Treatment of Acute Diarrhea in Children Replacement offluid and electrolyte losses is critical to prevention ofpotentially serious complications. by Ina Lee Stile Calligaro, PharmD
Introduction Acute nonspecific diarrhea usually is not life-threatening among children in developed countries. However, each year approxinlately 3.7 million children with this complaint visit a pediatrician and 10.6% of hospital admissions in children less than 5 years old result from complications of diarrhea. 1 Infants and children in daycare centers experience the highest incidence of diarrhea. Rates up to 3.64 cases per person per year were reported in one longitudinal study of diarrheal diseases in daycare centers. 2 Acute diarrheal illness results in many visits to the pediatrician 'S' office, and may result in requests for recommendations from pharmacists. Diarrhea is defmed as an increase in stool frequency and volume, and/or a decrease in consistency, when compared with the child's usual bowel habits. Acute nonspecific diarrhea may result from infection with a variety of microbial organisms or parasites, or from noninfectious causes such as side effects from medications or food intolerance. Infectious diarrhea, in children, is usually caused by viruses. The most common viral pathogens causing diarrhea include rotavirus, Norwalk-like viruses, and enteric adenovirus. 3,4 Antiviral agents effective against enteric viruses are unavailable; howVol. NS32, No. 11 November 1992/ 885
ever, a rotaviral vaccine is currently being studied. The availability of such a vaccine would be expected to significantly decrease the incidence of diarrhea in young children. Appropriate management of diarrhea in the initial stages can prevent fluid and electrolyte imbalances, which in extreme conditions can result in serious sequelae and even death. Many parents attempt to medicate their child before seeking medical attention. Pharmacists can advise parents if medical attention is warranted and can educate the parents about the proper management of mild disease to prevent more serious complications. This article focuses primarily on the nonprescription treatment of acute diarrhea in children.
Patient Assessment In children with diarrhea, dehydration and electrolyte loss are of particular concern. Young children may resist drinking extra fluids when they do not feel well, making fluid replaceAMERICANPHARMACY
ment more difficult and dehydration more likely. Because children also have increased metabolic rates as a result of their relatively large body surface areas, they need more fluid. 3 In addition, they may be less able to conserve fluid by not being able to concentrate urine maximally. It may be difficult for parents to determine if young children with diarrhea are dehydrated, because they generally do not verbalize their thirst. Parents of children with diarrhea need to be aware of the potential dangers of diarrhea and of the signs and symptoms of dehydration (Table 1). Moderate to severe dehydration must be managed by a physician, usually in a hospital setting. The parent should be questioned about the amolmt and nature of fluid intake, occurrence of vomiting, and frequency of urination. The presence of blood or mucus in the stool may indicate a bacterial infection requiring antibiotic therapy. Diarrhea also may be a manifestation of an infection at another site. Children with symptoms associated with illnesses of another organ system such as the respiratory or urinary tract should be evaluated by their physician. Before recommending a therapeutic approach for a child with diarrheal the pharmacist should question the parent to determine if a physician should be consulted (Table 2). The age of the patient, regardless of the character or chronicity of the diarrhea, is an important factor in determining whether to treat with nonprescription products or to refer the patient to a phYSician. Infants and children less than 3 years old should be referred to a physician because of the high risk of dehydration. In addition, children who are dehydrated, febrile, or immunocompromised should be referred to a phYSician.
Treatment
The treatment of acute diarrhea consists of the following therapeutic modalities: (1) fluid and electrolyte replacement, (2) early reintroduction of food, (3) antimicrobial therapy when indicated, and (4) antidiarrheal agents in selected patients.
Oral Rehydration Therapy The adnlinistration of an oral rehydration solution (ORS) to replace fluid and electrolyte losses is the foundation of therapy.6 Parents must understand that the role of ORS is to prevent dehydration and electrolyte imbalances rather than to hasten stool normalization. Osmotically balanced, commercially available electrolyte solutions (Table 3) are preferable to homemade solutions and should be recommended because the alTIounts of electrolytes are standardized and the carbohydrate content is appropriate to ensure maximum absorption of sodium and water. The major principle behind the use of ORS is the cotransport of sodium with glucose or another small organic molecule from the gastrointestinal tract into the bloodstream. Care should be given to avoid casual recommendation of "clear fluids " because they can be harmful if they contain inadequate amounts of electrolytes, excessive amounts of electrolytes or excessive amounts of carbohydrates (Table 3). In particular, clear fluids have a low sodium content and also lack potassium and base needed to prevent hypokalemia and
Table 2
Table 1
Signs and Symptoms Associated vvith Dehydration Degree Mild
Symptoms
Increased thirst Slightly dry mucous membranes
Patient Information Needed Before Recommending OTC Medications Age Duration of diarrhea and volume/frequency of diarrhea Presence of the following symptoms: Fever
Moderate
Loss of skin turgor Dry mucous membranes Sunken eyes Lack of tea rs
Temperature Vomiting Blood or mucus in the stool Recent antibiotic therapy
Depressed fontanelle in infants Decreased urine output
Travel history Similar illness in other family members
Severe
Cold extremities Decreased or absent urine output
Source: References 5 and 6.
