Management of Diarrhea

Evolution of Oral Rehydration Solution (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 (e.g., exposure to enterotoxins giving rise to an 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, resulting in an osmotic force acting in the lumen that drives water across the tight junctions from the serosa into the lumen (e.g., in lactose malabsorption) or the result of an active secretory state induced in the crypt cells (e.g., in enterotoxin-induced diarrhea). In many disease states, both mechanisms coexist ( Fig. 90.1 ).

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, the 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, 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 Oral Rehydration Solution

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 Oral Rehydration Solution

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 (IV) fluids (defined as the clinical requirement for IV fluids once oral rehydration has commenced); (2) a trend toward reduced stool output (about 20%); and (3) a 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 study 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 premixed 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 in the United States found that several barriers exist among pediatricians regarding the use of oral rehydration, including its lack of convenience, the need for additional training for support staff, and the discrepancy in reimbursement for IV 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 the prevention and reversal of ongoing dehydration and the minimization of its nutritional consequences. 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 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.

A historical review of published literature reveals that the introduction of a period of starvation dates back to 1926 when Powers wrote his treatise on the treatment of diarrhea. However, there was no scientific basis to support the recommendation of this practice. Following this practice, children were routinely starved while suffering from diarrhea and then gradually advanced from quarter-strength formula to full-strength formula over a period of 2 to 4 days. A study done in 1948 found that there was no scientific rationale for grading, but this information was ignored. In 1979, Rees and Brook and later Dugdale et al. and Placzek and Walker-Smith found that gradual feed grading up to full strength was not necessary. In 1985, a study by Khin-Maung found that continued breastfeeding at the time of acute diarrhea was beneficial. In 1986, Isolauri et al. found that children older than 6 months, after initial oral rehydration therapy, could tolerate full, age-appropriate feeding (including milk) with no adverse effects. Brown et al. then published studies that clearly showed the 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 upon the results of this study.

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 ( Fig. 90.2 ).

  

• 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 ( Figs. 90.3 and 90.4 ).

  
  

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 the minimization of protein loss and energy deficits and reduced functional hypotrophy associated with starvation. 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. The early reintroduction of food 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 the WHO.

Treatment Strategies and Practical Guidelines

Published guidelines from ESPGHAN outline the optimal management of acute diarrhea of mild to moderately dehydrated children and should consist of the following “Six Pillars of Good Practice.” ^,

• 1.

  The use of ORS to correct dehydration in the initial 4 hours of management is the key element in the treatment strategy;

• 2.

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

• 3.

  Continuation of breastfeeding throughout;

• 4.

  Early resumption of a normal diet during or after initial rehydration is complete;

• 5.

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

• 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 caretakers and health care providers to be familiar with these symptoms and signs, particularly those signs that may suggest worsening dehydration. In the early stages of dehydration, there may be no clinical signs or symptoms. However, as the dehydration worsens, a variety of symptoms may become apparent. These can include increased thirst, irritability, sunken eyes, a sunken fontanelle (infants), and reduced urine output, which have all been shown to have a good correlation with the degree of dehydration. When the degree of dehydration is severe, these features become more pronounced and may herald hypovolemic shock. 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 the studies were conducted in secondary care settings where children with more severe dehydration are managed, and therefore this 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; and/or (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 guidelines acknowledge 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, decreased urine output, dry mucous membranes, and reduced skin turgor. Clinical signs can also include increased heart rate, increased respiratory rate, and decreased capillary refill times. Children with such signs need close monitoring.

Workup and Laboratory Studies

Most children with acute gastroenteritis do not need any laboratory evaluation done. The guidelines development group for NICE 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 IV fluid therapy is required or there are symptoms and signs that suggest hypernatremia and measuring venous blood acid–base status and chloride concentration if significant dehydration and impending shock is suspected. In addition, it is strongly advised that a medical evaluation is in order for the following:

• 1.

  Infants less than 2 months of age

• 2.

  Significant comorbidities, such as immunodeficiencies, renal disease, type I diabetes

• 3.

  Presence of persistent vomiting along with diarrhea

• 4.

  Increased stool frequency defined as greater than 8 per day and/or large stool volumes

• 5.

  Caregivers report clinical signs of significant dehydration

• 6.

  Blood in the stool

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, those with a history of recent travel to high-risk areas that are associated with an increased risk of parasitic or bacterial mediated infections, or for patients with a severe case of gastroenteritis. Identification of pathogens may be significant since a specific antimicrobial treatment may be indicated. 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 (Prehospital Care)

Ideally, the management of acute diarrhea should begin at home because early intervention can reduce complications. The child should be rehydrated using ORS. Effective education for the parent or caretaker regarding the 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 osmotic concentration.

The calculated fluid deficit should be 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 commence. Feeding modifications, such as dilution, lactose or cow’s milk-free formula, or an elimination diet are not recommended in an otherwise healthy infant with acute gastroenteritis. Ongoing fluid losses in the form of vomiting or diarrhea should be made up in addition to maintenance fluid requirements by the administration of 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 for a child presenting with the 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. Therefore, it is 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 commence and maintenance fluids should be continued (100 mL/kg/day for the first 10 kg, plus 50 mL/kg/day for the next 10 kg, plus 20 mL/kg/day for the remainder of weight over 20 kg). Supplementary 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 compared the effectiveness of ORS to 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 the hospital, and those receiving IV therapy had a higher risk of phlebitis.

In 2014, the ESPGHAN published evidence-based guidelines for the management of diarrhea.

IV therapy is indicated in the following clinical scenarios:

• 1.

  Dehydration is estimated to be greater than 10%

• 2.

  Oral replacement therapy fails

• 3.

  Dehydration with lack of improvement despite oral rehydration

• 4.

  Persistent vomiting despite ORS

• 5.

  Abdominal distension and signs of an ileus

• 6.

  Clinical signs and symptoms of shock

If the child is in shock, the initial resuscitation is a rapid IV infusion of 20 mL/kg of an isotonic crystalloid solution, either normal saline or lactated Ringers. In children without shock, an initial infusion of 20 mL/kg of an isotonic solution is also recommended. Once the patient is stabilized, this is followed by replacing the deficits with isotonic solutions (0.9% saline or 0.9% saline in 5% dextrose) and making calculations based on uncorrected weight. Once dehydration is corrected, maintenance fluids should be continued, oral feeding started, and ongoing stool losses replaced with ORS (10 mL/kg per watery stool). Early and gradual reintroduction of ORS during IV therapy is recommended with the aim of continuing rehydration with ORS, if this is then tolerated.

Although many experts now support rapid IV rehydration (4 to 8 hours), rehydration with IV fluid therapy has traditionally been undertaken slowly—over 24 hours. The WHO recommends that IV 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 IV fluid replacement should be done for 24 hours or longer. The NPSA patient safety alert highlights the importance of measuring electrolytes at the start of IV fluids and regularly monitoring sodium concentrations thereafter. Randomized controlled trials are needed to examine the safety of the practice of rapid IV rehydration.