Pathophysiology of Diarrhea and the Evolution of ORS

Intestinal mucosa actively absorbs large quantities of sodium, chloride, bicarbonate, and solutes. It also secretes chloride and hydrogen ions. Water passively follows net solute transport. In villous cells, sodium potassium ATP (Na+,K+-ATPase) maintains low intracellular sodium, which allows the entry of sodium coupled to chloride and nutrients (glucose/amino acids). Absorptive processes in the villous cell exceed the minor secretory activity in the crypt, and therefore the net result is absorption of nutrients and electrolytes and water. Under pathologic influences, (for example, exposure to enterotoxins giving rise to increase in cyclic adenosine monophosphate [cAMP] or cyclic guanosine monophosphate [GMP]), chloride channels open up in the luminal membrane of crypt cells causing the leak of chloride and hence sodium, which follows along with water and this shift of ions moves the equilibrium from net absorption to net secretion. Diarrhea ensues when there is a derangement in the absorptive-secretory processes. The reversal of the net absorptive status can be the result of suboptimal absorption ensuing in an osmotic force acting in the lumen that drives water across the tight junctions from the serosa into the lumen (for example, in lactose malabsorption) or the result of an active secretory state induced in the crypt cells (for example, in enterotoxin-induced diarrhea). In many disease states, both mechanisms coexist ( Figure 90-1 ).

Absorptive and secretory processes in gut epithelium.

Fluid losses from the gastrointestinal tract can be profound and can lead to devastating effects, particularly in infants and young children. The discovery that in cholera, sodium/glucose–coupled transport remains intact, although sodium chloride transport is inhibited, and that oral administration of a sugar-salt solution can rehydrate and maintain hydration in patients with infective diarrhea, remains one of the greatest scientific advances in the last 50 years. The use of ORS in the management of gastroenteritis has been associated with a dramatic decrease in mortality, not only in developing countries but also in the developed world. In the United Kingdom, for instance, the mortality fell from 300 deaths annually in the 1970s to 25 in the 1980s. Hypernatremic dehydration, a major cause of mortality in acute gastroenteritis, has also become much less common. Although controversy continues about the ideal composition of ORS, there is consensus about the scientific rationale for its use. The sodium concentration of the standard WHO-ORS, 90 mmol/L, was in part based on the fecal sodium concentration in adults with cholera. This product with an osmolarity of 311 mmol/L has been used worldwide and has contributed substantially to the global reduction in mortality from diarrheal disease. Concerns that this solution, which is slightly hyperosmolar when compared to plasma, may cause hypernatremia in well-nourished children with noncholera diarrhea in the developed world, resulted in the proliferation of ORS formulations with a range of sodium concentrations (30 to 60 mmol/L). Stools in children with Rotavirus infection, the most common infective pathogen, particularly in the developed world, have a lower concentration of sodium. In the 1980s, the American Academy of Pediatrics (AAP) recommended a solution containing 45 mmol/L sodium for American children for the correction of dehydration. In 1992, a working group on Acute Diarrhea of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) considered the scientific evidence and published “Recommendations for the Composition of ORS for the Children of Europe.” ESPGHAN recommended a solution containing 60 mmol/L sodium and 70 to 110 mmol/L glucose with an osmolarity of 225 to 260 mmol/L. Various manufacturers of ORS adopted the recommendations, and this solution has gradually replaced other solutions in Europe.

Super ORS

During the last 20 years, there have been attempts to develop a super ORS by using rice powder, amino acids, glucose polymers, and so on, instead of glucose. Laboratory studies were encouraging, but in a clinical setting, results were disappointing for amino acids and harmful using a glucose polymer. The initial results using rice powder and other cereals were more encouraging. However, a meta-analysis in a well-conducted systematic review, evaluating 22 hospital-based randomized-controlled trials (RCTs) of rice-based ORS concluded that the benefit of rice-based ORS is sufficient to warrant use in patients with cholera but is considerably smaller in noncholera diarrhea. Furthermore, a study by Santhosham et al. showed that treatment with standard ORS and simultaneous feeding with boiled rice produced results similar to those using rice-based ORS.

