Modem Management of Acute Diarrhea and Dehydration in Children

ALAN MEYERS, M.D., M.P.H., Boston University School of Medicine and Boston City Hospital Boston, Massachusetts

Advances in clinical and laboratory knowledge have led to new concepts in the

management of acute infectious diarrhea in children. The major advance has been the

development of oral rehydration therapy. Which is effective for the treatment of diarrhea of

any etiology in patients of any age. Optimal management of acute infectious diarrhea

inciudes the following: (1) rapidrehydration (and maintenance of hydration) using an

appropriate glucose-based orcereai-based orai rehydration soiution; (2) early refeeding with a

mixed diet and no interruption of breast feeding; (3) continuation of iactose-containing foods

unless ciinicai signs of iactose intoierance deveiop,and (4) a staged iaboratory evaiuation,

with the administration of antimicrobial therapy when indicated.

Dramatic changes in the treatment of diarrheal disease in children have occurred

during the past 20 years, But physicians in the United States have been among thelast to

apply these advances to the care oftheir patients. Many of these therapeuticinnovations have

been pioneered in the world's poorest countries, Where dehydrating diarrhea is the leading

cause of mortality in children under five years of age and is responsible for as many as 4-

5million deaths every year.

The morbidity and mortality rates for acute diarrheal disease are much lower in the

United States than in most other partsof the world. However, it is estimated that the average

child in this country has 1.3 to 2.3 episodes of acute diarrhea each year during the first five

years of life and that 10 percent of these episodes are severe enough to prompt a visit to a

physician. Further more, 6.5 percent of all children are hospitalized for diarrhea during the

first five years of Hfe. Diarrheal illness is responsible for 10.6 percent of all hospitalizations

in this age group, or some 220,000 admissions per year,as well as 500 deaths. Thus, every

physician who treats children should be familiar with the optimal management of acute

diarrheal disease.

Pathophysiology

Most diarrheal disease is non inflammatory and primarily affects the small intestine.

Diarrhea may be broadly classified assecretory or malabsorptive (osmotic),depending on

whether stool output continues or ceases, respectively, in the fasting patient.

Over 10 L of fluid per day are secreted and absorbed by the normal adult gut. Inthe

small intestine, fluid secretion occurs by the extrusion of chloride ion from the cells of the

villus crypt; this extrusion is mediated by cyclic adenosine monophosphate (AMP).

Absorption of fluid occurs at the cells of the villus tip.

The balance between fluid secretion and absorption is upset in secretory diarrhea,and

the resultant loss of water and electrolytes in the stool can be rapid and massive. The stool

sodium concentration is high in secretory diarrheas (60 to 120 mEqper L) and, in severe

cases, approaches the serum sodium concentration.

In malabsorptive diarrhea, damage to the intestinal microvillus membrane leads to

malabsorption of luminal solute, with osmotic loss of free water into the gut lumen. The stool

sodium concentration is usually low (30 to 40 mEq per L). Luminal osmolality has important

therapeutic imphcations, which are discussed later in this article. Stool losses of bicarbonate

and potassium occur in both secretory and malabsorptive diarrhea.

ETIOLOGY

A variety of pathogens can cause acute infectious diarrhea in children (Table I) and

even more organisms may be responsible for diarrhea in immunocompromised hosts/ In the

United States, 30 to 40 percent of episodes of acute gastroenteritis in children are caused by

viruses and 20 to 30 percent are caused by bacteria or parasites no etiologic agent can be

identified in asmany as 40 percent of cases.

In addition to acute infectious gastroenteritis, the differential diagnosis of vomiting

and diarrhea in children includes other infections, such as otitis media and sepsis,as well as

noninfectious causes, including intestinal obstruction, toxic ingestions and inflammatory and

allergic conditions.

VIRUSES

Worldwide, rotavirus is the most common single pathogen identified in children with

severe diarrhea. This pathogen accounts for 35 percent of hospitalizations for acute diarrheal

illness. Infection probably occurs via fecal-oral transmission and is most common in children

six months to two years of age. By the time they reach. four years of age, most children are

immune to the syndrome of severe dehydrating rotaviral diarrhea. In this country, the disease

may occur at any time of the year, but it has a distinct pattern of winter sea sonality, with

peaks occurring in the Southwest in the fall and sweeping across the country toward the

Northeast by late winter to spring.

