehydrated children.^13,14

The band neutrophil counts, if raised, may help identify patient with bacterial gastroenteritis.¹⁵ Blood culture is needed whenever patient appears toxic or ill. It is useful when managing cases of Salmonella gastroenteritis because of its propensity for deep invasion, especially for infants <3 months and in immuno-compromised patients.¹⁶

As stool bacterial yield on culture is low, especially in developed countries, a more selective approach to stool culture is recommended.¹⁷ In one recent study in U.S.A., for example, only 7 out of 250 (2.8%) stools in paediatric patients admitted to hospital for diarrhoea were positive on culture.¹⁵ Local experience suggests that the proportion of positive stool cultures may be up to 30% in hospitalised patients.² If stool culture is needed in a patient, one specimen suffices. In a local study, the first specimens already picked up the bacterial pathogen in 95% of cases.¹⁸ A recent guideline suggested that stool be sent for microscopy, culture, sensitivity, and virology when there is a history suggestive of food poisoning, recent travel abroad or blood in the stool, with or without mucus. A stool should also be sent if the child is systemically unwell, or has severe or prolonged diarrhoea.¹³

Screening tests, including stool lactoferrin, occult blood and leucocytes, were studied for usefulness in assisting selective stool culture when these tests are positive. In terms of sensitivity with the least false positivity, stool lactoferrin is the best, followed by stool occult blood and finally stool leucocytes.¹⁹ However, stool lactoferrin is not currently available locally. As the positive or negative predictive values would depend on the local prevalence of various bacterial pathogens, the result of overseas studies may not be directly applicable locally. Therefore the usefulness of these test on top of clinical judgement is unclear.

Retrospective analysis showed that viruses (rotavirus, adenovirus, astrovirus, Norwalk-like virus and calicivirus taken together) were present only in <20% of stools from infants and children less than five during the period from 1987 to 1992.³ However, a more recent study suggests that approximately one third of children hospitalised with acute diarrhoea will have rotavirus.² Cost and epidemiological considerations will determine whether stool specimens should be tested for viruses.

Stool parasites are uncommonly detected in Hong Kong children with diarrhoea.² This is generally the case in developed countries where general hygienic standards are good.¹⁷ Giardiasis should be considered when the child passes loose offensive frothy stools and in such situations fresh stools should be sent for immediate examination. Examining stools for parasites may be considered for children arriving from regions where the prevalence of infection is higher. As special detection method may be needed for some parasites, e.g. cryptosporidium, adequate communication with the laboratory is prudent when parasites are considered.

Oral Rehydration Therapy

Safety and Efficacy of Oral Rehydration Therapy

• Oral Rehydration Therapy (ORT) is the preferred treatment of mild to moderate dehydration in children with acute diarrhoea. (Level Ia Evidence, Grade A Recommendation) Children who are very ill, lethargic, drink poorly, with shock or near shock should be treated initially with IV solutions. When the child's condition has stabilised and mental status is satisfactory, ORT may be instituted. (Level IV Evidence, Grade C Recommendation) ORT should not be given to children with intestinal ileus until bowel sounds are audible, (Level IV Evidence, Grade C Recommendation) or in the presence of glucose malabsorption i.e. patients with dramatic increase in stool output with ORT and glucose or reducing substances in the stool. (Level IV Evidence, Grade C Recommendation)

Replacement of fluid and electrolyte losses is the critical central element of effective treatment of acute diarrhoea. The discovery of coupled co-transport of sodium and glucose provides the scientific basis for ORT as an alternative to intravenous (IV) therapy. This co-transport mechanism works in an approximately equimolar ratio and remains intact even during copious secretory diarrhoea.²⁰

In 1975, the World Health Organisation (WHO) and the United Nations Children's Fund (UNICEF) agreed to promote a single solution (WHO-ORS) containing (in mmol/L): sodium 90, potassium 20, chloride 80, base 30 and glucose 111 (2%). Recently, the bicarbonate component of the WHO-ORS has been replaced with citrate because of its longer shelf-life. The standard WHO oral rehydration solution (ORS) can successfully rehydrate more than 90% of children with dehydration due to acute diarrhoea.²¹ However, ORT does not reduce the rate of stool loss or the duration of diarrhoea, which are the main concerns of parents.²²