Hypoosmolar ORS

In vitro experiments have shown that water absorption is increased from hypotonic ORS when compared to isotonic ORS. Clinical trials have shown that in both the developing world and the developed world, hypotonic ORS with a sodium concentration of 50 to 70 mmol/L is safe and effective for rehydration and maintenance therapy of mild-to-severe dehydration from noncholera diarrhea. In vitro and in vivo data suggest that low osmolarity may be the key for enhancing the clinical effectiveness of ORS. A meta-analysis of randomized trials of reduced osmolarity ORS versus standard WHO ORS in children with noncholera diarrhea, concluded that the use of a reduced osmolarity ORS was associated with: (1) a reduction in the need for unscheduled intravenous fluids (defined as the clinical requirement for intravenous fluids once oral rehydration has commenced); (2) a trend toward reduced stool output (about 20%); and (3) reduction in the incidence of vomiting (about 30%). The incidence of hyponatremia (serum sodium 130 mEq/L at 24 hours) was higher, but this difference was not statistically significant. The accumulating evidence on the greater efficacy of hypoosmolar ORS has resulted in an expert consultation on ORS formulation by WHO/UNICEF. This concluded that the efficacy of glucose-based ORS for treatment of children with acute noncholera diarrhea is significantly improved by reducing the sodium content to 60 to 75 mEq/L, glucose to 75 to 90 mmol/L, and total osmolarity to 215 to 260 mmol/L. The composition of the New Hypoosmolar WHO ORS (2002) is listed with the other ORS in Table 90-1 . It preserves the 1:1 molar ratio of sodium to glucose that is critical for the efficient cotransport of sodium. Citrate content allows for a longer pre-mixed shelf life.

Oral therapy remains the mainstay of the WHO efforts to reduce the morbidity and mortality caused by acute diarrheal disease. In the developing world, the uptake is still suboptimal. Simultaneous uptake of ORS in industrialized countries has been slow, despite many clinical trials having documented the safety and efficacy of this form of therapy. A major barrier to the wider uptake of ORS is that it is not perceived to be a medication. A WHO report estimates that less than 50% of acute diarrheal episodes are treated with ORS. An American study that looked at practices compared with AAP recommendations found that less than 30% of responding physicians used a recommended solution to treat dehydration. Another study showed that in the United States, several barriers among pediatricians exist to the use of oral rehydration, including its lack of convenience, the need for additional training for support staff, and the discrepancy in reimbursement for intravenous versus oral rehydration. Similar problems exist in Europe. An ESPGHAN survey reported that one in six doctors in Europe would not prescribe ORS.

Early Feeding

The primary goals in treating acute diarrhea are preventing and reversing ongoing dehydration and minimizing the nutritional consequences of mucosal injury. Diarrhea, malnutrition, and intestinal integrity have a close complex relationship. Malnutrition leads to an increased susceptibility to gastrointestinal infections and this vicious cycle leads to thousands of children dying every day worldwide. It has been observed in animal models that starvation alters mucosal barrier function. In addition to the development of ORS, one other milestone has been the advent of early feeding and the avoidance of the so-called intestinal rest.

Historical review of published literature reveals that introduction of a period of starvation dates back to 1926 when Powers wrote his treatise on treatment of diarrhea. There was no scientific basis to the recommendation of this practice. Following this, children were routinely starved during diarrhea and then gradually advanced from quarter strength formula to full strength formula over 2 to 4 days. A study in 1948 showing that there was no scientific rationale for grading was ignored. In 1979, Rees and Brook and later Dugdale et al. and Placzek and Walker-Smith showed that gradual grading of feed to full strength was not needed. In 1985, a study by Khin-Maung showed that continued breast-feeding at the time of acute diarrhea was of benefit. Isolauri et al. in 1986, showed that in children older than 6 months after initial oral rehydration therapy, full feeding appropriate for age (including milk) is well tolerated with no adverse effects. Brown et al. then published studies, which clearly showed advantages of continued feeding on clinical and nutritional outcomes.

A community based study in the United Kingdom and an Eastern European study involving infants 0 to 1 year of age further suggested that early feeding was safe, with no increase in lactose intolerance or vomiting and resulted in better weight gain.

The ESPGHAN Working Group on acute diarrhea conducted a large multicenter study that compared the effect of ORS and early or late feeding on the duration and severity of diarrhea, weight gain, and complications (carbohydrate intolerance and vomiting) in weaned European infants and has made recommendations based on this.