Rotavirus invades and lyses the absorp tive cells of the villus tip of the small intestinal

epithelium, causing decreased absorption and depletion of brushborderdisaccharidases with

consequent carbohydrate malabsorption. Typically, rotavirus causes a self limited syndrome

with an incubation period of one to three days. Vomiting may occur for up to three days, and

watery diarrhea may occur for three to eight days. The vomiting and diarrhea are often

accompanied by fever and upper respiratory signs. Dehydration can be severe.

Other viral agents also cause acute infectious diarrhea in children. The pathogenesis

and clinical syndromes of these infections are similar to those of rotavirus infection.

However, adenovirus infection tends to cause a more prolonged diarrhea,and Norwalk virus

infection often occursin the setting of epidemic outbreaks.

BACTERIA

Bacterial agents may cause diarrhea by several mechanisms, with some pathogens

acting by more than one mechanism.

TABLE 1

Pathogens That Cause Acute Infectious Diarrhea in Children.

Viruses

Rotavirus

Enteric adenovirus

Norwalk virus

Astrovirus

Calci virus

Bacteria

Toxigenic

Vibrio cholerae

Enterotoxigenic

Escherichia coli

Shigella species

Parasites

Giardia lamblia

Entamoeba histolytica

Cryptosporidium

species

Strongyloides stercoralis

Derived from Guerrant and BobaW and Blacklow and Greenber

Toxigenic bacteria elaborate an enterotoxin that binds to specific receptors on the

small bowel mucosa to cause a secretory diarrhea. The classic example is cholera, in which

enterotoxin secreted by the gram negative bacillus Vibrio cholerae stimulates cyclic AMP

production and net fluid secretion by the small intestinal epithelium. the United States, the

most common toxi genic bacteria is enterotoxigenic Escherichia coli, which is also the most

frequent cause of traveler's diarrhea.

Cytotoxic pathogens produce substances that cause cell damage and

inflammation,primarily in the colon. The cytotoxin mediated diarrhea of Clostridium difficil

infection is often associated with the use of antimicrobial agents.

Other bacterial pathogens damage the epithelium of both the small and large intestine

by tightly adhering to the mucosal surface.

Invasive bacteria act primarily in the colon by first colonizing the lumen, then

adhering to and invading the mucosa, where they multiply and elicit an acute inflammatory

reaction. This effect results in the clinical picture of dysentery, with fever, abdominal pain,

tenesmus, and blood and pus in the stool.

PARASITES

Infection with enteric parasites can cause a prolonged clirucal syndrome, which may

be dysenteric, as with invasive Entamoeba histolytica disease. The pathogenic mechanisms of

Giardia lamblia and Cryptosporidium species are not known.

Clinical Evaluation

HISTORY

The child's complete history should be obtained, including use of drugs, possible

ingestions, family history and travel history. Important aspects of the present illness include

the onset and duration of illness, presence or absence of fever and other symptoms, frequency

of vomiting, frequency and character of the stool (e.g., watery, foamy, bloody), urinary

output, and the child's feeding history and behavior.

TABLE 2

Degrees of Dehydration and Corresponding Clinical Signs.

Minimal, subclinical (1 to 2 percent, or 10 to20 mL per kg)

Increased thirst Mild oliguria.

Mild (3 to 5 percent, or 30 to 50 mL per kg)

Increased thirst and oliguria Slightly dry lips, thick saliva.

Moderate (6 to 9 percent, or 60 to 90 mL per kg)

Marked thirst and oliguria Dry lips and buccal mucosa, Diminished or absent tears,

Depressed fontanelle, Sunken eyes, Decreased skin turgor (delayed capillary refill),

Decreased skin elasticity (tenting) Listlessness or irritability.

Severe (more than 10 percent, or more than 100 mL per kg)

Clinical signs of moderate dehydration, plus one or more of the following: Cyanosis,

Cold extremities, Rapid, thready pulse, Grunting, Tachypnea,Lethargy,Coma.

Derived from Santosham" and the Centers for Disease Control and Prevention.