AMERICANPHARMACY
Concomitant disease states that might compromise the patient's immune status Weight loss
November 1992/ 886
Vol. NS32, No. 11
acidosis. Use of homemade solutions may also result in serious electrolyte imbalances because of errors in measuring and mixing the ingredients. Guidelines for the appropriate use of ORS have been published by the American Academy of Pediatrics (AAP) Committee on Nutrition (Table 4).10 This committee recommends the administration of solutions containing 75-90 mEq/L of sodium to rehydrate patients and solutions containing 40-60 mEq/L of sodium for maintenance therapy to replace ongoing losses, thus preventing the child from becoming dehydrated. Solutions containing the higher sodium concentration may be used as maintenance therapy if alternated 1: 1 with a solution low in sodium such as water or breast milk. The AAP recommends a carbohydrate-to-sodium ratio of 2: 1 to prevent osmotic diarrhea from excessive carbohydrates. The volume of solutions containing 40-60 mEq/L of sodium should not exceed 150 mL/kg/day. Solutions containing higher concentrations of sodium should be limited to 75 mL/kg/day. The child may be given water or breast milk to satisfy thirst. Contraindications to the use of ORS include (1) severe dehydration that can result in shock secondary to hypo-
volemia, (2) glucose intolerance evidenced by an increase in stool output with reducing substances in the stool, or (3) the inability to tolerate oral fluids. 5 Vomiting is not a contraindication; in this situation, parents may be advised to administer 1 to 2 teaspoonfuls (5-10 mL) of ORS every 10-15 minutes. 1O The volume should be slowly increased as tolerated. Use of a dropper or spoon may facilitate the administration of fluids to infants and small children. A concern with the currently marketed solutions for oral rehydration is that they do not change the clinical course of the disease and have minimal nutritional value. Oral rehydration solutions that contain proteins or use glucose polymers derived from starch as the carbohydrate source are being evaluated in the treatment of acute diarrhea. Ricelyte, a recently marketed ORS, contains glucose polymers derived from rice synlps as the carbohydrate source. Preliminary data indicate that solutions containing glucose polymers~ may increase the absorption of fluid and electrolytes resulting in decreased stool volume and weight ·loss and shortened course of diarrhea. 11 ,12 The ideal composition of glucose polymers and amino acids is currently tmder investigation.
Table 3
Contents of Commonly Used Oral Rehydration Solutions CHO Product
(gIL)
Na (mEq/L)
K (mEq/L)
CI (mEq/L)
Base (mEq/L)
Osmolality (mOsm/L)
OTC WHO Solution * t '
20
90
20
80
30(C)
310
Infalytet
20
50
20
40
30(8)
270 290
Lytrent
20
50
25
45
30(C)
Pedialytet
25
45
20
35
30(C)
250
Rehydralyte * t
25
75
20
65
30(C)
305
Resolt
20
50
20
50
34(C)
270
Ricelytet
30
50
25
45
34(C)
200
120
3.5
28
30
0
730
Clear Liquids § Apple juice Chicken broth Cola
0
250
8
250
0
450
70-120
3
0.1
2
39(8)
750
50
24
3
17
0
330
150- 270
15- 27
0 .2
0
0
570-640
0
0
0
0
0
5
Gatorade Jello Tea
CHO= carbohydrate; B = bicarbonate; C= citrate
tReady to use.
* Use for rehydration, all other solutions for maintenance therapy.
§Content may vary with specific brand.
tMust be reconstituted with water.
Source: References 5, 7- 9.
Vol. NS32, No. 11 November 1992/ 887
AMERICAN PHARMACY
Reintroduction of Food The traditional approach in managing children with diarrhea has been to withhold solid food. However, the AAP recommends reintroducing food within 24 hours of the start of a diarrheal episode unless there is an absolute contraindication.1O Contraindications to refeeding are significant dehydration, severe vomiting, or gastrointestinal distention. Early reintroduction of solid foods is encouraged to prevent weight loss and the complications of starvation. There are two potential concerns with feeding children with diarrhea: (1) the food will further irritate the gastrointestinal tract and worsen the diarrhea, and (2) the absorption of proteins or other macromolecules could lead to food allergies. Although some investigators have reported an increase in stool volume with feeding,1O others have demonstrated a more rapid recovery in children given food. 13 The clinical or immtIDologic consequences of absorbing proteins and other macromolecules during an episode of gastroenteritis is not known. The benefit of providing adequate nutrition during diarrhea is thought to outweigh the potential disadvantages in most children. Breast milk is usually well tolerated and is the preferred form of nutrition in infants. 1O The use of lactose-containing formulas is controversial. Some children will develop a transient lactase deficiency during an infectious gastroenteritis Table 4
Recommendations for Oral Therapy in Treating Diarrhea 1. Recommended content for rehydration solutions: Carbohydrate 2-2.50/0 Sodium 75-90 mEq/L Potassium 20 mEq/L Base 20-300/0 of anions as acetate, bicarbonate, citrate, or lactate CHO: sodium ratio::; 2:1 2. Recommended content for maintenance solutions: Same as rehydration solutions except the concentration of sodium should be 40-60 mEq/L. Solutions with higher sodium concentrations may be used if alternated 1:1 with a low-sodium fluid. 3. Vomiting is not a contraindication to oral therapy. 4. Premixed rehydration solutions are preferred. Powdered rehydration products should only be dispensed if a container of the appropriate volume is provided for accurate dilution. 5 . Reintroduce food within 24 hours unless there is an absolute contraindication (see text). Source: Reference 10. Note: Recommendations developed by the American Academy of Pediatrics Committee on Nutrition.