In randomised controlled trials in which ORT was compared with standard intravenous therapy, both in developed^23-25 and developing²⁶ countries, ORT was as effective as IV therapy in rehydrating children. In addition ORT was found to be more rapid in correcting dehydration and acidosis,²⁴ while being safer and with none of the complications associated with intravenous therapy.^23,26

In a meta-analysis of the efficacy of glucose-based ORT in developed countries among well-nourished young children with acute diarrhoea, 6 randomised-control trials comparing ORT with intravenous rehydration treatment and 7 randomised-control trials comparing ORSs with different sodium contents were included.²¹ The overall failure rate was 3.6% (95% CI, 1.4-5.8%) while the failure rate for those with or without IV arms were 5.7% (95% CI, 1.8-9.6%) and 3.0% (95% CI, 0.6-5.4%) respectively. Failure rates broken down by sodium content of the ORS failed to show a statistically significant difference. Iatrogenic hypernatraemia or hyponatraemia was only reported in 2 studies - hyponatraemia in 10 cases and hypernatraemia in 3 cases. When sodium content of ORS was divided into high (90 mmol/L), medium (50-75 mmol/L) and low (26-45 mmol/L), the number of cases of iatrogenic hyponatraemia was 1, 9 and 6 from the respective groups. One case of iatrogenic hypernatraemia occurred in each of the group. Therefore children rehydrated with medium to low sodium solutions may be at a slightly higher risk of mild iatrogenic hyponatraemia. When other outcome parameters including duration of diarrhoea, length of hospitalisation and weight gain at discharge were considered, there was a tendency favouring ORT over IV rehydration. There was little difference among these outcomes of ORSs with different concentration of sodium.

Composition of ORS

Recommendation

• Standard WHO-ORS, hypotonic ORS and rice-based ORS are all effective for the treatment of dehydration. (Level Ia Evidence, Grade A Recommendation) However hypotonic ORS with reduced sodium (50-75 mmol/L) and glucose (75-111 mmol/L) concentration and low osmolarity (200 -250 mmol/L) is preferred in developed countries where mainly non-cholera diarrhoea occurs. (Level IV Evidence, Grade C Recommendation) Compared to WHO-ORS, hypotonic ORS may decrease stool output and shorten duration of diarrhoea, without increased risk of hyponatraemia. (Level Ia Evidence, Grade A Recommendation) Rice-based ORS does not have beneficial effects over the WHO-ORS in the treatment of dehydration due to non-cholera diarrhoea, especially when food is given immediately after rehydration. (Level Ia Evidence, Grade A Recommendation)

Despite the proven efficacy and safety of the WHO-ORS, there is concern over the risk of hypernatraemia in developed countries where children are well-nourished and mostly suffering from non-cholera diarrhoea with lower sodium loss in stool, especially in infants less than 3 months of age.²⁷ WHO actually recommended the use of complete WHO-ORS for initial rehydration only. During maintenance therapy, the addition of free water to the WHO-ORS in a ratio of 1:2 was recommended to give a sodium concentration of 60 mmol/L.²⁸

Currently, WHO recommends using solutions with a glucose-to-sodium ratio of less than 1.4:1,²⁹ whereas the American Academy of Pediatrics recommends a ratio of less than 2:1.³⁰ The inability of the WHO-ORS to reduce stool volume may be due to its slight hypertonicity, combined with incomplete absorption of glucose in some children, resulting in osmotic diarrhoea. In addition, perfusion studies in animals and humans have also shown that osmolarity rather than sodium concentration and the sodium-glucose ratio, may be the most critical determinant of intestinal absorption of an ORS solution.^31,32 From these studies, it was concluded that optimal water absorption could be obtained by using a hypotonic solution with a sodium concentration of 50-60 mmol/L and a glucose concentration of 50-100 mmol/L. In randomised controlled trials, oral rehydration solutions containing 50-60 mmol/L sodium are safe and effective treatment for the dehydration and electrolyte abnormalities associated with acute diarrhoea of varied aetiology and in all age groups including neonates, eliminating the need for additional free water for maintenance therapy.^23,27 Mild and asymptomatic hyponatraemia was observed in some children. In 1992, the European Society of Paediatric Gastroenterology and Nutrition (ESPGN) recommended an ORS solution containing 60 mmol/L sodium, 74-111 mmol/L glucose and an osmolarity between 200-250 mmol/L for European children (Table 5).³³ Very similar recommendations were made for United Kingdom children.¹³

In a few clinical trials comparing low sodium ORSs with WHO-ORS, stool output, fluid intake and treatment failures were reduced in children treated with hypotonic ORS without an increased risk of hyponatraemia (Tables of Evidence - Table C2). Studies that compared other high osmolarity ORSs with low osmolarity ORSs are shown in Tables of Evidence - Table C3.

