6.1 Introduction 

A North American child will develop between 6 and 12 episodes of acute diarrhea before the age of 5. This contributes to approximately 12% of childhood hospitalizations and approximately 300 deaths per year. Worldwide, acute diarrheal disease is the leading cause of childhood morbidity and mortality, accounting for three million deaths each year. Most deaths are caused by failure to treat acute dehydration properly and to correct electrolyte imbalances. Studies from both the developing and developed world demonstrate that hospitalization can be avoided and morbidity and mortality can be drastically reduced by the prompt introduction of two simple treatments: oral rehydration therapy and early refeeding. In spite of recommendations to use oral rehydration therapy and to continue or resume feeding early in mild to moderate diarrheal illnesses, the use of unsuitable treatments persists. These include unnecessary intravenous therapy, inappropriate oral fluids (unbalanced sugar- electrolyte solutions), prolonged starvation with a slow introduction of limited feeds, and the inappropriate use of antibiotics as well as antimotility and antidiarrheal agents.

An understanding of the physiology of intestinal fluid, electrolyte and nutrient transport provides a basis for understanding the mechanisms of acute diarrheal disease and successful oral rehydration therapy. Water absorption occurs primarily in the small intestine, driven by osmotic gradients that depend on the transport of the electrolytes sodium and chloride, as well as nutrients such as glucose and amino acids. Sodium, glucose and several amino acids are transported through the apical membranes of intestinal epithelial cells by sodium-dependent nutrient cotransporters. Sodium is then transported from the cell across the basolateral membrane to the extracellular space by the enzyme Na⁺/K⁺-ATPase. This enzyme utilizes energy to reduce the intracellular sodium concentration, which produces a negative extracellular electrical charge. The resultant electrochemical gradient facilitates sodium absorption by the epithelial cell, which drives the sodium-dependent nutrient cotransporters. The anion chloride is absorbed to maintain electrical neutrality across the epithelium, and water is passively absorbed in response to the transport of these electrolytes and nutrients. Successful oral rehydration therapy with balanced sugar-salt solutions depends upon these simple physiologic principles.

Diarrhea associated with small intestinal injury in infants and children is caused by four major mechanisms. These include (1) increased osmotic fluid losses, (2) inappropriate secretion, (3) inflammation associated with exudative fluid and protein losses and finally, (4) altered intestinal motility. The most frequent cause of osmotic diarrhea and acute infectious diarrhea worldwide is viral enteritis due to the rotavirus. This virus stimulates the shedding of mature absorptive epithelial cells from the small intestinal villi. These cells are replaced by immature cells with inadequately developed transporters, including the sodium-dependent glucose cotransporter and Na⁺/K⁺-ATPase. When unbalanced sugar-electrolyte solutions such as fruit juice, soda pop and broth are provided as treatments, the intestine's immature transport capacity is overwhelmed. The osmotic forces created by nonabsorbed nutrients that remain in the lumen stimulate watery diarrheal fluid losses. Children with intestinal injury caused by an acute enteritis may also develop secondary disaccharidase deficiencies, which contribute to osmotic diarrhea by the malabsorption of the disaccharides lactose and sucrose. Interestingly, the frequency of this complication has been markedly decreased in children with mild to moderate dehydration by the prompt implementation of treatment protocols that stress oral rehydration and early refeeding. Osmotic diarrhea is also caused by infections due to Giardia lamblia, Cryptosporidium, Salmonella and enteroadherent E. coli. Medications that contain nonabsorbable sugars such as sorbitol, lactulose and mannitol and poorly absorbable ions such as magnesium, sulfate, phosphate and citrate may also provoke osmotic diarrhea. Healthy children who ingest excessive quantities of fruit juice, soda pop or sugar-free products such as sorbitol-containing gum or mints may develop osmotic diarrhea due to the malabsorption of the fructose and sorbitol found in these products. This is a major cause of chronic nonspecific diarrhea of childhood.

