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LAXATIVES-GENERAL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Laxatives are primarily used to treat acute or chronic constipation. Lactulose is also used to treat or prevent hepatic encephalopathy. This management is intended to be used when the mechanism of laxative effects is unknown or is not included in the bulk-forming, emollient, stimulant, or saline class.

Specific Substances

    A) DEHYDROCHOLIC ACID (synonym)
    1) 3,7,12-Trioxo-5beta-cholan-24-oic acid
    2) Chologon
    3) Triketocholanic acid
    4) CAS 81-23-2
    LACTULOSE (synonym)
    1) 4-O-beta-D-Galactopyranosyl-D-fructose
    2) CAS 4618-18-2
    LACTITOL (synonym)
    1) E966
    2) beta-Galactosido-sorbitol
    3) Lactit
    4) Lactitolum
    5) Lactobiosit
    6) Lactositol
    7) CAS 585-86-4
    GENERAL TERMS
    1) Laxative
    2) Laxative (General)
    3) Laxatives

Available Forms Sources

    A) FORMS
    1) Lactulose is available as 10 g/15 mL oral solution, 10 g/15 mL oral syrup, and 10 g/packet and 20 g/packet oral powder for suspension (Prod Info lactulose oral solution, 2007; Prod Info Enulose oral, rectal solution, 2006).(Prod Info KRISTALOSE(TM) oral solution, 2006).
    2) Lactitol is not available in the US. It is a disaccharide analogue of lactulose with similar actions and uses (Sweetman, 2004).
    3) Dehydrocholic acid is also not available in the United States.
    B) USES
    1) Lactulose solution is used to treat chronic constipation. It is also indicated for the prevention and treatment of hepatic encephalopathy (Prod Info lactulose oral solution, 2007; Prod Info Enulose oral, rectal solution, 2006).(Prod Info KRISTALOSE(TM) oral solution, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Laxatives are used primarily to treat acute or chronic constipation. Lactulose is also used to treat or prevent hepatic encephalopathy. This management is intended to be used when the mechanism of laxative effects is unknown or is not included in the bulk-forming, emollient, stimulant, or saline class.
    B) PHARMACOLOGY: Lactulose is a synthetic disaccharide. Bacteria in the colon degrade lactulose into lactic acid, acetic acid, and formic acid resulting in an increase in osmotic pressure and acidification of intestinal contents which in turn, softens the stool by promoting stool water content.
    C) TOXICOLOGY: Since stool water increases proportionately greater than stool sodium excretion, hypernatremia and dehydration can result.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) For the most part, laxatives are locally acting agents and except under extremely rare circumstances are not expected to produce symptoms associated with systemic poisoning.
    2) LACTULOSE: Initially, lactulose can cause transient flatulence and intestinal cramps. Nausea and vomiting may also occur. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia. Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a man with hepatic encephalopathy and adynamic ileus.
    F) WITH POISONING/EXPOSURE
    1) LACTULOSE: Nausea, vomiting, diarrhea, and abdominal pain may occur with overdose of lactulose. Diarrhea may develop with overdose and can lead to loss of fluids, hypokalemia, and hypernatremia.
    0.2.20) REPRODUCTIVE
    A) Administration of 10 to 20 times the expected human dose to pregnant mice during organogenesis demonstrated no adverse or teratogenic effects. Lactulose is in pregnancy category B.