In a multicentre evaluation of reduced-osmolarity ORS in developing countries, standard ORS with osmolarity of 311 mmol/L was compared to reduced-osmolarity ORS of 224 mmol/L (sodium 60 mmol/L, glucose 84 mmol/L) in the rehydration of mild to moderate dehydration in non-cholera diarrhoea.³⁴ Treatment with reduced-osmolarity ORS resulted in decreased stool output (39%), decreased ORS intake (18%), decreased duration of diarrhoea (22%) and increased urine output. The risk of developing or worsening hyponatraemia was not increased in children given the reduced-osmolarity ORS. A significant reduction in the need for unscheduled intravenous therapy of up to 33% was demonstrated in another recent multicentre, randomised, double-blind study in 5 countries including Bangladesh, Brazil, India, Peru and Vietnam. In this study, a reduced-osmolarity ORS (75 mmol/L sodium, 20 mmol/L potassium, 65 mmol/L chloride, 10 mmol/L citrate,

75 mmol/L glucose and osmolarity 245 mosmol/L) was compared with the standard WHO-ORS in 675 children. However, there was no significant difference in terms of stool output, duration of diarrhoea and percentage with vomiting. The risk of hyponatraemia at 24 hours was not significantly different but can be up to doubling the number when compared with the WHO group.³⁵

In a recent systemic review of the effect of reduced osmolarity ORS in children, the results in 15 randomised controlled studies including 2397 children were analysed. Standard WHO-ORS was compared with reduced-osmolarity ORS (osmolarity <270 mosmol/L). Reduced-osmolarity ORS was associated with a 35% reduction in unscheduled intravenous therapy, a 20% reduction in stool output and a 30% reduction in vomiting, with no difference in the incidence of hyponatraemia.³⁶ Very similar results were shown in the systemic review of the Cochrane Library of reduced osmolarity ORS for treating dehydration caused by acute diarrhoea in children.³⁷ Based on this evidence, WHO has recently announced the use of a new formula for ORS with sodium 75 mmol/L, glucose 75 mmol/L and total osmolarity of 245 mosmol/L on 8 May 2002.³⁸

The substitution of cereal for glucose in ORS is one of the many efforts to improve the WHO-ORS. The apparent superiority of rice-based ORS has been attributed to its capacity to release more glucose from rice starch than is present in glucose-based ORS, facilitating greater coupled transport with sodium while maintaining low osmolarity.³⁹ In addition to glucose polymers, cereal also provides amino acids and short chain peptides that have all been demonstrated to enhance sodium and water reabsorption without incurring an osmotic penalty in the gut.⁴⁰ Many clinical trials have been conducted with conflicting results.⁴¹ Most studies were characterised by highly heterogeneous patient groupings with different causes of diarrhoea. In addition, the quantity and quality of the maintenance diet often were not standardised, measured, or described adequately. Since early feeding reduces the severity, duration and nutritional consequences of diarrhoea, variations in diet may account for the differences in results.⁴² Details of randomised controlled trials comparing rice-based ORS with WHO-ORS were shown in Tables of Evidence ?Table C4. In a meta-analysis of 13 randomised clinical trials involving more than 1300 children and adults, the efficacy of rice-based ORS (containing 50-80 g/L rice powder) was compared with that of WHO-ORS. Rice-based ORS resulted in a significant reduction in stool output in the first 24 hours and reduction of duration of diarrhoea in adults and children with cholera, but not in children with non-cholera diarrhoea.²² The authors concluded that "the benefit of rice-based ORS for children with acute, non-cholera diarrhoea should be more precisely defined before its practical value can be judged". In order to define more precisely the benefit of rice-based ORS for children with non-cholera diarrhoea, the meta-analysis was updated in 1996 by the addition of 9 trials in children with non-cholera diarrhoea. Rice-based ORS only caused a small and non-significant reduction in stool output.⁴³ The authors concluded that "rice-based ORS does not reduce stool output when compared with standard ORS in children with acute, non-cholera diarrhoea, especially when food is given immediately after rehydration". Similar results and conclusions were obtained in the systematic review of the Cochrane Library to assess the effects of rice-based ORS compared with WHO-ORS on reduction of stool output and duration of diarrhoea.⁴⁴