The second major mechanism of diarrheal disease results from the active secretion of the anions chloride and bicarbonate, followed by passive water secretion. Luminal secretagogues include bacterial enterotoxins produced by V. cholerae, heat-labile and heat-stable E. coli, staphylococcal enterotoxins, Clostridium perfringens and Bacillus cereus, as well as hydroxy fatty acids from malabsorbed dietary lipids and nonabsorbed bile acids. Recently, investigators described rotavirus-induced intestinal secretion. Endogenous secretagogues include hormones secreted by intestinal tumors and inflammatory mediators released in response to food allergy, inflammatory bowel disease and systemic infections. These mediators include histamine, eicosanoids, platelet-activating factor, serotonin and IL-1. They are released after direct activation of inflammatory cells or through stimulation of these cells by the enteric nervous system. Cholera toxin was the first described and remains the classic cause of secretory diarrhea. The B subunit of this toxin binds to the luminal surface of the microvillus membrane of the enterocyte. The A subunit is then internalized and irreversibly activates adenylate cyclase, which stimulates the formation of cyclic adenosine monophosphate (cAMP). This activates protein phosphorylation, which triggers chloride secretion and impairs Na⁺Cl^- absorption. In secretory diarrhea no morphologic epithelial injury is present and the sodium-dependent glucose transporter and the enzyme Na⁺/K⁺-ATPase function normally. This permits successful oral rehydration therapy in the face of ongoing intestinal secretion.

The third mechanism causing diarrhea results from exudation of fluid and protein secondary to inflammation and ulceration of intestinal or colonic mucosa. This results in bloody diarrhea or dysentery caused by the bacteria Shigella, Campylobacter jejuni, Salmonella, Yersinia enterocolitica, enteroinvasive and enterohemorrhagic E. coli, as well as the protozoa Entamoeba histolytica. This type of diarrhea is also seen in inflammatory bowel disease, particularly ulcerative colitis. The diarrheal stools contain mucus, exudate and blood. As mentioned above, the release of inflammatory mediators also stimulates fluid secretion.

Finally, both hyper- and hypomotility result in diarrheal fluid losses. Hypermotility occurs in intestinal infections, hyperthyroidism, functioning tumors and irritative-type laxative abuse. Hypomotility is observed in the intestinal pseudo-obstructive syndromes and with partial anatomic obstruction that results in the intestinal blind loop syndrome. With decreased motility, bacterial contamination develops with resultant malabsorption of nutrients and stimulation of secretory diarrheal fluid losses.

The infant or child with an acute watery diarrheal illness has most likely contacted a viral enteritis. However, these symptoms can be presenting features of other gastrointestinal and nongastrointestinal illnesses, including otitis media, urinary tract infection, bacterial sepsis, meningitis, pneumonia, allergy and toxic ingestion. Children who develop loose, watery stools in conjunction with infections such as those involving the middle ear or urinary tract usually do not become dehydrated. This is known as "parental diarrhea" and is likely due to the release of inflammatory mediators. A careful history and physical examination play a crucial role in differentiating an acute gastroenteritis from the other causes of acute diarrhea. In addition, accurate assessment of the degree of dehydration, ongoing fluid losses and the ability to drink are required to ensure adequate fluid replacement and maintenance of intake.

Specific questions about the frequency, volume and duration of vomiting and diarrhea are required to determine the severity of fluid deficit and electrolyte imbalance. Significant dehydration can also be manifested by a decreased activity level, reduced urine volume and weight loss. A summary of the assessment of dehydration appears in Table 7. Information about the consistency of stool as well as the presence and quantity of blood aids in establishing a diagnosis and in determining appropriate investigation. In infants suspected of having a gastrointestinal infection, a history of illness among contacts, including playmates, siblings and day-care attendees, as well as exposure to visiting travelers may provide clues to the source of infection. Mild upper respiratory infections in parents or older children may result in acute vomiting and diarrhea in the infant or toddler. In addition to person-to-person contact, exposure to animals and contaminated drinking water and food may lead to enteric infections. Foods cause acute vomiting and diarrhea by multiple mechanisms. These include immunologic reactions resulting in food allergies as well as metabolic, pharmacologic and toxin-induced reactions to food and its contaminants. Lactose intolerance due to adult-onset lactase deficiency; "Chinese restaurant syndrome" due to monosodium glutamate ingestion; and staphylococcal food poisoning occurring one to six hours after the ingestion of preformed toxins are examples of the nonimmunologic causes of food poisoning. Infants who suffer an acute diarrheal illness in the first few weeks of life are more likely to have a congenital anatomic abnormality of the GI tract or an inherited metabolic disease such as abetalipoproteinemia, cystic fibrosis or one of the rare intestinal transporter deficiencies.