DEGREE OF DEHYDRATION

An assessment of the degree of dehydration and attendant circulatory compromise is

of paramount importance in the evaluation of a child with diarrheal disease. Dehydration may

be classified as minimal,mild, moderate or severe, based on clinical signs that correspond to

the water deficit expressed as a percentage of the body weight (tabel 2)

1. At less than 3 percent dehydration (minimal), no physical signs of dehydration are

present, but the child may have a history of increased thirst and mild oliguria.

2. At 3 to 5 percent dehydration (mild), the child begins to show physical signs,

especially dryness of the mucous membranes.

3. At 6 to 9 percent dehydration (moderate), physical signs become more marked, and

the child begins to show behavioral signs, such as listlessness or irritability.

TABLE 3

Capillary Refill Time in Dehydration

CAPILLARY REFILL

DEHYDRATION

TIME (SECONDS)

<1.51.5 to 3.0

>3

TIME (SECONDS)

(%)

<5

5 to 10

>10

WATER DEFICIT

(mLperkg)

<50

50 to 100

>100

Adapted from Saavedra JM, Harris GD, Li S, Finberg L. Capillary refilling (skin turgor) in

the assessment of dehydration. Am J Dis Child 1991;145:296-8. Used with permission.

4. At 10 percent dehydration and above(severe), the child may demonstrate one or more

signs of impending shock or overt shock, such as cool extremities,

cyanosis,hypotension, tachycardia, thready pulse, grunting and obtundation.

Capillary refill time has been shown to correlate well with the degree of dehydration in

young children (Table 3). The time required for capillaries to refill is measured by applying

pressure to the fingernail bed until blanching occurs, then releasing the pressure and timing

the capillary refill.

LABORATORY EVALUATION

I f a child has moderate to severe dehydration, serum electrolytes should be measured,

both to establish a baseline for monitoring progress and to identify electrolyte abnormalities,

particularly hyponatremia and hypernatremia, that may affect the course of therapy.

Metabolic acidosis usually accompanies clinically apparent diarrheal dehydration, with the

serum bicarbonate level inversely proportional to the degree of dehydration. In some cases,

lifethreatening hypoglycemia may accompany diarrhea.

Although less common than viral pathogens, bacterial and parasitic etiologies should

be considered in the child with acute diarrheal disease. In such cases, specific antimicrobial

therapy may be indicated and some complications may be anticipated. For example,

bacteremia may develop in young infants and immunocompromised patients with Salmonella

infection, and seizures may occur in patients with Shigella infection. Furthermore, certain

diagnoses carry public health implications; among these are Salmonella or Shigella food

poisoning and outbreaks of G. lamblia and Cryptosporidium infections in day care centers.

Stool cultures do not need to be obtained in all patients. In one study of children under

four years of age,Bacterial disease was unHkely in the absence of a cluster of three historical

variables: abrupt onset of diarrhea, absence of vomiting before the onset of diarrhea and the

passage of more than four stools per day Bacterial disease was also unlikely in the absence of

fecal leukocytes. Thus, it is reasonable to obtain stool cultures only in patients who present

with the three historical findings, white cells on a stool smear or a picture of clinical

dysentery.

Stool may be examined for white cells by smearing a small amount on a slide and

adding a drop of saline. A drop of methylene blue also may be added; this will stain the

nuclei of viable white cells after a few minutes. The smear is then viewed under the 103 and

403 objectives.

Confirmation of the clinical diagnosis of rotavirus gastroenteritis may be helpful in

some cases and is readily accomplished with commercially available kits for the detection of

rotaviral antigens in the stool. Parasitic disease should be considered inchildren with

prolonged diarrhea (duration of more than 10 days), A highly specific and sensitive assay for

G, lamblia antigen in stool is commercially available.

MANAGEMENT

ORAL REHYDRATION THERAPY

The major advance in the treatment of diarrheal disease has been the development of

oral rehydration therapy. In view of the global magnitude of the problem of diarrheal disease

and the simplicity, low cost and effectiveness of oral rehydration therapy, an editorial in

Lancet referred to this treatment as "potentially the most important medical advance of this

century.