The conclusions of this study were as follows:

• 1.
  

  Complete resumption of a child’s normal feeding including lactose containing formula after 4 hours of rehydration with glucose ORS (ESPGHAN recommended composition) led to significantly greater weight gain after rehydration and during hospitalization ( Figure 90-2 ).

  
  

  
  

  
  

  

  
  

  
  

  European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) study on early feeding. Comparison of weight gain between early feeding group and late feeding group.

  
  
  
  
• 2.
  

  There was no worsening of diarrhea, no prolongation of diarrhea, and no increased vomiting or lactose intolerance in the early feeding group compared with the late feeding group ( Figures 90-3 and 90-4 ).

  
  

  
  

  
  

  

  
  

  
  

  Frequency of vomiting between early feeding group and late feeding group (European Society of Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN] study).

  
  

  
  

  
  

  

  
  

  
  

  Frequency of watery stools between early feeding group and late feeding group (European Society of Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN] study).

  
  

In malnourished children, the nutritional benefits of early feeding have been clearly established. This study, involving a range of hospitals from around Europe, lends further credence to this practice and suggests that there are benefits for children who are not necessarily nutritionally compromised. Theoretical benefits of continuing feeding are minimizing protein loss and energy deficits and reduced functional hypotrophy associated with starving. There is indirect evidence to support the strategy of early feeding, based on studies revealing the positive effects of luminal nutrition on regeneration and mucosal growth as seen in short bowel syndrome. Early re-feeding reduces the abnormal increase in intestinal permeability that occurs in acute gastroenteritis and may promote recovery of the brush border membrane disaccharidase. Early resumption of feeding is now recommended by the ESPGHAN, the AAP, and WHO.

Treatment Strategies and Practical Guidelines

There is now consensus among pediatric gastroenterologists that the optimum management of acute diarrhea of mild to moderately dehydrated children should consist of the following “Six Pillars of Good Practice.”

• 1.
  

  The use of oral rehydration solution (ORS) to correct dehydration in the initial 4 hours of management

  
  
• 2.
  

  The use of the hypoosmolar solution (60 mmol/L sodium, 74 to 111 mmol/L glucose)

  
  
• 3.
  

  Continuation of breast-feeding throughout

  
  
• 4.
  

  Early re-feeding, that is, resumption of a normal diet once rehydration is complete

  
  
• 5.
  

  Prevention of further dehydration by supplementing maintenance fluids with ORS (10 mL/kg ORS for every watery stool)

  
  
• 6.
  

  Avoidance of the routine use of medication.

Clinical Signs and Symptoms

A range of symptoms and signs has traditionally been considered useful in the detection of dehydration. It is important for carers and health care professionals to be familiar with these symptoms and signs, particularly those signs that suggest worsening of dehydration. Irritability, sunken eyes, and reduced urine output have been shown to have good correlation with dehydration and therefore should be part of the systemic inquiry process. It should be remembered that infants with acute diarrhea are more prone to dehydration than are older children because they have a higher body surface area to weight ratio.

History and examination should guide the clinician to the severity of dehydration. The severity of dehydration is most accurately assessed in terms of weight loss as a percentage of total body weight. The reference standard used for assessing dehydration is the percentage of volume lost calculated as the difference between rehydration weight (posthydration weight) and the acute (prehydration) weight. This is the gold standard against which other tests are measured. In the absence of weight, clinical markers may be used to approximate the degree of dehydration ( Tables 90-2 and 90-3 ). Previous studies have suggested that prolonged skin retraction time and deep breathing may be reliable indicators of dehydration, and have pointed out a good correlation between capillary refill and fluid deficit. These observations have been corroborated in a systematic review that suggests that specific signs are associated with dehydration (prolonged capillary refill time, abnormal skin turgor, and abnormal respiratory pattern). However, all studies were conducted in secondary care settings where children with more severe dehydration are managed, and therefore there may not necessarily be the same degree of correlation with lesser degrees of dehydration. If dehydration is less than 5%, the child can be managed at home. Indications for hospital admission include the following: (1) the child is more than 5% dehydrated; (2) parents are unable to manage oral rehydration at home; (3) the child does not tolerate oral rehydration (severe vomiting, insufficient intake); (4) failure of treatment, worsening diarrhea, and/or dehydration despite oral rehydration treatment; (5) other concerns, for example, uncertain diagnosis, potential for surgery, child “at risk,” irritable or drowsy, or a child younger than 2 months.