The inaccurate assessment of fluid deficits and ongoing fluid losses is the most important cause of the morbidity and mortality associated with acute vomiting and diarrhea in children. Infants are particularly susceptible to the development of dehydration for they sustain greater fluid losses because of an increased intestinal surface area per kilogram of body weight compared to adults. An immature renal concentrating ability, increased metabolic rate and dependence on others to provide fluids also contribute to the rapid development of severe fluid deficits in the pediatric patient. An immediate pre-illness weight provides the most sensitive mechanism of determining severity of dehydration. Unfortunately, this is rarely available. A weight should be obtained at the time of initiation of treatment in order to judge ongoing losses and gauge successful therapy. As outlined in Table 7, the severity of dehydration used to gauge the level of rehydration therapy can be assessed rapidly with history and physical examination. Watery diarrhea sometimes is mistaken for urine in the diaper. This may result in an underestimation of fluid losses. Evidence of particulant matter or a positive dipstick for sugar or protein suggests watery stool. Rapid, deep breathing may suggest an uncomplicated metabolic acidosis. In the child with a distended abdomen, auscultation of bowel sounds should be performed to rule out a paralytic ileus, and a rectal exam should be performed to determine if fluid is being third-spaced in the gut lumen. Examination of the stool for blood, white blood cells, reducing substances, pH, fat and fatty acid crystals may provide valuable clues about the etiology of a diarrheal illness.

The majority of episodes of acute watery diarrhea in previously healthy children are self-limited and associated with only mild dehydration. In this situation, the performance of biochemical or microbiologic examination is rarely required. When an advanced stage of dehydration is suspected, assessment of serum electrolytes, urea nitrogen, and acid/base chemistry will aid in tailoring ongoing rehydration therapy. Virologic and microbiologic examination should be performed only when results will be utilized to alter patient management or treat patient contacts, or for the protection of other hospitalized patients. Examples that require further investigation include an outbreak of diarrheal disease in a day-care center or hospital, diarrhea in a patient with a recent history of travel to an area of endemic diarrheal disease, and evaluation of the immunocompromised patient or of the patient where initial therapeutic measures are unsuccessful. In the infant or child with bloody diarrhea, stool cultures and antibiotic sensitivities should be performed to guide appropriate antibiotic therapy, if treatment is indicated. In areas where enterohemorrhagic E. coli causes bloody diarrhea, additional laboratory investigations including a CBC with a platelet count, blood smear for evidence of intravascular hemolysis, serum electrolytes, serum creatinine and serial urinalyses are warranted to aid in the diagnosis and management of hemolytic-uremic syndrome, the leading cause of acute renal failure in children under the age of 6.

6.4.1 ORAL REHYDRATION

In children with acute diarrhea associated with mild to moderate dehydration, the administration of a balanced oral rehydration solution (ORS) should be immediately instituted as described in Table 7. Parents should be instructed in the proper administration of oral rehydration therapy as part of preventive health care. An oral rehydration solution with a carbohydrate-to-sodium ratio of less than 2:1 and an osmolality that is similar to or slightly less than plasma is recommended. In North America, most oral rehydration solutions have a sodium content of 45-75 mmol/L because stool sodium losses (approximately 35-45 mmol/L) in viral enteritis are much less than those in secretory diarrheas such as cholera (90-140 mmol/L). For children with continued high purging rates (>10 mL/kg/hr), solutions with a higher sodium content may be required. When solutions with a sodium content of >60 mmol/L are used for maintenance, low-sodium fluids such as breast milk, infant formula, diluted juice or water must be provided simultaneously to prevent the development of hypernatremia. In North America, intravenous electrolyte solutions are used to manage children with severe dehydration because of their wide availability and high degree of success. In the developing world, children suffering from severe dehydration can usually be successfully rehydrated with oral solutions. More than 90% of vomiting infants can be successfully rehydrated and maintained with oral hydration providing 5-10 mL every 2 to 3 minutes and gradually increasing the amount administered.