Rehydration Regimen

Recommendation

• Oral rehydration should usually be completed over four hours. (Level IV Evidence, Grade C Recommendation)

  • NO signs of dehydration give maintenance therapy
  • Mild-moderate dehydration give 50-75 ml/kg ORS
    
    

  Rehydration should be carried out under medical supervision and regular and frequent assessment of hydration status is essential. (Level IV Evidence, Grade C Recommendation) ORT may fail in children with continuing rapid stool loss (>10-20 ml/kg/hour), insufficient intake of ORS or frequent, severe vomiting. (Level IV Evidence, Grade C Recommendation) If the child still has signs of dehydration at the end of four hours, appropriate rehydration therapy should be instituted accordingly.
  

• Maintenance fluids can be given as breast milk, formula, or other fluids appropriate for age, offered ad libitum. (Level IV Evidence, Grade C Recommendation) More fluids than usual should be offered to prevent dehydration. (Level IV Evidence, Grade C Recommendation) Drinks sweetened with sugar (e.g. soft drinks, sweetened juices) should be avoided as they may cause osmotic diarrhoea and hypernatraemia. (Level IV Evidence, Grade C Recommendation)

• Ongoing losses can be replaced by normal diets given ad libitum in children with mild diarrhoea and NO signs of dehydration. (Level IV Evidence, Grade C Recommendation) In high risk cases with persistent profuse diarrhoea or vomiting, ongoing losses should be replaced with extra feeds of low-sodium ORS (40- 60 mmol/L of sodium). (Level IV Evidence, Grade C Recommendation) When high-sodium ORS (>60 mmol/L) is used to replace ongoing losses after rehydration, other low-sodium fluids (e.g. breast milk, formula, or water) should be given in alternate feeds. (Level IV Evidence, Grade C Recommendation) The following guide may be useful for caregivers to replace ongoing losses (stool and vomitus) during both rehydration and maintenance therapy: (Level IV Evidence, Grade C Recommendation)

• Families should be advised to seek further medical advice should the child: (Level IV Evidence, Grade C Recommendation)

  • Starts to pass many watery stools
• Has repeated vomiting
• Becomes very thirsty
• Is eating or drinking poorly
• Develops a fever
• Has blood in the stool
• Deteriorates in any other way

Evidence

In the past many regimes aimed at gradual rehydration over 24 hours, but this approach was not evidence-based. Most authorities now recommend rapid rehydration over three to four hours.^42,45,46

Management guidelines for the treatment of acute diarrhoea have been published by the WHO,⁴⁷ the Centers for Disease Control and Prevention,⁴² and the American Academy of Paediatrics.¹⁴ A recent evidence and consensus based guideline has been published in the United Kingdom,¹³ and there is also a review article by Murphy.⁴⁸ In essence, the objectives of treatment are to prevent dehydration, treat dehydration and to prevent nutritional damage.

Vomiting

• ORT can successfully rehydrate most children even with vomiting. (Level Ia Evidence, Grade A Recommendation) Small volumes of ORS (5-10 ml) should be administered every 1-2 minutes, with a gradual increase in the amount consumed. (Level IV Evidence, Grade C Recommendation) Continuous, slow infusion of ORS via a nasogastric tube may be an alternative in non-comatose patients and those without ileus. (Level III Evidence, Grade B Recommendation)

Greater than 90% of children who have vomiting and dehydration can be successfully rehydrated with ORT^25,49,50 when small volumes of ORS (5-10 mL) are administered every 1-2 minutes, with a gradual increase in the amount consumed. Continuous, slow nasogastric infusion through a feeding tube is another option in a child with frequent vomiting.^13,42