Recently published guidelines from the National Institute of Clinical Excellence (NICE) in the United Kingdom adopt a new and even simpler clinical assessment scheme. Patients are merely classified as follows: “no clinically detectable dehydration,” “clinical dehydration,” and “clinical shock.” The guideline acknowledges that this simplified scheme does not imply that the degree of dehydration is uniform. The NICE guidelines highlight that the presence of red flag symptoms and signs should alert the clinician to a risk of progression to shock. These symptoms and signs are altered responsiveness (lethargy, irritability), sunken eyes, tachycardia, tachypnea, and reduced skin turgor. Children with such signs need close monitoring.

Workup and Laboratory Studies

Most children with acute gastroenteritis do not need any laboratory workup. The guidelines development group for the NICE guidelines found that there was a lack of satisfactory evidence with regard to the incidence of clinically important biochemical disturbances in children with gastroenteritis in the United Kingdom. Never­theless, the guidelines recommend measuring plasma sodium, potassium, urea, creatinine, and glucose concentrations if intravenous fluid therapy is required or there are symptoms and signs that suggest hypernatremia, and measuring venous blood acid–base status and chloride concentration if shock is suspected or confirmed.

Stool microscopy and culture and electron microscopy or enzyme-linked immunosorbent assay (ELISA) for rotavirus may be useful for etiologic information but usually have little influence on immediate management. Microscopy for leukocytes in the stool and gram staining of the stool may help in differentiating bacterial from nonbacterial diarrhea. Stool cultures are indicated for patients with bloody diarrhea. There may be circumstances in which identification would be important because of the significance of pathogens. For example, amebic dysentery would require antibiotics and Escherichia coli O157:H7 is associated with hemolytic uremic syndrome (HUS)—a serious and potentially fatal disorder.

Management in the Home Setting (Pre-Hospital Care)

Ideally, management of acute diarrhea should begin at home because early intervention can reduce complications. The child should be rehydrated using ORS. Effective teaching of the parent or the guardian of procedures for administering the solution and instructions about when to bring the child back for reassessment is crucial. The use of “clear fluids” (water alone, cola, or fruit juice) is inappropriate and may be dangerous because these fluids lack adequate sodium. Fruit juices and cola can potentially worsen diarrhea as they have a high osmolar load.

The calculated fluid deficit is replaced over 4 hours. Thus, in a 10 kg child, with 5% dehydration, the deficit is 5% of 10 kg, which equals 500 mL. This is given as ORS over 4 hours. It is vital to emphasize the importance of adequate hydration with clear instructions to make up the ORS. If the child is breast-fed, this should continue. Ideally, a child should be reassessed 4 hours after rehydration and if fully hydrated, normal feeding should be commenced. Ongoing fluid losses in the form of vomiting or diarrhea should be made up in addition to maintenance fluid requirements, by administering ORS 10 mL/kg for every loose stool or vomitus.

Hospital Management

An accurate estimate of the degree of dehydration should be made, ideally by using current and previous weights (when available). Rehydration with ORS is usually carried out over a period of 4 hours. A reasonable approach in a child presenting with clinical manifestations of dehydration is to assume 5% dehydration at the outset. Based on that assumption, rehydration should be attempted by giving 50 mL/kg over the initial 4-hour rehydration period. However, one must be aware that in other, more severely dehydrated children, 50 mL/kg may be insufficient. It would therefore be important to regularly reassess the child’s state of hydration and when necessary to increase the final volume of replacement fluid administered.

The child should be fully assessed to exclude other causes of acute diarrhea. If the patient does not tolerate oral rehydration (refuses, vomits profusely, or takes inadequate amounts), a nasogastric tube can be used to give ORS. The patient should be reviewed after 4 hours and if sufficiently hydrated, a normal diet should be commenced and maintenance fluids continued (100 mL/kg per day for the first 10 kg, plus 50 mL/kg per day for the next 10 kg, plus 20 mL/kg per day for the remainder of weight over 20 kg). Supplement ORS, 10 mL/kg for every watery stool, should be continued to make up for ongoing losses. If dehydration persists, the degree of dehydration should be reassessed and the fluid deficit corrected with ORS over the following 4 hours. If the child is moderately or severely dehydrated, investigations should include plasma urea and electrolytes, and a stool analysis for viruses and bacteria.