About 5-10% of children fail initial oral rehydration therapy as a result of either persistent vomiting or a persistently high stooling rate of > 10 mL/kg/hr. Parents should be instructed to seek further care if the child develops (1) irritability or lethargy that inhibits drinking, (2) intractable vomiting, (3) worsening fluid deficits associated with persistent diarrhea, (4) bloody diarrhea, or (5) decreased urinary output. These children require re-evaluation and intravenous rehydration similar to that provided for the severely dehydrated child. Their hydration status should be monitored, and when rehydration is complete, maintenance therapy to replace ongoing losses can be commenced. If dehydration persists, the fluid deficit should be recalculated and rehydration therapy continued for an additional 2 to 4 hours with ongoing assessment of fluid losses.

There are only a few contraindications to the use of oral rehydration therapy for the initial management of acute diarrheal disease. These include (1) severe (>10%) dehydration associated with hemodynamic instability, (2) refusal to drink due to extreme irritability, lethargy, stupor or coma, and (3) intestinal ileus. These children should be managed initially with intravenous fluids and switched to oral rehydration therapy when they can safely drink. Homemade oral rehydration solutions are not recommended because electrolyte abnormalities caused by inappropriate mixing are a well-recognized complication.

Recommendations for the dietary management of acute diarrheal disease stress the importance of continued breastfeeding throughout the illness and early refeeding of the formula-fed infant and older child. Continued feeding throughout a diarrheal illness improves nutritional status, stimulates intestinal repair, and diminishes the severity as well as the duration of illness. Breastfed infants should be allowed to nurse as often and as long as they want throughout a diarrheal illness. The refeeding of the non-breastfed infant remains somewhat controversial. Recent evidence suggests that the infant with mild to moderate dehydration should receive the full-strength infant formula that was fed prior to illness. There is no need to routinely switch to a lactose-free milk or to refeed with dilute formula. Treatment failure rates of 10-15% when refeeding is carried out in this manner are no higher than with more cautious approaches. Infants with severe dehydration, pre-existing intestinal injury and severe malnutrition, and those who have failed initial refeeding, should receive a lactose-free formula; they occasionally require a more predigested formula during refeeding.

The older child, who is established on a wider variety of foods, should receive a well-balanced, energy-rich, and easily digestible diet. Complex carbohydrates including rice, noodles, potatoes, toast, crackers and bananas should be offered initially, with the rapid addition of vegetables and cooked meats. Foods to avoid include those high in simple sugars such as soft drinks, undiluted fruit juice, caffeinated beverages, presweetened gelatins and sugar-coated cereals. Foods high in fat may be poorly tolerated because of delayed gastric emptying that results in increased vomiting. In some children watery stools will persist for longer than 10 days, but not to the extent where they cause recurrent dehydration. In these cases infection should be excluded and stools examined for reducing substances to rule ongoing carbohydrate malabsorption.

The prescription of antiemetic, antimotility and antidiarrheal agents for the treatment of acute diarrhea seldom benefits the child and may be associated with serious complications. In children with acute diarrheal disease, these agents do not reduce stool volume or duration of illness. They often have anorexic or sedating effects, which prevent successful oral rehydration therapy. Their use results in a third spacing of fluid, which leads to an under-estimation of ongoing losses. This results in inadequate fluid replacement therapy.

Antibiotics should be used in the treatment of diarrheal disease only when specifically indicated. Antibiotics are not effective for the treatment of viral enteritis. Giardiasis should be treated when the diarrheal illness persists and when cysts or trophozoites are identified in the stool. There is no benefit to treating asymptomatic carriers of Giardia lamblia. Antibiotic therapy for the bacterial diarrheas remains controversial because most infections are self-limiting and antibiotic therapy does not shorten the duration of illness. Antibiotic therapy is indicated (1) when a treatable pathogen has been identified, (2) in the immunocompromised host, (3) as an adjunctive therapy in the treatment of cholera and (4) in infants less than 3 months of age with positive stool cultures. Infants at this age are at increased risk to develop septicemia. Infants and children with diarrhea who display signs of septicemia should be treated with parenteral antibiotics.