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Treatment: Diarrhea

Prevention

Acute viral diarrheal illness often occurs in day care centers and nursing homes. As person-to-person contact is the mechanism by which viral disease spreads, isolation techniques must be initiated. For bacterial, parasite, and protozoal infections, strict food handling, sanitation, water, and other environmental hygiene practices can prevent transmission. If diarrhea is secondary to another illness, controlling the primary condition is necessary. Antibiotics and bismuth subsalicylate are advocated to prevent traveler’s diarrhea, in conjunction with treatment of drinking water and caution with consumption of fresh vegetables.

Desired Outcome

If prevention is not successful and diarrhea occurs, therapeutic goals are to (a) manage thediet; (b)preventexcessive water, electrolyte, and acid-base disturbances; (c) provide symptomatic relief; (d) treat curable causes; and (e) manage secondary disorders causing diarrhea (Figs. 1 and 2).

Clinicians must clearly understand that diarrhea, like a cough, may be a body defense mechanism for ridding itself of harmful substances or pathogens. The correct therapeutic response is not necessarily to stop diarrhea at all costs.

Nonpharmacologic Management

Dietary management is a first priority in the treatment of diarrhea. Most clinicians recommend discontinuing consumption of solid foods and dairy products for 24 hours. However, fasting is of questionable value, as this treatment modality has not been extensively studied. In osmotic diarrhea, these maneuvers control the problem. If the mechanism is secretory, diarrhea persists. For patients experiencing nausea and/or vomiting, a mild, digestible low-residue diet should be administered for 24 hours. If vomiting is present and uncontrollable with antiemetics (see site on nausea and vomiting), nothing is taken by mouth. As bowel movements decrease, a bland diet is begun.

Feeding should continue in children with acute bacterial diarrhea. Fed children have less morbidity and mortality, whether or not they receive oral rehydration fluids. Studies are not available in the elderly or in other high-risk groups to determine the value of continued feeding in bacterial diarrhea.

Figure 1. Recommendations for treating acute diarrhea. Follow these steps: (1) Perform a complete history and physical examination. (2) Is the diarrhea acute or chronic? If chronic diarrhea, go to Fig. 2. (3) If acute diarrhea, check for fever and/or systemic signs and symptoms (i.e., toxic patient). If systemic illness (fever, anorexia, or volume depletion), check for an infectious source. If positive for infectious diarrhea, use appropriate antibiotic/anthelmintic drug and symptomatic therapy. If negative for infectious cause, use only symptomatic treatment. (4) If no systemic findings, then use symptomatic therapy based on severity of volume depletion, oral or parenteral fluid/electrolytes, an-tidiarrheal agents (see Table 4), and diet.

Treatment: Diarrhea

Figure 2. Recommendations for treating chronic diarrhea. Follow these steps: (1) Perform a careful history and physical examination. (2) The possible causes of chronic diarrhea are many. These can be classified into intestinal infections (bacteri al or protozoal), i nflammatory d isease (Croh n’s d isease or u Icerati ve colitis), malabsorption (lactose intolerance), secretory hormonal tumor (intestinal carcinoid tumor or VIPoma), drug (antacid), factitious (laxative abuse), or motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyperthyroidism). (3) If the diagnosis is uncertain, selected appropriate diagnostic studies should be ordered. (4) Once diagnosed, treatment is planned for the underlying cause with symptomatic antidiarrheal therapy. (5) If no specific cause can be identified, symptomatic therapy is prescribed.

Water And Electrolytes

Rehydration and maintenance of water and electrolytes are primary treatment goals until the diarrheal episode ends. If the patient is volume depleted, rehydration should be directed at replacing water and electrolytes to normal body composition. Then water and electrolyte composition are maintained by replacing losses. Many patients will not develop volume depletion and therefore will only require maintenance fluid and electrolyte therapy. Parenteral and enteral routes may be used for supplying water and electrolytes. If vomiting and dehydration are not severe, enteral feeding is the less costly and preferred method. In the United States, many commercial oral rehydration preparations are available (Table 3).