Hypernatraemic Dehydration

• In hypernatraemic dehydration ORT is safer than intravenous rehydration. (Level Ib Evidence, Grade A Recommendation) Provided the child's neurological status is stable and the child is able to drink, use "Slow ORT", aiming to complete rehydration over 12 hours and monitoring serum sodium to avoid a rapid reduction. (Level III Evidence, Grade B Recommendation)

In cases of hypernatraemia (serum sodium >150 mmol/L), "slow ORT" with fluid replacement over 12 hours has been recommended to reduce the risk of seizures.⁵¹ None of 34 infants with hypernatraemic dehydration suffered seizures when rehydration was treated with WHO-ORS over 12 hours.⁵¹ In another controlled trial of IV therapy versus ORT, 6% of hypernatraemic patients treated with ORT developed seizures compared with 25% in the group given intravenous treatment.²⁶

Nutrition Therapy

• reastfeeding should continue through rehydration and maintenance phases of treatment. (Level Ib Evidence, Grade A Recommendation)

• Exclusive breastfeeding should be promoted to reduce the severity of acute diarrhoea in infants during the first six months of life. (Level IIa Evidence, Grade B Recommendation)

• Children who are not dehydrated should continue to be fed age-appropriate diets. (Level Ia Evidence, Grade A Recommendation)

• Dehydrated infants and children should be fed age-appropriate diets as soon as they are rehydrated (usually within 4 hours). (Level Ia Evidence, Grade A Recommendation)

• Gradual reintroduction of milk-based formulas or cow's milk is not routinely required. (Level Ia Evidence, Grade A Recommendation)

• Lactose free or lactose-reduced formulas are not routinely required. (Level Ia Evidence, Grade A Recommendation) They may be considered if there is no improvement in the stool consistency after several days or if reducing substances are identified in the stool. (Level IV Evidence, Grade C Recommendation)

• Complex carbohydrates (e.g. rice, wheat, potatoes, bread and cereals), lean meat, yoghurt, fruits, and vegetables are better tolerated and more preferred than foods which are sugary (e.g. tea, juices and soft drinks) or fatty. (Level IV Evidence, Grade C Recommendation)

Although there has been a common belief that bowel rest would hasten the recovery of the bowel and decrease the severity and duration of the diarrhoea, there is evidence to the contrary. Early feeding may in fact decrease intestinal permeability changes induced by infection.⁵² (Level IIb Evidence, Grade B Recommendation) Animal studies suggest it may also facilitate enterocyte healing and help maintain disaccharidase activity.⁵³ (Level IIb Evidence, Grade B Recommendation)

Evidence based guidelines on managing acute diarrhoea recommend that breastfeeding should continue through rehydration and maintenance phases of treatment of acute diarrhoea.^48,54 (Level Ib Evidence, Grade A Recommendation) The ESPGAN working group on acute diarrhoea recommended that at all times, breastfeeding should be continued.⁵⁵ (Level IV Evidence, Grade C Recommendation) It is noted that if a baby is being breast-fed at the time of a diarrhoeal episode, the progress of that episode is milder, particularly if breastfeeding is continued.^56-58 (Level IV Evidence, Grade C Recommendation) Discontinuation of breastfeeding during diarrhoea significantly increases the risk of dehydration.⁵⁹ (Level IIa Evidence, Grade B Recommendation)

Clinical studies with a variety of early feeding regimens have demonstrated unrestricted diets do not worsen the course or symptoms of mild diarrhoea and can decrease stool output compared with oral rehydration therapy (ORT) or intravenous therapy alone.^54,58,60-66 (Level Ib Evidence, Grade A Recommendation) When used with ORT, early feeding can reduce stool output as much as cereal-based ORT can.^67,68 (Level Ib Evidence, Grade A Recommendation) Meta-analysis on the studies from developed countries shows that early refeeding reduces the duration of diarrhoea by 0.43 days (95% CI, -0.74 to -0.12), and improves nutrition.^14,63-65 (Level Ia Evidence, Grade A Recommendation) Currently early refeeding is recommended by the European Society of Paediatric Gastroenterology and Nutrition, the American Academy of Pediatrics and in a recent evidence and consensus based review.^13,14,55 (Level IV Evidence, Grade C Recommendation)