While oral therapy for diarrhea has been used by traditional cultures for centuries, the

origins of modern oral rehydration therapy date to the 1940s, when Harrison at Johns

Hopkins and Darrow at Yale began using an oral electrolyte solution that approximated the

ion losses in the stool, with glucose added because of its protein-sparing effect, several

investigators independently discovered that water absorption in the proximal small bowel of

laboratory animals was mediated by an active process of sodium transport that was coupled in

anobligatory fashion to the cotransport of glucose or other substrate in an approximately

equimolar ratio, Water absorption was maximized at sodium concentrations of 100 to 120

mEq per L and glucose concentrations of 110 mmol per L (2 percent).

The finding that this cotransport mechanism also mediates water absorption in the

human gut and is preserved in patients with diarrhea led to the formulation of a sodium- and

glucose-based oral rehydration solution, which was first used on a large scale when cholera

broke out among refugees fleeing into India during the Bangladeshi wa r of independenc e in

2972 13,21 Supplies and personne l for administering intravenous therapy were scant, but the

use of oral rehydration therapy reduced the mortality rate from over 30 percent to 3 percent.

Subsequently, the World Health Organization (WHO) developed and began to

promote the use of a single oral rehydration solution (ORS) to treat dehydrating in children

and adults of all ages. The WHO-ORS consists of sodium (90 mEqper L), glucose (2

percent), potassium (to replace the inevitable stool and urinary losses) and bicarbonate (to

help correct acidosis). The dry ingredients (Table 4) are distributed in packets for

reconstitution with water. More recently, trisodium citrate has replaced bicarbonate as the

base to prolong the packet shelf life.

Today, oral rehydration therapy is being used to treat an estimated one-third of the

diarrheal episodes in children living in the poorer countries of the world. As a result, 1

million lives are being saved each year.

WHO-ORS has been studied in thousands of children. It has been found to be safe and

effective in children of all ages (including neonates^) with diarrhea of all etiologies,

dehydration of aU degrees of severity up to the point of shock, and electrolyte disturbances,

including both hyponatremia and hypematremia.Parents and other caregivers may administer

the solution in a bottle, cup or spoon, or the solution may be given by nasogastric tube.

In randomized controlled trials, both in the United States and Europe and in poor

countries, oral rehydration therapy was found to be more rapid than intravenous therapy in

correcting dehydration and acidosis.Oral rehydration therapy was also safer, with none of the

comphcations associated with intravenous therapy 25,2 8 Finally, fewer seizures occurred in

children with hypernatremia who were given oral rehydration therapy.

Reported success rates for oral rehydration therapy exceed 95 percent. Failure is most

often due to extremely rapid purging(i.e., stool output of more than 10 g per kg per hour)." In

an editorial in the New England Journal of Medicine, Carpenter compared oral rehydration

therapy with intravenous therapy and suggested that"oral rehydration be accepted not only as

an equal but, perhaps, as the superior means of treating acute diarrheal illnesses in the

sophisticated and sanitized medical centers of the Western world as well as in rural

Bangladesh.

TABLE 4

Composition of WHO-ORS

Component

Sodium chloride

Potassium chloride

Glucose

Sodium bicarbonate or

Trisodium citrate

Water

Amount

3.5 g

1.5 g

20 g

2.5 g

2.9 g

l L

WHO-ORS = World Health Organization oral rehydration solution. Adapted from Santosham M, Brown KH,

Sack RB.Oral rehydration and dietary therapy for acute child-hood diarrhea. Pediatr Rev 1987;8:27.

Few complications have been reported in patients treated with WHO-ORS, and these

have been limited to clinically insignificant periorbital edema and, rarely, uncomplicated

hypernatremia.In the United States,the WHO-ORS with a sodium concentration of 90 mEq

per L has been shown to be safe in children treated as inpatients and outpatients, with

clinically apparent dehydration and without clinically apparent dehydration.

Nonetheless, physicians in the United States have been reluctant to use a rehydrating

solution with a relatively high sodium content. One reason is that in the 1950s,a commercial

oral solution containing 50 mEq of sodium per L was associated with fatal hypernatremia. In

retrospect, However,this hypernatremia was probably caused by the solution's high

carbohydrate content (8percent) and, possibly, by improper reconstitution of the dried powder

not by thesolution's sodium concentration.