AMERICAN PHARMACY
and may not tolerate lactose-containing formulas. Some clinicians restart infants on their usual formula, changing to a lactose-free product only if the diarrhea gets worse. Other pediatricians recommend restarting all infants on a short course of lactose-free formula. The formula should initially be diluted to half strength and the concentration increased as tolerated by the child. 6,10 The severity of the illness often dictates how quickly food is tolerated. An infant with mild diarrhea lasting less than a day will usually tolerate full feedings earlier than infants with a more virulent course. The parents of children who are started on a lactose-free formula should be advised that this is a transient problem and that lactose-containing foods can be reintroduced after a few weeks. This knowledge will avoid misconceptions regarding milk intolerance by the parents. Older children may be offered rice, bananas, applesauce, or toast. Apple juice should be avoided because of the high carbohydrate content.
Antimicrobial Therapy If children have a fever or have blood or mucus in the stools, their parents should be advised to take them to their physician, because these symptoms may indicate the diarrhea is caused by a bacterial pathogen. SpecifiC antibiotic therapy is indicated only after isolation of a pathogen that has been shown to respond to antimicrobial therapy. Several references are available for guidelines on the treatment of common bacterial and parasitic enteropathogens. 3,6,14 IrOnically, diarrhea may occur as a treatment-related side effect of broad-spectrum antibiotic therapy. Broad-spectrum antibiotics can induce diarrhea not only by suppressing the bacteria causing the infection being treated, but also by suppressing the growth of bacteria present in the bowel. This upsets the natural balance of organisms. While not a common syndrome, pseudomembranous colitis is potentially serious and may occur secondary to treatment with almost any oral or parenteral antibiotic that alters colonic flora. The clinical spectrum is diverse; most often, diarrhea is profuse and watery without gross blood or mucus. Other associated signs and symptoms may include abdominal cramps and tenderness and fever. Antibiotic-associated colitis secondary to overgrowth of Clostridium difficile should be suspected in a child with diarrhea during or after (within four to six weeks) a course of antibiotic therapy. Such patients should be referred to a physician. Oral vancomycin is the drug of choice for pediatric patients with a stool culture positive for C. difficile.
OTC Antidiarrheal Agents Most cases of acute nonspecific diarrhea last one to two days, can be treated symptomatically with adequate hydration, and do not require a visit to the physician'S office. November 1992/ 888
Vol. NS32, No. 11
Although the symptoms of acute nonspecific diarrhea may be controlled with nonprescription medications, it is important to remember that the use of antidiarrheal agents is not a substitute for adequate hydration. The role of antidiarrheal agents in children with acute diarrhea is somewhat controversial. Medications that improve the clinical course of acute diarrhea without side effects may have an adjtillctive role to O RS in selected children. The phamlacist should not recommend the use of any antidiarrheal agents for children less than three years of age; these children should be referred to a physician for evaluation. Currently, nonprescription antidiarrheal products considered safe for use in children contain one of three active ingredients: activated attapulgite, loperamide, and polycarbophil (Table 5). Bismuth subsalicylate , an antisecretory agent that may also have some antimicrobial activity, has been shown to decrease the severity of diarrheal symptoms in a group of children studied in Chile. IS The Food and Drug Administration Gastrointestinal Drugs Advisory Committee has deferred its decision on use in children 3 to 12 years old because of insufficient data in this age group.16 The efficacy of kaolinpectin as compared to placebo was studied in children with an acute diarrheal illness. The group receiving kaolin-pectin had more formed stools, but the number of stools, fluid content of stools, and the weight of stools remained unchanged. 17 Nonprescription therapy with antidiarrheal agents should be limited to two days; if diarrhea persists despite therapy, the patient should be referred to a physician for further evaluation.
associated with diarrhea. Attapulgite is a naturally occurring hydrous magnesium aluminum silicate w ith a large surface area capable of adsorbing up to eigh t times its original weight in water. It is inert, is not absorbed systemically, and has few side effects. Loperamide
In combination with fluid replacement, loperamide is effective for the treatment of acute diarrhea in pediatric patients. 18 As a nonprescription product for use in children, loperamide is approved for the symptomatic relief of acute nonspecific diarrhea in children 6 to 12 years old. For dosing children less than 6 years old, package labeling refers parents to physicians for dosing; professional dosing is available for children 2 through 5 years old. The dnlg is not approved for use in children less than 2 years of age. Loperamide acts directly on the musculature of the small and large intestine to normalize peristaltic intestinal movements. 19-21 In addition, it normalizes the balance between absorption and the secretion of water and electrolytes. 22 Loperamide has been shown to decrease the frequency of bowel movements and to increase the consistency of stools. 23 Although this drug is systemically absorbed, serious adverse effects in children have not been reported. Polyc arboph il
Polycarbophil is a hydrophilic polyacrylic resin. As an absorbent, polycarbophil can absorb 60 times its original weight in water. Polycarbophil has been recommended for the treatment of both diarrhea (by increasing consistency, resulting in more formed stools) and constipation (by p rovid-
Adsorbents
General adsorbents are substances that, theoretically , adsorb toxins, viruses, and bacteria and prevent these substances from reaching the cell to produce their effect. The adsorption action of these agents is not specific; nutrients , enzymes, and other dnlgs, in addition to toxins and . bacteria, may be adsorbed. Adsorbents interfere with cultures for parasites and should not be used until a stool specimen for culture has been collected. Activated attapulgite is an adsorbent that is considered safe and effective in reducing the number of bowel movements, improving stool consistency, and relieving cramps Vol. NS32, No. 11 November 1992/889
Table 5
Antidiarrheal Agents Used in Children lNith Acute Diarrhea Antidiarrheal Agent
Age (years )
Dose
M ax Recommended Daily Dose (mg)
Attapulgite
3- 6
750 mg
2,250
6-12
1,500 mg
4,500
>12
3,000 mg
9,000
After each bowel movement or Q 2 hr prn Polycarbophil
Loperamide
3- 6
500 mg BID
1,000
6- 12
500 mg TI D
1,500
Children
0.4--0.8 mg/kg/ day in 2- 4 divided doses
0.8 mg/kg
Source: References 15, 24-27.