Water And Electrolytes

Because of concerns about hypernatremia, physicians continue to hospitalize and intravenously correct fluid and electrolyte deficits in severe dehydration. Oral solutions are strongly recommended. In developing countries, the World Health Organization Oral Rehydration Solution (WHO-ORS) saves the lives of millions of children annually.

During diarrhea, the small intestine retains its ability to actively transport monosaccharides such as glucose. Glucose actively carries sodium with water and other electrolytes. Because the WHO-ORS has a high sodium concentration, U.S. physicians have been reluctant to use it in well-nourished children. Yet controlled comparative studies describe more favorable results with the WHO-ORS than with parenteral fluids. Amino acids promote sodium transport and act as an antisecretory agent. Researchers have added glycine to oral rehydration solution in an attempt to create a “super-ORS.” Reports, however, are disappointing, because glycine causes an osmotic diarrhea and diuresis in experimental concentrations.

Table 3 Oral Rehydration Solutions

  WHO-ORSa Pedialyteb (Ross) Rehydralyte (Ross) Infalyte (Mead Johnson) Resolb (Wyeth)
Osmolality (mOsm/L) 333 249 304 200 269
Carbohydrates (g/L) 20 25 25 30c 20
Calories (cal/L) 85 100 100 126 80
Electrolytes (mEq/L)          
Sodium 90 45 75 50 50
Potassium 20 20 20 25 20
Chloride 80 35 65 45 50
Citrate 30 30 34 34
Bicarbonate 30
Calcium 4
Magnesium 4
Sulfate
Phosphate 5

aWorld Health Organization Oral Rehydration Solution.
bCarbohydrate is glucose.
cRice syrup solids are carbohydrate source.

Rice-based oral solution is a hyposmotically active substrate that elutes glucose without increasing stool or urine outflows. Pizarro and associates reported effective rehydration of infants with acute diarrhea using a rice-based solution. They also reported decreased stool output and greater absorption and retention of fluid and electrolytes. In summary, oral rehydration solution is a lifesaving treatment for millions afflicted in developing countries. Acceptance in developed countries is less enthusiastic; however, the advantage of this product in reducing hospitalizations may prove its use as a cost-effective alternative, saving millions of dollars in health care expenditures.

Pharmacologic Therapy

Various drugs have been used to treat diarrheal attacks (Table 4). These drugs are grouped into several categories: antimotility, adsorbents, antisecretory compounds, antibiotics, enzymes, and intestinal microflora. Usually these drugs are not curative but palliative.

Opiates And Their Derivatives

Opiates and opioid derivatives (a) delay the transit of intraluminal contents or (b) increase gut capacity, prolonging contact and absorption. Enkephalins, endogenous opioid substances, regulate fluid movement across the mucosa by stimulating absorptive processes. Limitations to the use of opiates include an addiction potential (a real concern with long-term use) and worsening of diarrhea in selected infectious diarrhea.

Most opiates act through peripheral and central mechanisms with the exception of loperamide, which acts only peripherally. Loperamide is antisecretory; it inhibits the calcium-binding protein calmodulin, controlling chloride secretion. Loperamide, available as 2-mg capsules or 1 mg/5 mL solution (both are nonprescription products), is suggested for managing acute and chronic diarrhea. The usual adult dose is initially 4 mg orally, followed by 2 mg after each loose stool, up to 16 mg/day. Used correctly, this agent has rare side effects such as dizziness and constipation. If the diarrhea is concurrent with a high fever or bloody stool, the patient should be referred to a physician. Also, diarrhea lasting 48 hours beyond initiating loperamide warrants medical attention. Loperamide can also be used in traveler’s diarrhea. It is comparable to bismuth subsalicylate for treatment of this disorder.

Diphenoxylate is available as 2.5-mg tablets and as a 2.5 mg/ 5 mL solution. A small amount of atropine (0.025 mg) is included to discourage abuse. In adults, when taken as 2.5 to 5 mg three or four times daily, not to exceed a 20-mg total daily dose, diphenoxylate is rarely toxic. Some patients may complain of atropinism (blurred vision, dry mouth, and urinary hesitancy). Like loperamide, it should not be used in patients at risk of bacterial enteritis with Escherichia coli, Shigella, or Salmonella.