Lactose intolerance should be suspected in the presence of frothy watery acidic stools and with associated excoriation of the buttocks. Although transient lactase deficiency is common, particularly after rotavirus gastroenteritis, most children with decreased lactase levels do not have clinical features of malabsorption.⁴² (Level IV Evidence, Grade C Recommendation) Clinically significant lactose intolerance secondary to acute diarrhoea is apparently uncommon in Europe.⁶⁹ (Level IIb Evidence, Grade B Recommendation) This has also been our experience on hospitalised children with acute diarrhoea in Hong Kong. (Level IV Evidence, Grade C Recommendation) A meta-analysis of clinical trials has indicated that lactose free diet is rarely necessary after acute diarrhoea.⁷⁰ (Level Ia Evidence, Grade A Recommendation) If children are followed up to identify the few in whom signs of malabsorption develop, a regular age-appropriate diet, including full-strength milk, can be safely used for refeeding.

The question of which foods are best for refeeding has been an issue of continuing study. Although agreement is not universal, controlled clinical trials suggest that certain foods, including complex carbohydrates (rice, wheat, potatoes, bread, and cereals), lean meat, yoghurt, fruits, and vegetables, are better tolerated.^60,67,68,71 (Level Ib Evidence, Grade A Recommendation) Fatty foods or foods high in simple sugars (including tea, juices, and soft drinks) should be avoided.^13,42 (Level IV Evidence, Grade C Recommendation)

Drug Therapy

Antibiotic Use

• Antibiotics are not recommended for uncomplicated diarrhoea. (Level III Evidence, Grade B Recommendation)
• Most cases of Salmonella gastroenteritis do not require antibiotic therapy as symptoms are not improved by antibiotics. (Level Ib Evidence, Grade A Recommendation)
• Parenteral antibiotics, e.g. third generation cephalosporins may be required for young infants (<3 months), any ill or septic looking patient and immunocompromised children with Salmonella gastroenteritis who have a higher risk of complications. (Level IV Evidence, Grade C Recommendation)
• Campylobacter gastroenteritis is usually self-limiting and antibiotic may only be of value if given early. Antibiotic may be indicated for children in institutional settings to shorten bacterial excretion. (Level IV Evidence, Grade C Recommendation)
• Shigellosis is highly infectious and notifiable. Antibiotic may shorten the infectious period but the disease is often self-limiting and hence antibiotic is used in ill patients or those who are still symptomatic when the pathogen is detected. (Level IV Evidence, Grade C Recommendation)
• Antibiotics are not usually required for diarrhoeagenic E. Coli, Yersinia enterocolitica, Vibrio para-haemolyticus, Aeromonas spp., Plesiomonas spp. Oral metronidazole or vancomycin is indicated for severe Clostridium difficile associated diarrhoea. Metronidazole is helpful for giardia lamblia. (Level IV Evidence, Grade C Recommendation)

Evidence

Salmonella

Salmonellosis is very common in Hong Kong. Randomised control trials have shown that antibiotic treatments, even with higher generation cephalosporins or macrolides, did not shorten the duration of diarrhoea or fever.⁷² Antibiotics are not indicated, except for extra-intestinal involvement, immunocompromised patients, very ill children, or infants younger than 3 months old.¹⁶ Ampicillin, cefotaxime or ceftriaxone parenterally are useful in such situations.^16,73 Although local sensitivity patterns indicate that co-trimoxazole and chloramphenicol may also be effective,⁷⁴ they are seldom used as empirical therapy because of their potential side effects, especially in young infants.

Campylobacter

Campylobacter gastroenteritis is usually mild and self-limited. The benefit of antibiotic is questionable for the individual unless it is given within the first few days of the illness. However it shortens the period of bacterial shedding and hence may be useful for institutional children or nursery infants to reduce cross-infection.⁷⁵ Campylobacter spp. are sensitive to erythromycin and chloramphenicol.⁷⁴

Shigella

Antibiotic therapy for shigellosis is controversial. Antibiotic is probably not needed in mild diarrhoea as the disease is often self-limited but it should be considered in severely ill patients and those who are still symptomatic when the stool culture is positive. It may shorten bacterial excretion.⁷⁵ The haemolytic uraemic syndrome (HUS) was associated with the use of antibiotics in shigella gastroenteritis. However, the risk of HUS may in fact be reduced if patients were given an appropriate antibiotic early. It is postulated that the inappropriate antibiotics, to which the bacteria are resistant, would allow the disease to progress or may even enhance the disease severity.⁷⁶ Nalidixic acid and ceftriaxone are usually effective.^74,75