AMERICAN PHARMACY
ing bulk to stools). Like attapulgite, polycarbophil is not systemically absorbed, is metabolically inactive, and is essentially free of systemic side effects.
5. Santosham M, Greenough WB. Oral rehydration therapy: a global perspective. J Pediatr. 1991;118:S44-S50. 6. Leung AKC, Robson WLM. Acute diarrhea in children. What to do and what not to do. Postgrad Med. 1989;86:161 - 73. 7. Avery ME, Snyder JD. Oral therapy for acute diarrhea. The underused simple solution. N Engl J Med. 1990;323:891-3. 8. DeWitt TG. Acute diarrhea in children. Pediatr Rev. 1989;11:6-12. 9. Brook LS. Vomiting and diarrhea. Pediatrics. 1984;74:S950-S954.
Conclusion The pharmacist can playa vital role in helping to prevent the morbidity and mortality associated with diarrheal illness in children. Educating parents about the appropriate use of ORS and antidiarrheal agents is essential to prevent the uncommon, but potentially serious, complications associated with acute diarrhea. The future development of more effective oral rehydration solutions and vaccines effective against common enteric pathogens will have an important impact in reducing the incidence of diarrheal illness in children. Ina Lee Stile Calligaro, PharmD, is associate professor, Temple University School of Pharmacy, Philadelphia, Pa. The author gratefully acknowledges the assistance of Katherine V. Mann, PharmD, for her.. assistance in reviewing this manuscript.
10. American Academy of Pediatrics, Committee on Nutrition. Use of oral fluid therapy and posttreatment feeding following enteritis in children in a developed country. Pediatrics. 1985;75:358-61. 11. Lebenthal E, Lu RB. Glucose polymers as an alternative to glucose in oral rehydration solutions. J Pediatr. 1991;118:S62-S69. 12. Pizarro D, Posada G, Sandi L, et al: Rice-based oral electrolyte solutions for the management of infantile diarrhea. N Engl J Med. 1991; 324:517-21. 13. Brown KH. Dietary management of acute childhood diarrhea: Optimal timing of feeding and appropriate use of milks and mixed diets. J Pediatr.1991;118:S92-S98. 14. Nelson JD. Pocketbook of Pediatric Antimicrobial Therapy. 9th ed. Baltimore: Williams & Wilkins; 1991-1992:32,58. 15. Soriano-Brucher H, Avendano P, O'Ryan M, et al. Bismuth subsalicylate in the treatment of acute diarrhea in children: a clinical study. Pediatrics. 1991 ;87: 18-27. 16. Pickering LK. Therapy for acute infectious diarrhea in children. J Pediatr.1991;118:S118-S128. 17. Portnoy BL, DuPont HL, Pruitt D, et al. Antidiarrheal agents in the treatment of acute diarrhea in children. JAMA. 1976;236:844-6. 18. Chavarria AP. Control of pediatric diarrhea. Adv Ther. 1984;1:115-9. 19. Heel RC, Brogden RN, Speight TM, et al. Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs. 1978;15:33-52. 20. Niemegeers CJE. Pharmacology of antidiarrheal agents in vivo. Clin Res Rev. 1981;1:125-9. 21. Schiller LR, Santa Ana, CA, Morowski SG, et al. Mechanism of the antidiarrheal effect of loperamide. Gastroenterology. 1984;86:1475-80.
References
22. Hughes S, Higgs NB, Turnberg LA. Loperamide has antisecretory activity in the human jejunum in vivo. Gut. 1984;25:931-5.
1. Glass RI, Lew JF, Gangarosa RE, et al. Estimates of morbidity and morality rates for diarrheal diseases in American children. J Pediatr. 1991;118:S27-S33.
23. Diarrhoeal Diseases Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double blind, placebo controlled multicentre clinical trial. Br Med J. 1984;289:1263-7.
2. Sullivan P, Woodward WE, Pickering LK, et al. Longitudinal study of diarrheal diseases in daycare centers. Am J Pub Health. 1984;74:987-91.
24. Greene MG, ed. The Harriet Lane Handbook. 12th ed. St. Louis: Mosby Year Book; 1991:200.
3. Fitzgerald JF. Management of acute diarrhea. Pediatr Infect Dis J. 1989;8:564-9. 4. Guerrant RL, Hughes JM, Lima NL, et al. Diarrhea in developed and developing countries: Magnitude, special settings and etiologies. Rev Infect Dis. 1990;12:S41-S48.
AMERICAN PHARMACY
25. Benitz WE, Tatro DS. The Pediatric Drug Handbook. 2nd ed. Chicago: Year Book Medical Publishers, Inc; 1988:393. 26. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. Cleveland: Lexi-Comp Inc; 1992:273. 27. Handbook of Nonprescription Drugs. 9th ed. Washington DC: American Pharmaceutical Association; 1990:324- 5.