The child with diarrhea generally has an isotonic depletion of body fluids. When the

child is rehydrated with plain water, the serum is diluted and hyponatremia can ensue. When

the child is given a hyperosmolar solution (especially when the absorptive capacity of the gut

is compromised, as in the malabsorptive diarrheas),free water is drawn into the gut lumen

froni the serum, and hypernatremia may develop, even if the hydrating solution contains no

sodium.Thus, a critical principle of oral rehydration therapy is the avof hypertonic solutions ^

The traditionally recommended "clear fluids" all are hyperosmolar and should not be given to

the child with diarrhea (table 5 ) .

The oral rehydration solutions offered by commercial manufacturers in the United

States have been lower in sodium than the WHO solution, although their sodium content has

been increased in recent years. The compositions of the currently available oral rehydration

solutions are given in Table 6. The sodium cocentrations of these products range from 45 to

75 mFq per L.

TABLE 5

Composition Of Selected Clear Liquids Used In The Treatment Of Dehydration

Liquid Sodium{mEq

iper L)

Potassium(mEq per

L)

Chloride(mEq per

L)

Base(mEq per L)

Carbohydrate(g per L)

Osmolality(mOsm per L)

ColaGinger

aleApple juice

Chicken broth

GatoradeTea

233

250230

0.1128835

2230250170

1340030

120901200460

7505407304503305

Derived from Avery and Snyder^ and Ghishan.

Solutions with sodium concentrations of 50 to 60 mEq per L have been found to be as

efficacious as the WHO solution. Since solutions with a low sodium concentration (30 to 35

mEq per L) may produce,or fail to correct, hyponatremia, they are not recommended for the

treatment of moderately dehydrated children.Currently, WHO recommends using solutions

with a carbohydrate-to-sodium ratio of less than 1.4:1 (e.g., 2 percent glucose with more than

70 mEq of sodium perL). The American Academy of Pediatrics recommends a ratio of less

than 2:1. percent glucose with more than 55 mEq of sodium per L). Some experts have

advocated that solutions with a lower sodium concentration (60 to 75 mEq per L) be used,

because of their equal efficacy, the lower risk of hypernatremia and the possible benefits of

their lower osmolality.

REHYDRATION PHASE

Rehydration the first phase of treatment should be achieved under direct medical

supervision.The degree of dehydration should be estimated for the child with clinical signs of

dehydration, and the child should be offered, ad libituman oral rehydation solution with a

sodium concentration of 50 to 90 mEq per L. The child with mild dehydration should take 50

mL of the oral rehydration solution per kg of body weight over four to six hours. Over the

same period, the child with moderate dehyration should take 100 mL perkg. The child with

signs of shock must receive intravenous fluid (Ringer's lactate or normal saline) in boluses of

40 mL per kg per hour until normal circulatory status is restored; the child then should

receive oral rehydration therapy.

Breast feeding may continue during oral rehydration therapy and may reduce stool

output.^' Other feedings should be withheld until rehydration is complete. In the child with

hypernatremia (serum sodium concentration of more than 150 mEq per L [150 mmol per L]),

the estimated deficit should be replaced over 12 hours ("slow"oral rehydration therapy) to

mirumize the risk of seizure.

Vomiting is frequent in acute diarrheal disease, but it rarely causes oral rehydration

therapy to fail. The child may be adequately rehydrated by giving 5 mL of the oral

rehydration solution every two to five minutes in a teaspoon or an oral syringe, and vomiting

usually ceases once rehydration is under way.

MAINTENANCE PHASE

The second phase of oral rehydration therapy is maintenance. This phase begins following

rehydration in the child with clinical signs of dehydration or begins immediately in the child

without clinically apparent dehydration. A minimum of 150 mL per kg per day of total fluids

should be given. In the formulafed infant, the fluidsmay consist of alternate feedings of

formula and rehydration solution.

TABLE 6

Composition Of Oral Rehydration Solutions

Product

(manufacturer)

Sodium

(mEq per

L)

Potassium

(mEq per

L)

Chloride

(mEq per

L

Base

(mEq

per L)

Carbohydrate

(g per L)

Osmolality

(mOsm

per L)

WHO-ORSPedialyte

(Ross)Rehydralyte

(Ross)Infalyte (Mead-

Johnson)

90

45

75

50

20

20

20

25

80

35

65

45

30

30

30

10

20

25

25

30

310

250

305

200

WHO-ORS = World Health Organization oral rehydration solution. Derived from Avery and Snyder/ Ghishanf' Santosham

and Greenough and Pizarro, et al.