Laboratory Monitoring

    A) Monitor fluid status and serum electrolytes in severely symptomatic patients. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia.
    B) Monitor vital signs in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Diarrhea: Rapid correction of fluid and electrolyte deficits with oral or IV fluid therapy and careful monitoring of intake and output are essential. Restrict solid food and maintain high fluid intake until diarrhea resolves. Oral fluid should consist of polyionic hypotonic solution containing appropriate electrolytes. Monitor serum electrolytes to evaluate the extent of hypokalemia and hypernatremia.
    B) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not indicated as toxicity is self-limited.
    2) HOSPITAL: Gastrointestinal decontamination is generally not indicated unless more toxic co-ingestants are involved.
    C) AIRWAY MANAGEMENT
    1) Ingestion of these products should not require airway management.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION PROCEDURE
    1) Enhanced elimination is generally unnecessary except in patients with renal failure and severe hypernatremia.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or have mild diarrhea after inadvertent overdose can be monitored at home.
    2) ADMISSION CRITERIA: Patients with significant hypernatremia, confusion, or dehydration should be admitted, observed, and carefully rehydrated.
    3) OBSERVATION CRITERIA: Patients with deliberate overdose or severe diarrhea should be referred to a healthcare facility for evaluation.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. Severe toxicity is rare.
    G) PITFALLS
    1) Pitfalls in managing these patients include missing alternative diagnoses or not recognizing iatrogenic overdoses. When managing a suspected overdose, the possibility of multi-drug involvement should be considered. These products may be surreptitiously abused by patients with eating disorders or other psychiatric conditions.
    H) PHARMACOKINETICS
    1) LACTULOSE: Lactulose is minimally absorbed following oral administration. Metabolism: Lactulose is a disaccharide that is broken down by colonic bacteria into lactic acid, acetic acid, formic acid, and carbon dioxide. Excretion: Less than 0.4% of a 8 gram dose was excreted in the urine within 24 hours; which increased to 2% of a 97 gram dose.
    I) DIFFERENTIAL DIAGNOSIS
    1) Gastroenteritis, food poisoning, parasites, infectious disease or drugs or chemicals that cause nausea, vomiting, or diarrhea.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Doses of lactulose solution in excess of 100 mL/day may be associated with diarrhea and hypernatremia. Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a man with hepatic encephalopathy and adynamic ileus. A patient developed pneumatosis coli after receiving lactulose 240 mL/day for the early manifestations of portal-systemic encephalopathy.
    B) THERAPEUTIC DOSES: ADULTS: Constipation: 15 to 30 mL (10 to 20 grams lactulose) orally once daily for 24 to 48 hours; may increase to 60 mL (40 grams lactulose)/day if needed. CHILDREN: 6 months to 3 years: 5 to 10 mL (3.33 to 6.66 grams lactulose) orally daily. Higher doses are used for hepatic encephalopathy: ADULTS: up to 45 mL every hour until laxative effect, then 3 to 4 times daily; CHILDREN: infants: 2.5 to 10 mL in divided doses; older children and adolescents: up to 90 mL/day.

Clinical Effects

Summary Of Exposure

    A) USES: Laxatives are used primarily to treat acute or chronic constipation. Lactulose is also used to treat or prevent hepatic encephalopathy. This management is intended to be used when the mechanism of laxative effects is unknown or is not included in the bulk-forming, emollient, stimulant, or saline class.
    B) PHARMACOLOGY: Lactulose is a synthetic disaccharide. Bacteria in the colon degrade lactulose into lactic acid, acetic acid, and formic acid resulting in an increase in osmotic pressure and acidification of intestinal contents which in turn, softens the stool by promoting stool water content.
    C) TOXICOLOGY: Since stool water increases proportionately greater than stool sodium excretion, hypernatremia and dehydration can result.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) For the most part, laxatives are locally acting agents and except under extremely rare circumstances are not expected to produce symptoms associated with systemic poisoning.
    2) LACTULOSE: Initially, lactulose can cause transient flatulence and intestinal cramps. Nausea and vomiting may also occur. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia. Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a man with hepatic encephalopathy and adynamic ileus.
    F) WITH POISONING/EXPOSURE
    1) LACTULOSE: Nausea, vomiting, diarrhea, and abdominal pain may occur with overdose of lactulose. Diarrhea may develop with overdose and can lead to loss of fluids, hypokalemia, and hypernatremia.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) DEHYDROCHOLIC ACID
    a) Cardiac effects in humans following sodium dehydrocholate 15 mg/kg intravenously have included hypotension, hypertension, cyanosis, bradycardia, tachycardia, and premature ventricular contractions.
    b) The frequent finding of negative allergic histories and skin tests suggest that in some patients the mechanism is a direct cardio-toxic effect, rather than allergic (Patton, 1970).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported (Prod Info lactulose oral solution, 2007).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are frequent findings of overdose.
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea occurs frequently with overdose (Prod Info lactulose oral solution, 2007). The presence of lactulose in some infant formulas was associated with the development of persistent diarrhea (Hendrickse et al, 1977).
    C) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Lactulose can cause transient flatulence and intestinal cramps (Prod Info lactulose oral solution, 2007; Stone-Dorshow & Levitt, 1987).
    D) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain and cramping may occur (Prod Info lactulose oral solution, 2007).
    E) PNEUMATOSIS CYSTOIDES INTESTINALIS
    1) WITH THERAPEUTIC USE
    a) PNEUMATOSIS CYSTOIDES: Submucosal gas-filled cysts in the colon have been reported in patients receiving lactulose (Janssen et al, 1987; Zimmerman et al, 1979).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A patient developed pneumatosis coli after receiving lactulose for the early manifestations of portal-systemic encephalopathy. The authors considered this to be a localized effect of excessive lactulose dosage (240 mL/day) in which ammonia was forced into the wall of the bowel (Zimmerman et al, 1979).
    F) DRUG-INDUCED MEGACOLON
    1) WITH THERAPEUTIC USE
    a) Colonic dilation may occur with therapeutic doses of lactulose (Wright, 1988).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a 31-year-old man with hepatic encephalopathy and adynamic ileus (Mann et al, 1985).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) SODIUM DEHYDROCHOLATE: Anaphylactoid reactions, consisting of circulatory collapse, acute laryngeal edema, urticaria, and bronchospasm, have been reported following intravenous injection of sodium dehydrocholate (Peters & Witten, 1971; Norman, 1947; Elliott et al, 1960; Coggins et al, 1953; Patton, 1970; Martinez-Lopez et al, 1962; Sanchez & Morris, 1954; Suckle, 1950; Leys, 1944).