November 1992/890
Vol. NS32, No. 11
Introduction Acute nonspecific diarrhea usually is not life-threatening among children in developed countries. However, each year approxinlately 3.7 million children with this complaint visit a pediatrician and 10.6% of hospital admissions in children less than 5 years old result from complications of diarrhea. 1 Infants and children in daycare centers experience the highest incidence of diarrhea. Rates up to 3.64 cases per person per year were reported in one longitudinal study of diarrheal diseases in daycare centers. 2 Acute diarrheal illness results in many visits to the pediatrician 'S' office, and may result in requests for recommendations from pharmacists. Diarrhea is defmed as an increase in stool frequency and volume, and/or a decrease in consistency, when compared with the child's usual bowel habits. Acute nonspecific diarrhea may result from infection with a variety of microbial organisms or parasites, or from noninfectious causes such as side effects from medications or food intolerance. Infectious diarrhea, in children, is usually caused by viruses. The most common viral pathogens causing diarrhea include rotavirus, Norwalk-like viruses, and enteric adenovirus. 3,4 Antiviral agents effective against enteric viruses are unavailable; howVol. NS32, No. 11 November 1992/ 885
ever, a rotaviral vaccine is currently being studied. The availability of such a vaccine would be expected to significantly decrease the incidence of diarrhea in young children. Appropriate management of diarrhea in the initial stages can prevent fluid and electrolyte imbalances, which in extreme conditions can result in serious sequelae and even death. Many parents attempt to medicate their child before seeking medical attention. Pharmacists can advise parents if medical attention is warranted and can educate the parents about the proper management of mild disease to prevent more serious complications. This article focuses primarily on the nonprescription treatment of acute diarrhea in children.
Patient Assessment In children with diarrhea, dehydration and electrolyte loss are of particular concern. Young children may resist drinking extra fluids when they do not feel well, making fluid replaceAMERICANPHARMACY
ment more difficult and dehydration more likely. Because children also have increased metabolic rates as a result of their relatively large body surface areas, they need more fluid. 3 In addition, they may be less able to conserve fluid by not being able to concentrate urine maximally. It may be difficult for parents to determine if young children with diarrhea are dehydrated, because they generally do not verbalize their thirst. Parents of children with diarrhea need to be aware of the potential dangers of diarrhea and of the signs and symptoms of dehydration (Table 1). Moderate to severe dehydration must be managed by a physician, usually in a hospital setting. The parent should be questioned about the amolmt and nature of fluid intake, occurrence of vomiting, and frequency of urination. The presence of blood or mucus in the stool may indicate a bacterial infection requiring antibiotic therapy. Diarrhea also may be a manifestation of an infection at another site. Children with symptoms associated with illnesses of another organ system such as the respiratory or urinary tract should be evaluated by their physician. Before recommending a therapeutic approach for a child with diarrheal the pharmacist should question the parent to determine if a physician should be consulted (Table 2). The age of the patient, regardless of the character or chronicity of the diarrhea, is an important factor in determining whether to treat with nonprescription products or to refer the patient to a phYSician. Infants and children less than 3 years old should be referred to a physician because of the high risk of dehydration. In addition, children who are dehydrated, febrile, or immunocompromised should be referred to a phYSician.
Treatment
The treatment of acute diarrhea consists of the following therapeutic modalities: (1) fluid and electrolyte replacement, (2) early reintroduction of food, (3) antimicrobial therapy when indicated, and (4) antidiarrheal agents in selected patients.
Oral Rehydration Therapy The adnlinistration of an oral rehydration solution (ORS) to replace fluid and electrolyte losses is the foundation of therapy.6 Parents must understand that the role of ORS is to prevent dehydration and electrolyte imbalances rather than to hasten stool normalization. Osmotically balanced, commercially available electrolyte solutions (Table 3) are preferable to homemade solutions and should be recommended because the alTIounts of electrolytes are standardized and the carbohydrate content is appropriate to ensure maximum absorption of sodium and water. The major principle behind the use of ORS is the cotransport of sodium with glucose or another small organic molecule from the gastrointestinal tract into the bloodstream. Care should be given to avoid casual recommendation of "clear fluids " because they can be harmful if they contain inadequate amounts of electrolytes, excessive amounts of electrolytes or excessive amounts of carbohydrates (Table 3). In particular, clear fluids have a low sodium content and also lack potassium and base needed to prevent hypokalemia and
Table 2
Table 1
Signs and Symptoms Associated vvith Dehydration Degree Mild
Symptoms
Increased thirst Slightly dry mucous membranes
Patient Information Needed Before Recommending OTC Medications Age Duration of diarrhea and volume/frequency of diarrhea Presence of the following symptoms: Fever
Moderate
Loss of skin turgor Dry mucous membranes Sunken eyes Lack of tea rs
Temperature Vomiting Blood or mucus in the stool Recent antibiotic therapy
Depressed fontanelle in infants Decreased urine output
Travel history Similar illness in other family members
Severe
Cold extremities Decreased or absent urine output
Source: References 5 and 6.