An oral rehydration solution with a lower sodium concentration (40 to 60 mEq per L) should

be used during the maintenance phase. I f a solution with a high sodium concentration (75 to 90 mEq

per L) is used, it should be alternated with liquids that are low in solutes (i.e., water or formula).

Additional oral rehydration solution should be given to replace ongoing stool losses on a one

to one basis, orapproximately 10 mL per kg or one half to one cup of solution for each

diarrhealstool.

CEREAL-BASED FORMULATIONS

` More recently, oral rehydration solutions made with complex carbohydrate have been

shown to be as effective as glucose based solutions in restoring and maintain ing hydration.

The advantage of these cereal based solutions is that they also reduce the volume and

duration of diarrhea, the frequency of vomiting and the volume of solution needed for

rehydration and maintenance.Use of these solutions was found to reduce stool volume by one

third in children with cholera and by one fifth in children with diarrhea due to other causes.

Cereal-based oral rehydration solutions have been made with rice powder, as well as

various other cereals. The solutions typically contain 50 to 80 g of cereal per Lalong with an

electrolyte mixture similar to that of the WHO oral rehydration solution. Since the organic

substrates are polymeric (starch and protein), a much larger quantity of substrate may be used

than in the glucose-based solutions, without increased osmolality {Figure 3).Whenthese

molecules are digested at the intestinal brush border, more sugar and amino acid monomers

are presented for cotrans port with sodium and water than can be provided by glucose-based

solutions with out a dangerous increase in osmolality.

A second advantage of the cereal-based solutions—one that is especially important in

poor coimtries is that the solutions may be prepared from ingredients that are readily

available in virtually every home. Home preparation is also safer, since the carbohydrate in

the cereal-based solutions (unlikethe carbohydrate in sugar-based solutions) cannot be

overconcentrated without producing an vmdrinkable mixture.

At present, no cereal-based solution is commercially available in the United States.

Infalyte, a commercial oral rehydration solution, is prepared from refined rice syrup and

contains only 30 g of glucose and short glucose polymers per L. In one controlled clinical

trial, Infalyte was found to reduce stool volume only during the first six hours of therapy.

A homemade cereal-based solution can be prepared by mixing one-half cup of

dry,precooked baby rice cereal with two cups of water and one-quarter teaspoon of salt. This

should produce an oral rehydration solution containing about 60 g of rice per L and 50 mEq

of sodium per L. The salt must be measured carefully, using a level quarter teaspoon. The

resulting mixture should be thick, but pourable and drinkable, and it should not taste salty.

Although even a twofold error (i.e., use of as much as one-half teaspoon of salt)

would not result in a dangerously high sodium concentration, studies on the safety and

efficacy of homemade cereal basedrehydration solutions in the United States nhave not yet

been reported. The ability of the parent or other caretaker to follow formulation instructions

should be assessed before use of a homemade solution is recommended. Homemade oral

rehydrationsolutions may be especially helpful for low income parents, who may have to pay

$6 per L for a commercial rehydration product, an expense that often is not covered by

Medicaid.

DIETARY MANAGEMENT

A rational approach to feeding the child with acute diarrhea has also evolved. It has

been common practice to "rest the bowel" by giving "clear fluids" for a variable period after

the onset of illness; this step is followed by feeding with dilute formula of gradually

increasing strength. However, no controlled clinical trials have demonstrated the efficacy of

this approach.

In fact, studies20'29' have shown that fasting in children not only has a negative impact on

nutritional status but actually prolongs the course of diarrhea. This finding should not be

surprising, since the fasting child loses approximately 1 percent of lean body mass per day.

The gut mucosa may also suffer atrophy. Furthermore, the injured gut requires luminal

foodstuff for rapid repair.

In one controlled trial, hospitalizedir fants who were fed full strength soy formula

immediately after a four-hour rehydration period had 60 percent less stool output and a 42

percent reduction in the duration of diarrhea, compared with infants who received only oral

rehydration solution and water for 48 hours and then half strength soy formula for 24

hours.Similar findings have been demonstrated in outpatients.

No adverse effects of early or continuous feeding have been reported.While there is a

theoretic risk of atopic disease following the increased absorption of intact protein across the

injured gut wall, this problem has not occurred in clinical studies.