E. Coli

Diarrhoeagenic E. Coli are not a significant clinical problem locally.⁷⁷ Data on the use of antibiotics is limited.^78,79 There are six types: ETEC - Enterotoxigenic (traveller's diarrhoea and watery diarrhoea in weaning children); EPEC - Enteropathogenic (persistent watery diarrhoea in young children) where non-absorbable oral antibiotics, e.g., aminoglycosides, have been shown to be effective; EHEC - Enterohaemorrhagic (haemorrhagic colitis and HUS) where use of antibiotics is controversial; EIEC - Enteroinvasive (less severe invasive colitis); EAEC - Enteroaggregative (mucoid secretory acute or persistent diarrhoea); DAEC - Diffuse-adherent.

Other Bacteria

Yersinia enterocolitica, Vibrio parahaemolyticus, Aeromonas spp., and Plesiomonas spp. gastroenteritis are usually mild. Use of antibiotics is not necessary in general.⁷⁵ Staphylococcus aureus toxin causes vomiting and diarrhoea. Use of antibiotic is not indicated. Enteral symptoms caused by Bacillus cereus usually resolve within a day and do not require antibiotic.⁷⁵ Oral metronidazole or vancomycin is indicated for severe Clostridium difficile associated diarrhoea. A second course of these antibiotics and/or probiotics may be helpful to treat relapse, which may be up to 40%.^75,80

Parasites

Giardia lamblia and Entamoeba histolytica very occasionally cause diarrhoea. Metronidazole is helpful.^81,82

Probiotics

• Probiotics (Lactobacillus) are safe and effective and can be recommended for the treatment of children with acute infectious diarrhoea. (Level Ia Evidence, Grade A Recommendation)

Microflora of the large intestine normally ferment residual carbohydrate and produce short chain fatty acids (SCFAs). This reduces the luminal pH and discourages intestinal pathogens. The SCFAs also enhance colonic water absorption. In acute diarrhoea, as intestinal microflora is altered, production of SCFAs is reduced and there is increased water loss.¹⁴ Given these theoretical advantages, probiotics have been tried on acute infectious diarrhoea.⁸³ Among the probiotics, Lactobacillus spp. and Saccharomyces boulardii are more widely studied and used clinically. Still the number of studies for treatment of acute diarrhoea is small. The evidence that Lactobacillus spp. alter the course of diarrhoea is not consistently demonstrated.¹⁴ Saccharomyces boulardii is a non-pathogenic yeast and was found to be effective in the treatment of diarrhoea associated with Clostridium difficile.⁸⁴ One randomised placebo-controlled study demonstrated its efficacy in shortening the duration of acute childhood diarrhoea.⁸⁵ A recent meta-analysis suggests that Lactobacillus is safe and effective as treatment for children with acute infectious diarrhoea.⁸⁶ Issues of cost effectiveness need further investigation to better delineate the role of probiotics in management of acute diarrhoea (Table 6).

Antidiarrhoeal Agents

• Antidiarrhoeal drugs are not routinely recommended for acute diarrhoea in children. (Level IV Evidence, Grade C Recommendation)

• These agents should not be used in children with fever, toxaemia or blood in the stool. (Level IV Evidence, Grade C Recommendation)

• Users of these agents as adjunctive therapy should pay attention to precautions and possible risks. Attention to the appropriate dosage and proper education of parents are prudent. (Level IV Evidence, Grade C Recommendation)

Anti-motility Drugs

Examples of these drugs include loperamide, diphenoxylate + atropine, difenoxin & atropine, paregoric. These drugs act rapidly by producing segmental contractions of the intestine, thereby reducing peristalsis, diarrhoea and pain. They may also inhibit intestinal secretion. Side effects include dizziness, dry mouth, drowsiness, constipation & vomiting. They should be avoided in patients with high fever, toxaemia, or bloody mucoid stools.⁸⁷ They are usually not necessary for the management of acute diarrhoea as it is usually self-limiting. Most are not approved for children less than 2 or 3 years of age.⁸⁸ In certain circumstances, they may be used as an adjunctive treatment to oral rehydration therapy. These drugs should only be prescribed to children of appropriate age group and with the recommended dosage. Parents should be routinely reminded the directions of dosing and the possible side effects.