AMERICANPHARMACY
Concomitant disease states that might compromise the patient's immune status Weight loss
November 1992/ 886
Vol. NS32, No. 11
acidosis. Use of homemade solutions may also result in serious electrolyte imbalances because of errors in measuring and mixing the ingredients. Guidelines for the appropriate use of ORS have been published by the American Academy of Pediatrics (AAP) Committee on Nutrition (Table 4).10 This committee recommends the administration of solutions containing 75-90 mEq/L of sodium to rehydrate patients and solutions containing 40-60 mEq/L of sodium for maintenance therapy to replace ongoing losses, thus preventing the child from becoming dehydrated. Solutions containing the higher sodium concentration may be used as maintenance therapy if alternated 1: 1 with a solution low in sodium such as water or breast milk. The AAP recommends a carbohydrate-to-sodium ratio of 2: 1 to prevent osmotic diarrhea from excessive carbohydrates. The volume of solutions containing 40-60 mEq/L of sodium should not exceed 150 mL/kg/day. Solutions containing higher concentrations of sodium should be limited to 75 mL/kg/day. The child may be given water or breast milk to satisfy thirst. Contraindications to the use of ORS include (1) severe dehydration that can result in shock secondary to hypo-
volemia, (2) glucose intolerance evidenced by an increase in stool output with reducing substances in the stool, or (3) the inability to tolerate oral fluids. 5 Vomiting is not a contraindication; in this situation, parents may be advised to administer 1 to 2 teaspoonfuls (5-10 mL) of ORS every 10-15 minutes. 1O The volume should be slowly increased as tolerated. Use of a dropper or spoon may facilitate the administration of fluids to infants and small children. A concern with the currently marketed solutions for oral rehydration is that they do not change the clinical course of the disease and have minimal nutritional value. Oral rehydration solutions that contain proteins or use glucose polymers derived from starch as the carbohydrate source are being evaluated in the treatment of acute diarrhea. Ricelyte, a recently marketed ORS, contains glucose polymers derived from rice synlps as the carbohydrate source. Preliminary data indicate that solutions containing glucose polymers~ may increase the absorption of fluid and electrolytes resulting in decreased stool volume and weight ·loss and shortened course of diarrhea. 11 ,12 The ideal composition of glucose polymers and amino acids is currently tmder investigation.
Table 3
Contents of Commonly Used Oral Rehydration Solutions CHO Product
(gIL)
Na (mEq/L)
K (mEq/L)
CI (mEq/L)
Base (mEq/L)
Osmolality (mOsm/L)
OTC WHO Solution * t '
20
90
20
80
30(C)
310
Infalytet
20
50
20
40
30(8)
270 290
Lytrent
20
50
25
45
30(C)
Pedialytet
25
45
20
35
30(C)
250
Rehydralyte * t
25
75
20
65
30(C)
305
Resolt
20
50
20
50
34(C)
270
Ricelytet
30
50
25
45
34(C)
200
120
3.5
28
30
0
730
Clear Liquids § Apple juice Chicken broth Cola
0
250
8
250
0
450
70-120
3
0.1
2
39(8)
750
50
24
3
17
0
330
150- 270
15- 27
0 .2
0
0
570-640
0
0
0
0
0
5
Gatorade Jello Tea
CHO= carbohydrate; B = bicarbonate; C= citrate
tReady to use.
* Use for rehydration, all other solutions for maintenance therapy.
§Content may vary with specific brand.
tMust be reconstituted with water.
Source: References 5, 7- 9.
Vol. NS32, No. 11 November 1992/ 887
AMERICAN PHARMACY
Reintroduction of Food The traditional approach in managing children with diarrhea has been to withhold solid food. However, the AAP recommends reintroducing food within 24 hours of the start of a diarrheal episode unless there is an absolute contraindication.1O Contraindications to refeeding are significant dehydration, severe vomiting, or gastrointestinal distention. Early reintroduction of solid foods is encouraged to prevent weight loss and the complications of starvation. There are two potential concerns with feeding children with diarrhea: (1) the food will further irritate the gastrointestinal tract and worsen the diarrhea, and (2) the absorption of proteins or other macromolecules could lead to food allergies. Although some investigators have reported an increase in stool volume with feeding,1O others have demonstrated a more rapid recovery in children given food. 13 The clinical or immtIDologic consequences of absorbing proteins and other macromolecules during an episode of gastroenteritis is not known. The benefit of providing adequate nutrition during diarrhea is thought to outweigh the potential disadvantages in most children. Breast milk is usually well tolerated and is the preferred form of nutrition in infants. 1O The use of lactose-containing formulas is controversial. Some children will develop a transient lactase deficiency during an infectious gastroenteritis Table 4
Recommendations for Oral Therapy in Treating Diarrhea 1. Recommended content for rehydration solutions: Carbohydrate 2-2.50/0 Sodium 75-90 mEq/L Potassium 20 mEq/L Base 20-300/0 of anions as acetate, bicarbonate, citrate, or lactate CHO: sodium ratio::; 2:1 2. Recommended content for maintenance solutions: Same as rehydration solutions except the concentration of sodium should be 40-60 mEq/L. Solutions with higher sodium concentrations may be used if alternated 1:1 with a low-sodium fluid. 3. Vomiting is not a contraindication to oral therapy. 4. Premixed rehydration solutions are preferred. Powdered rehydration products should only be dispensed if a container of the appropriate volume is provided for accurate dilution. 5 . Reintroduce food within 24 hours unless there is an absolute contraindication (see text). Source: Reference 10. Note: Recommendations developed by the American Academy of Pediatrics Committee on Nutrition.