Difenoxin, a diphenoxylate derivative, is also combined with atropine and has the same uses, precautions, and side effects. Marketed as 1-mg tablet, the adult dosage is 2 mg initially followed by 1 mg after each loose stool, not to exceed 8 mg/day.

Paregoric, tincture of opium, is marketed as a 2 mg/5 mL solution and is indicated for managing both acute and chronic diarrhea. It is not widely prescribed today because of its abuse potential.

Adsorbents

Adsorbents are used for symptomatic relief. These products, many not requiring a prescription, are nontoxic, but their effectiveness remains unproven. Adsorbents are nonspecific in their action; they adsorb nutrients, toxins, drugs, and digestive juices. Coadministration with other drugs reduces their bioavailability. The Food and Drug Administration over-the-counter review panel recommends only polycarbophil as an effective adsorbent.

Adsorbents

Polycarbophil absorbs 60 times its weight in water and can be used to treat both diarrhea and constipation. It is a nonprescription product and is sold as 500-mg chewable tablets. This hydrophilic nonabsorbable product is safe and may be taken four times daily, up to 6 g/day in adults.

Table 4. Selected Antidiarrheal Preparations

  Dose Form Adult Dose
Antimotility
Diphenoxylate 2.5 mg/tablet2.5 mg/5 mL 5 mg four times daily; do not exceed 20 mg/day
Loperamide 2 mg/capsule1 mg/5 mL Initially 4 mg, then 2 mg after each loose stool; do not exceed 16 mg/day
Paregoric 2 mg/5 mL (morphine) 5-10 mL 1-4 times daily
Opium tincture 5 mg/mL (morphine) 0.6 mL four times daily
Difenoxin 1 mg/tablet Two tablets, then one tablet after each loose stool; up to 8 tablets/day
Adsorbents
Kaolin-pectin mixture 5.7 g kaolin + 130.2 mg pectin/30 mL 30-120 mL after each loose stool
Polycarbophil 500 mg/tablet Chew 2 tablets four times daily or after each loose stool; do not exceed 12 tablets/day
Attapulgite 750 mg/15 mL300 mg/7.5 mL

750 mg/tablet

600 mg/tablet

300 mg/tablet

1200-1500 mg after each loose bowel movement or every 2 hours; up to 9000 mg/day
Antisecretory
Bismuth subsalicylate 1050mg/30 mL262 mg/15 mL

524 mg/15 mL

262 mg/tablet

Two tablets or 30 mL every 30 min to 1 h as needed up to 8 doses/day
Enzymes (lactase) 1250 neutral lactase units/4 drops3300 FCC lactase units per tablet 3^f drops taken with milk or dairy product 1 or 2 tablets as above
Bacterial replacement (Lactobacillus acidophilus, Lactobacillus bulgaricus)   2 tablets or 1 granule packet 3 to 4 times daily; give with milk, juice, or water

Antisecretory Agents

Bismuth subsalicylate appears to have antisecretory, antiinflammatory, and antibacterial effects. As a nonprescription product, it is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler’s diarrhea. Bismuth subsalicylate dosage strengths are 262-mg chewable tablets, 262 mg/5 mL liquid, and 524 mg/15 mL liquid. The usual adult dose is 2 tablets or 30 mL every 30 minutes to 1 hour up to 8 doses per day.

Bismuth subsalicylate contains multiple components that might be toxic if given excessively to prevent or treat diarrhea. For instance, an active ingredient is salicylate, which may interact with anticoagulants or may produce salicylism (tinnitus, nausea, and vomiting). Bismuth reduces tetracycline absorption and may interfere with select gastrointestinal radiographic studies. Patients may complain of a darkening of the tongue and stools with repeat administration. Salicylate can induce gout attacks in susceptible individuals.

Bismuth subsalicylate suspension has been evaluated in the treatment of secretory diarrhea of infectious etiology as well. In a dose of 30 mL every 30 minutes for eight doses, unformed stools decrease in the first 24 hours. Bismuth subsalicylate may also be effective in preventing traveler’s diarrhea.