Intravenous Therapy

A high quality Cochrane review compares the effectiveness of ORS with intravenous (IV) therapy for the treatment of dehydration due to gastroenteritis in children. A systematic review of 17 trials that compared an IV therapy arm with one or more ORS arms (oral or nasogastric) did not find any significant difference in the incidences of hyponatremia, hypernatremia, the duration of diarrhea, weight gain, or total fluid intake in children treated with ORS compared with IV therapy. Dehydrated children treated with ORS had a significantly shorter stay in hospital and those receiving IV therapy had a higher risk of phlebitis.

Intravenous therapy is indicated only if the estimate of dehydration is 10% or more, the child is in shock, or if there is failure of oral replacement therapy. If the child is shocked, he should first be resuscitated with 20 mL/kg of normal saline. Deficits should be replaced with isotonic solutions (0.9% saline or 0.9% saline in 5% dextrose) and calculations based on uncorrected weight. Once dehydration is corrected, maintenance fluids should be continued, oral feeding commenced, and ongoing stool losses replaced with ORS (10 mL/kg per watery stool). Early and gradual reintroduction of ORS during intravenous therapy is recommended with the aim of continuing rehydration with ORS, if this is then tolerated.

Although many experts now support rapid intravenous rehydration (4 to 8 hours), rehydration with intravenous fluid therapy has traditionally been undertaken slowly—over 24 hours. WHO recommends that intravenous rehydration be completed in 3 to 6 hours. However, incidences of hypernatremia have led the NPSA (National Patient Safety Agency) in the United Kingdom to advise that intravenous fluid replacement should be over 24 hours or longer. The NPSA patient safety alert highlights the importance of measuring electrolytes both at the start of IV fluids and regularly monitoring of sodium concentrations thereafter. Randomized controlled trials are needed to examine the safety of the practice of rapid intravenous rehydration.

Hypernatremic Dehydration

The recent NICE guidelines did not find any evidence for the oft-quoted “doughy skin” as a sign of hypernatremic dehydration, but they do highlight the increased frequency in children younger than 6 months of age. Children with hypernatremic dehydration have an increased frequency of central nervous system (CNS) manifestations such as jitteriness, altered conscious levels, or convulsions. A child with hypernatremia (i.e., sodium level greater than 150 mmol/L) needs careful monitoring with frequent reassessment. Oral rehydration or nasogastric rehydration is by far the safest method. If this fails, resuscitation with IV fluids should be carried out slowly, as the aim is a gradual reduction in the sodium as a sudden fall can be dangerous and lead to cerebral edema and convulsions. The calculated deficit should be replaced with 0.9% saline in 5% dextrose over 48 hours, with careful monitoring of the plasma sodium until the child becomes normonatremic. The rate of fall of serum sodium should not exceed 0.5 mmol/L per hour. The management should then be as for nonhypernatremic dehydration.

Complications

If diarrhea continues for more than 10 days, parents should be advised to return with the child for a reassessment and the stool checked for persistent infection. The recurrence of diarrhea each time with reintroduction of milk should alert the physician to the possibility that the child may have developed lactose intolerance. Stool pH and reducing substances can be checked at the bedside using standard methods. A level of reducing substances of 1% or more is considered diagnostic of lactose malabsorption, and the child should be placed on a lactose-free diet for a 2-week period and then reassessed. Most lactose intolerance is temporary and caused by patchy villous damage, and once the gut villi regenerate, lactase and other disaccharidases levels normalize. If the stool is negative for reducing substances and the diarrhea is related to milk protein intake, the child may have developed cow’s milk protein intolerance and may require a protein hydrolysate formula.