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and may not tolerate lactose-containing formulas. Some clinicians restart infants on their usual formula, changing to a lactose-free product only if the diarrhea gets worse. Other pediatricians recommend restarting all infants on a short course of lactose-free formula. The formula should initially be diluted to half strength and the concentration increased as tolerated by the child. 6,10 The severity of the illness often dictates how quickly food is tolerated. An infant with mild diarrhea lasting less than a day will usually tolerate full feedings earlier than infants with a more virulent course. The parents of children who are started on a lactose-free formula should be advised that this is a transient problem and that lactose-containing foods can be reintroduced after a few weeks. This knowledge will avoid misconceptions regarding milk intolerance by the parents. Older children may be offered rice, bananas, applesauce, or toast. Apple juice should be avoided because of the high carbohydrate content.
Antimicrobial Therapy If children have a fever or have blood or mucus in the stools, their parents should be advised to take them to their physician, because these symptoms may indicate the diarrhea is caused by a bacterial pathogen. SpecifiC antibiotic therapy is indicated only after isolation of a pathogen that has been shown to respond to antimicrobial therapy. Several references are available for guidelines on the treatment of common bacterial and parasitic enteropathogens. 3,6,14 IrOnically, diarrhea may occur as a treatment-related side effect of broad-spectrum antibiotic therapy. Broad-spectrum antibiotics can induce diarrhea not only by suppressing the bacteria causing the infection being treated, but also by suppressing the growth of bacteria present in the bowel. This upsets the natural balance of organisms. While not a common syndrome, pseudomembranous colitis is potentially serious and may occur secondary to treatment with almost any oral or parenteral antibiotic that alters colonic flora. The clinical spectrum is diverse; most often, diarrhea is profuse and watery without gross blood or mucus. Other associated signs and symptoms may include abdominal cramps and tenderness and fever. Antibiotic-associated colitis secondary to overgrowth of Clostridium difficile should be suspected in a child with diarrhea during or after (within four to six weeks) a course of antibiotic therapy. Such patients should be referred to a physician. Oral vancomycin is the drug of choice for pediatric patients with a stool culture positive for C. difficile.
OTC Antidiarrheal Agents Most cases of acute nonspecific diarrhea last one to two days, can be treated symptomatically with adequate hydration, and do not require a visit to the physician'S office. November 1992/ 888
Vol. NS32, No. 11
Although the symptoms of acute nonspecific diarrhea may be controlled with nonprescription medications, it is important to remember that the use of antidiarrheal agents is not a substitute for adequate hydration. The role of antidiarrheal agents in children with acute diarrhea is somewhat controversial. Medications that improve the clinical course of acute diarrhea without side effects may have an adjtillctive role to O RS in selected children. The phamlacist should not recommend the use of any antidiarrheal agents for children less than three years of age; these children should be referred to a physician for evaluation. Currently, nonprescription antidiarrheal products considered safe for use in children contain one of three active ingredients: activated attapulgite, loperamide, and polycarbophil (Table 5). Bismuth subsalicylate , an antisecretory agent that may also have some antimicrobial activity, has been shown to decrease the severity of diarrheal symptoms in a group of children studied in Chile. IS The Food and Drug Administration Gastrointestinal Drugs Advisory Committee has deferred its decision on use in children 3 to 12 years old because of insufficient data in this age group.16 The efficacy of kaolinpectin as compared to placebo was studied in children with an acute diarrheal illness. The group receiving kaolin-pectin had more formed stools, but the number of stools, fluid content of stools, and the weight of stools remained unchanged. 17 Nonprescription therapy with antidiarrheal agents should be limited to two days; if diarrhea persists despite therapy, the patient should be referred to a physician for further evaluation.
associated with diarrhea. Attapulgite is a naturally occurring hydrous magnesium aluminum silicate w ith a large surface area capable of adsorbing up to eigh t times its original weight in water. It is inert, is not absorbed systemically, and has few side effects. Loperamide
In combination with fluid replacement, loperamide is effective for the treatment of acute diarrhea in pediatric patients. 18 As a nonprescription product for use in children, loperamide is approved for the symptomatic relief of acute nonspecific diarrhea in children 6 to 12 years old. For dosing children less than 6 years old, package labeling refers parents to physicians for dosing; professional dosing is available for children 2 through 5 years old. The dnlg is not approved for use in children less than 2 years of age. Loperamide acts directly on the musculature of the small and large intestine to normalize peristaltic intestinal movements. 19-21 In addition, it normalizes the balance between absorption and the secretion of water and electrolytes. 22 Loperamide has been shown to decrease the frequency of bowel movements and to increase the consistency of stools. 23 Although this drug is systemically absorbed, serious adverse effects in children have not been reported. Polyc arboph il
Polycarbophil is a hydrophilic polyacrylic resin. As an absorbent, polycarbophil can absorb 60 times its original weight in water. Polycarbophil has been recommended for the treatment of both diarrhea (by increasing consistency, resulting in more formed stools) and constipation (by p rovid-
Adsorbents
General adsorbents are substances that, theoretically , adsorb toxins, viruses, and bacteria and prevent these substances from reaching the cell to produce their effect. The adsorption action of these agents is not specific; nutrients , enzymes, and other dnlgs, in addition to toxins and . bacteria, may be adsorbed. Adsorbents interfere with cultures for parasites and should not be used until a stool specimen for culture has been collected. Activated attapulgite is an adsorbent that is considered safe and effective in reducing the number of bowel movements, improving stool consistency, and relieving cramps Vol. NS32, No. 11 November 1992/889
Table 5
Antidiarrheal Agents Used in Children lNith Acute Diarrhea Antidiarrheal Agent
Age (years )
Dose
M ax Recommended Daily Dose (mg)
Attapulgite
3- 6
750 mg
2,250
6-12
1,500 mg
4,500
>12
3,000 mg
9,000
After each bowel movement or Q 2 hr prn Polycarbophil
Loperamide
3- 6
500 mg BID
1,000
6- 12
500 mg TI D
1,500
Children
0.4--0.8 mg/kg/ day in 2- 4 divided doses
0.8 mg/kg
Source: References 15, 24-27.