Octreotide, a synthetic octapeptide analog of endogenous somatostatin, is prescribed for the symptomatic treatment of carcinoid tumors and vasoactive intestinal peptide-secreting tumors (VIPomas). Metastatic intestinal carcinoid tumors secrete excessive amounts of vasoactive substances, including histamine, bradykinin, serotonin, and prostaglandins. Primary carcinoid tumors occur throughout the gastrointestinal tract, with most in the ileum. Predominant signs and symptoms experienced by patients with these tumors are attributable to excessive concentrations of 5-hydroxytryptophan and serotonin. The totality of their clinical effects is termed the carcinoid syndrome. Paroxysmal vasomotor attacks characterize carcinoid syndrome, most notably sudden red to purple flushing of the face and neck. These attacks are often caused by emotional outbursts or by ingestion of food or alcohol. Some patients have a violent, watery diarrhea with abdominal cramping. Initially, diarrhea might be managed with various agents such as codeine, diphenoxylate, cyproheptadine, methysergide, phenoxybenzamine, or methyldopa. Recently, octreotide has become the drug of choice.

Octreotide blocks the release of serotonin and many other active peptides and has been effective in controlling diarrhea and flushing. It is reported to have direct inhibitory effects on intestinal secretion and stimulatory effects on intestinal absorption. Non-gastrin-secreting adenomas of the pancreas are tumors associated with profuse watery diarrhea. This condition has been referred to as Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, pancreatic cholera, watery diarrhea syndrome, and VIPoma. Excessive secretion of vasoactive intestinal peptide (VIP) from a retroperitoneal or pancreatic tumor produces most of the clinical features. Excessive VIP is isolated in about half of patients, along with numerous other peptide hormones (peptide histidine methionine [PHM], serotonin, somatostatin, gastrin, and glucagon). Surgical tumor dissection is the treatment of choice. In nonsurgical candidates, the profuse watery diarrhea and other symptoms commonly encountered are managed with octreotide.

The dose of octreotide varies with the indication, disease severity, and patient response. For managing diarrhea and flushing associated with carcinoid tumors in adults, the initial dosage range is 100 to 600 meg/day in two to four divided doses subcutaneously for 2 weeks. For controlling secretory diarrhea of VIPomas, the dosage range is 200 to 300 meg/day in two to four divided doses for 2 weeks. Some patients may require higher doses for symptomatic control. Patients responding to these initial doses may be switched to Sandostatin LAR Depot, a long-acting octreotide formulation. This product consists of microspheres containing the drug. Initial doses consist of 20 mg given intramuscularly intragluteally at 4-week intervals for 2 months. It is recommended that during the first 2 weeks of therapy the short-acting formulation also be administered subcutaneously. At the end of 2 months, patients with good symptom control may have the dose reduced to 10 mg every 4 weeks, while those without sufficient symptom control may have the dose increased to 30 mg every 4 weeks. For patients experiencing recurrence of symptoms on the 10-mg dose, dosage adjustment to 20 mg should be made. It is not uncommon for patients with carcinoid tumors or VIPomas to experience periodic exacerbation of symptoms. Subcutaneous octreotide for several days should be reinstituted in these individuals. In so-called carcinoid crisis, octreotide is given as an intravenous infusion at 50 meg/h for 8 to 24 hours.

Because octreotide inhibits many other gastrointestinal hormones, it has a variety of intestinal side effects. With prolonged use, gallbladder and biliary tract complications such as cholelithiasis have been reported. About 5% to 10% of patients complain of nausea, diarrhea, and abdominal pain. Local injection pain occurs with about an 8% incidence. With high doses, octreotide may reduce dietary fat absorption, leading to steatorrhea.

Two other somatostatin analogs, lanreotide and vapreotide, have been studied. Lanreotide is indicated for patients with carcinoid tumors in a dose of 30 mg intramuscularly (as a depot) every 14 days. If necessary the dose can be increased to 30 mg intramuscular every 7 to 10 days. Vapreotide is an orphan drug that is indicated for pancreatic and gastrointestinal fistulas.

Miscellaneous Products

Lactobacillus preparations replace colonic microflora. This supposedly restores normal intestinal function and suppresses the growth of pathogenic microorganisms. However, a dairy product diet containing 200 to 400 g of lactose or dextrin is equally effective in producing recolonization of normal flora. The dosage varies depending on the brand used and lactobacillus preparations should be administered with milk, juice, water, or cereal. Intestinal flatus is the primary patient complaint experienced with this modality.