Antimicrobial Therapy

Because viral agents are the predominant cause of acute diarrhea, antibiotics play a limited role in its management. Treatment with appropriate antibiotics is indicated if there is evidence of systemic bacterial infection. Predisposing factors include a history of recent travel, immunodeficiency, and history of recent antibiotic use (in which case Clostridium difficile should be suspected). Appropriate antibiotics have been shown to be effective in the treatment of Shigellosis, C. difficile , and Campylobacter . Randomized control trials have shown that in shigellosis, appropriate antibiotic therapy shortens the duration of diarrhea by 2.4 days, decreases the duration of fever, and reduces the excretion of infectious organisms. Ciprofloxacin has been shown to be safe and effective in children with shigellosis. Nontyphoidal Salmonella gastroenteritis is usually self-limiting, and studies have failed to show any benefit from antibiotic treatment. Protozoal pathogens associated with diarrhea that persists for more than 7 to 10 days are Giardia lamblia and Cryptosporidium . Metronidazole or tinidazole is used for treating proven Giardia infection, whereas nitazoxanide, which was recently approved by the U.S. Food and Drug Administration (FDA) for use in children, is effective against Cryptosporidium . Regardless of the causative agent, initial therapy should include rehydration.

Probiotics

In recent years, there has been a growing interest in probiotics as a potential method for altering intestinal bacterial flora. Probiotics may potentiate host gastro­intestinal defenses and stimulate nonspecific host resistance to microbial pathogens. They may protect by increasing nonimmunologic defenses. The exact mechanisms by which probiotics carry this out is not yet known, although the possible mechanisms include the synthesis of antimicrobial substance and competition at the substrate level.

Lactobacillus rhamnosus strain GG (ATCC 53103) has been the most common bacterial species used to counteract intestinal infections. It has been shown in trial settings to have a number of potentially beneficial effects in preventing and treating acute diarrhea. A multicenter trial to evaluate the efficacy of Lactobacillus GG administered in the oral rehydration solution in children aged 1 month to 3 years with acute-onset diarrhea of all causes, was conducted by the ESPGHAN Working Group on acute diarrhea. This showed that in rotavirus-positive children, diarrhea lasted longer in children in the placebo arm of the trial and the risk of having diarrhea for more than 1 week was reduced nearly fourfold in the Lactobacillus -treated group. In concordance with previous reports, the study showed no benefit in children who were more likely to have had a bacterial cause of diarrhea.

A systematic review of published randomized, double-blind, placebo-controlled trials reviewed 13 studies carried out between 1974 and 2000. The outcome measures that were considered included duration of diarrhea, number of watery stools per day, risk of diarrhea lasting more than 7 days, duration of hospitalization, and weight gain. The meta-analysis concluded that the use of probiotics was associated with a significant reduced risk of diarrhea lasting more than 3 days. This observation was limited to Lactobacillus GG and there were no adverse outcome measures seen. However, based on WHO recommendations of using stool output rather than duration of diarrhea as a primary outcome measure when evaluating diarrhea treatment, no firm conclusions could be drawn on the effect of probiotics on stool output in acute diarrhea. A Cochrane systematic review that studied randomized-controlled trials comparing a specified probiotic with placebo or no probiotic in children with persistent diarrhea concluded that there was limited evidence that probiotics are effective in treating diarrhea in children.

Antidiarrheal Agents

Table 90-4 shows a summary of the evaluation of safety and efficacy of various antidiarrheal drugs. Antidiarrheal agents are not indicated in the management of acute diarrhea. Opioids have an antimotility effect that may mask the severity of diarrhea; they can also have serious side effects. Few over-the-counter antidiarrheal products have been demonstrated as effective in randomized-controlled trials. Because antimotility agents have been implicated in hemolytic-uremic syndrome in children infected with Shiga toxin–producing E. coli, these agents should be avoided in children with bloody diarrhea. There are insufficient data to support the routine use of adsorbents such as kaolin-pectin, activated charcoal, and attapulgite. Despite pediatric guidelines that discourage the use of antidiarrheal drugs in children, various studies have highlighted the widespread use of drugs by caregivers in treating children with diarrhea. Easy availability of antidiarrheal drugs is an important factor in perpetuating their misuse. The key strategy in regulating therapy would be to make antidiarrheal agents unacceptable to caregivers and physicians through appropriate education and training. Caregivers and physicians must realize that such drugs are not only unnecessary, but also potentially harmful. Simultaneously, confidence in the ORS needs to be boosted.

TABLE 90-4

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