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ing bulk to stools). Like attapulgite, polycarbophil is not systemically absorbed, is metabolically inactive, and is essentially free of systemic side effects.
5. Santosham M, Greenough WB. Oral rehydration therapy: a global perspective. J Pediatr. 1991;118:S44-S50. 6. Leung AKC, Robson WLM. Acute diarrhea in children. What to do and what not to do. Postgrad Med. 1989;86:161 - 73. 7. Avery ME, Snyder JD. Oral therapy for acute diarrhea. The underused simple solution. N Engl J Med. 1990;323:891-3. 8. DeWitt TG. Acute diarrhea in children. Pediatr Rev. 1989;11:6-12. 9. Brook LS. Vomiting and diarrhea. Pediatrics. 1984;74:S950-S954.
Conclusion The pharmacist can playa vital role in helping to prevent the morbidity and mortality associated with diarrheal illness in children. Educating parents about the appropriate use of ORS and antidiarrheal agents is essential to prevent the uncommon, but potentially serious, complications associated with acute diarrhea. The future development of more effective oral rehydration solutions and vaccines effective against common enteric pathogens will have an important impact in reducing the incidence of diarrheal illness in children. Ina Lee Stile Calligaro, PharmD, is associate professor, Temple University School of Pharmacy, Philadelphia, Pa. The author gratefully acknowledges the assistance of Katherine V. Mann, PharmD, for her.. assistance in reviewing this manuscript.
10. American Academy of Pediatrics, Committee on Nutrition. Use of oral fluid therapy and posttreatment feeding following enteritis in children in a developed country. Pediatrics. 1985;75:358-61. 11. Lebenthal E, Lu RB. Glucose polymers as an alternative to glucose in oral rehydration solutions. J Pediatr. 1991;118:S62-S69. 12. Pizarro D, Posada G, Sandi L, et al: Rice-based oral electrolyte solutions for the management of infantile diarrhea. N Engl J Med. 1991; 324:517-21. 13. Brown KH. Dietary management of acute childhood diarrhea: Optimal timing of feeding and appropriate use of milks and mixed diets. J Pediatr.1991;118:S92-S98. 14. Nelson JD. Pocketbook of Pediatric Antimicrobial Therapy. 9th ed. Baltimore: Williams & Wilkins; 1991-1992:32,58. 15. Soriano-Brucher H, Avendano P, O'Ryan M, et al. Bismuth subsalicylate in the treatment of acute diarrhea in children: a clinical study. Pediatrics. 1991 ;87: 18-27. 16. Pickering LK. Therapy for acute infectious diarrhea in children. J Pediatr.1991;118:S118-S128. 17. Portnoy BL, DuPont HL, Pruitt D, et al. Antidiarrheal agents in the treatment of acute diarrhea in children. JAMA. 1976;236:844-6. 18. Chavarria AP. Control of pediatric diarrhea. Adv Ther. 1984;1:115-9. 19. Heel RC, Brogden RN, Speight TM, et al. Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs. 1978;15:33-52. 20. Niemegeers CJE. Pharmacology of antidiarrheal agents in vivo. Clin Res Rev. 1981;1:125-9. 21. Schiller LR, Santa Ana, CA, Morowski SG, et al. Mechanism of the antidiarrheal effect of loperamide. Gastroenterology. 1984;86:1475-80.
References
22. Hughes S, Higgs NB, Turnberg LA. Loperamide has antisecretory activity in the human jejunum in vivo. Gut. 1984;25:931-5.
1. Glass RI, Lew JF, Gangarosa RE, et al. Estimates of morbidity and morality rates for diarrheal diseases in American children. J Pediatr. 1991;118:S27-S33.
23. Diarrhoeal Diseases Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double blind, placebo controlled multicentre clinical trial. Br Med J. 1984;289:1263-7.
2. Sullivan P, Woodward WE, Pickering LK, et al. Longitudinal study of diarrheal diseases in daycare centers. Am J Pub Health. 1984;74:987-91.
24. Greene MG, ed. The Harriet Lane Handbook. 12th ed. St. Louis: Mosby Year Book; 1991:200.
3. Fitzgerald JF. Management of acute diarrhea. Pediatr Infect Dis J. 1989;8:564-9. 4. Guerrant RL, Hughes JM, Lima NL, et al. Diarrhea in developed and developing countries: Magnitude, special settings and etiologies. Rev Infect Dis. 1990;12:S41-S48.
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25. Benitz WE, Tatro DS. The Pediatric Drug Handbook. 2nd ed. Chicago: Year Book Medical Publishers, Inc; 1988:393. 26. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. Cleveland: Lexi-Comp Inc; 1992:273. 27. Handbook of Nonprescription Drugs. 9th ed. Washington DC: American Pharmaceutical Association; 1990:324- 5.
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