Anticholinergic drugs such as atropine block vagal tone and prolong gut transit time. Drugs with anticholinergic properties are present in many nonprescription products. Their value in controlling diarrhea is questionable and limited due to side effects. To stop diarrhea, clinicians have been falsely taught to dose anticholinergics until they decrease salivary and sweat secretion. Angle-closure glaucoma, selected heart diseases, and obstructive uropathies are relative contraindications to the use of anticholinergic agents.

Lactase enzyme products are helpful for patients experiencing diarrhea secondary to lactose intolerance. Lactase is required for carbohydrate digestion. When a patient lacks this enzyme, eating dairy products causes an osmotic diarrhea. Several products are available for use each time a dairy product, especially milk or ice cream, is consumed.

Clinical Controversy

Long-term use of oral opiates is not routinely recommended for several pharmacologic reasons. Some opioids such as morphine and codeine have the tendency to cause constipation by slowing down the peristaltic action of the bowels, which can also result in a functional ileus. This effect can be minimized by administering laxatives and/or stool softeners in patients who require longer-term opiate therapy. Prokinetic agents may also be helpful in treating opiate-related constipation.

Investigational Drugs

Many experimental drugs have been used to control diarrhea. Phenothiazines, β-blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and a-adrenergic agonists are only a few agents under investigation in either animals or humans. Nifalatide is an enkephalin analog that delays the onset of castor oil-induced diarrhea and decreases stool frequency. Dizziness and dry mouth are frequent side effects. Enkephalinase inhibitors (e.g., acetorphan or racecadotril) are other therapeutic options that reduce hypersecretion of water and electrolytes into the intestinal lumen. Prostaglandin inhibitors, aspirin and its analogs, and indomethacin are safe and effective in childhood gastroenteritis; studies in animals support indomethacin use in enteropathogen secretory states such as Vibrio cholerae infection.

Vaccines are a new therapeutic frontier in controlling infectious diarrheas, especially in developing countries. Cholera vaccine, which is available in the United States in the parenteral form of whole-cell inactivated bacteria, yields some protection but is not totally effective and does not prevent transmission. However, live oral vaccine is thought to be protective against V. cholerae. Oral Shigella vaccine, although effective under field conditions, requires five doses and repeat booster doses, thereby limiting its practicality for use in developing nations. With about 1,500 serotypes for Salmonella, a vaccine is not currently available. There are three parenteral typhoid vaccine formulations available in the United States. In addition, an oral vaccine of S. typhi (Tyza) is now available and is administered in 4 doses on days 1, 3, 5, and 7, to be completed at least 1 week before exposure. Rotavirus vaccine is effective in infants and children, and is administered as a three-oral dose sequence.

Evaluation of Therapeutic Outcomes

General Outcomes Measures

Therapeutic outcomes are directed toward key symptoms, signs, and laboratory studies. Constitutional symptoms usually improve within 24 to 72 hours. Monitoring for changes in the frequency and character of bowel movements on a daily basis in conjunction with vital signs and improvement in appetite are of utmost importance. Also, the clinician needs to monitor body weight, serum osmolality, serum electrolytes, complete blood cell counts, urinalysis, and culture results (if appropriate).

Acute Diarrhea

Most patients with acute diarrhea experience mild to moderate distress. In the absence of moderate to severe dehydration, high fever, and blood or mucus in the stool, this illness is usually self-limiting within 3 to 7 days. Mild to moderate acute diarrhea is usually managed on an outpatient basis with oral rehydration, symptomatic treatment, and diet. Elderly persons with chronic illness and infants may require hospitalization for parenteral rehydration and close monitoring.

 

Severe Diarrhea

In the urgent/emergent situation, restoration of the patient’s volume status is the most important outcome. Toxic patients (fever, dehydration, hematochezia, or hypotension) require hospitalization, intravenous fluids and electrolyte administration, and empiric antibiotic therapy while awaiting culture and sensitivity results. With timely management, these patients usually recover within a few days.

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