Results of clinical trials on loperamide are too conflicting to allow any conclusion about the risk benefit ratio. Seven placebo-controlled trials with loperamide were identified and four showed either an antidiarrhoeal effect or better weight gain in the loperamide group,^87,89-91 while the other studies found no benefit.^92-94 However, side effects were associated with loperamide use, especially with the higher dose of 0.4-0.8 mg/kg/day.⁹¹ The most recent study that demonstrated benefit with minimal side effects used a dose of 0.14-0.28 mg/kg/day in children 2 years or more.⁸⁷

Loperamide is approved by U.S. Food and Drug Administration for treating acute diarrhoea only in patients at or above 2 years old. Diluted syrup form may be safer than concentrated drops as the chance of overdose for the latter preparation is probably higher. The risk of inadvertent overdose is a concern.⁹⁵ The American Academy of Pediatrics does not recommend loperamide to treat acute diarrhoea in children based on strong committee consensus and limited scientific evidence that the risks of adverse effects outweigh the limited benefits.¹⁴

Loperamide has often been used by paediatricians locally as reported in a recent retrospective questionnaire survey.⁹⁶ The Private Practising Paediatricians Study Group recommended the following dosage for loperamide: ?.1 mg/kg/dose three times a day as required. The diluted preparation rather than loperamide drops were recommended and only limited doses per visit should be given.⁹⁶

Adsorbents

Examples of these drugs include smectite, kaolin-pectin, attapulgite. These theoretically act by adsorbing bacterial toxins and binding water to improve stool consistency. They may also adsorb nutrients, enzymes and medications in the intestine.⁸⁸ Although a few controlled studies have shown possible benefit,^97-101 most medical authorities still do not think the evidence is convincing enough for recommending their routine use.^14,82,102 Passage of a formed stool does not imply therapeutic success because water content can remain high in such "formed" stools. Such cosmetic changes may give patients or their families a false sense of security, causing a delay in seeking more effective treatment. Therefore careful explanation to parents is needed when prescribing these drugs.

Anti-secretory Drugs

Examples of these drugs include bismuth-subsalicylate and racecadotril. Bismuth subsalicylate has been used as adjunctive therapy for acute diarrhoea. The mechanism of action is uncertain. It may act by inhibiting intestinal secretion. It was shown to reduce the frequency of unformed stools and decreased stool weight. No side effect was reported with the dosage of 100-150 mg/kg/day.^103,104 However, the beneficial effects have been modest. As systemic absorption was noted, Reye syndrome is a theoretical risk.¹⁰⁵ Racecadotril (synonyms: acetorphan, ecatorfate) inhibits enkephalinase to exert its anti-secretory effect by prolonging the action of endogenous enkephalins. It has a potential application in acute diarrhoea but studies are too few for any recommendation at present.^106,107

In summary, all of the above drugs are not routinely needed because of lack of convincing clinical benefit while hydration therapy is well established. However individualised use as adjunctive therapy is sometimes useful while paying attention to the possible risk and precautions.^14,82

Tables of Evidence

Acknowledgements

The provisional working draft of this document was prepared by a Task Force on Management Guidelines for Gastroenteritis convened by the Hong Kong Society of Paediatric Gastroenterology, Hepatology and Nutrition (Ip Kin-Sing, Lau CY David, Leung CW Paul, Leung Ying-Kit, Nelson EAS, Ng Chi-Hang, Poon Kin-Hung, Tse Kong, Yiu Wai-Lim, Yeung KY Wilson). The participation of the Task Force in this project is greatly appreciated. Many thanks also go to Li Kai-Ming of the Hong Kong College of Emergency Medicine, Tsang CY Luke of the Education and Training Centre in Family Medicine, Department of Health, Cheng Chun-Fai of the Private Practising Paediatricians Study Group and Chik Ki-Wai, Fung Lai-Wah, Sin Ngai-Chuen, Wong Hiu-Lei of the Prince of Wales Hospital for their assistance in reviewing the document during the drafting process.

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