Reproductive

    3.20.1) SUMMARY
    A) Administration of 10 to 20 times the expected human dose to pregnant mice during organogenesis demonstrated no adverse or teratogenic effects. Lactulose is in pregnancy category B.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) LACTULOSE -
    a) MICE - Administration of 10 to 20 times the expected human dose to pregnant mice during organogenesis demonstrated no adverse or teratogenic effects (Avery et al, 1972).
    b) RATS - No teratogenic effects were observed in rats following administration of 6 mL/kg (Avery et al, 1972).
    c) RABBITS - No teratogenic effects were observed in rabbits following an unspecified dose (Avery et al, 1972).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    LACTULOSEB
    Reference: Briggs et al, 1998.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid status and serum electrolytes in severely symptomatic patients. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia.
    B) Monitor vital signs in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant hypernatremia, confusion, or dehydration should be admitted, observed, and carefully rehydrated.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or have mild diarrhea after inadvertent overdose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. Severe toxicity is exceedingly rare.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose or severe diarrhea should be referred to a healthcare facility for evaluation.

Monitoring

    A) Monitor fluid status and serum electrolytes in severely symptomatic patients. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia.
    B) Monitor vital signs in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not indicated as toxicity is self-limited.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Gastrointestinal decontamination is generally not indicated unless more toxic co-ingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor fluid and serum electrolytes in severely symptomatic patients. Diarrhea may develop with excessive doses and can lead to loss of fluids, hypokalemia, and hypernatremia.
    2) Monitor vital signs in symptomatic patients.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) DIARRHEA: Rapid correction of fluid and electrolyte deficits with oral or IV fluid therapy and careful monitoring of intake and output are essential. Restrict solid food and maintain high fluid intake until diarrhea resolves. Oral fluid should consist of polyionic hypotonic solution containing appropriate electrolytes.
    2) Monitor serum electrolytes to evaluate the extent of hypokalemia and hypernatremia.
    3) MILD DIARRHEA: Although oral rehydration requires careful management and must be administered slowly, this approach is appropriate for patients with mild diarrhea who have normal vital signs and minimal evidence of dehydration, and are willing to take fluids orally.
    a) Oral rehydration is not appropriate in children with severe circulatory collapse or intractable vomiting (Finberg, 1982).
    C) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Doses of lactulose solution in excess of 100 mL/day may be associated with diarrhea and hypernatremia. Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a man with hepatic encephalopathy and adynamic ileus. A patient developed pneumatosis coli after receiving lactulose 240 mL/day for the early manifestations of portal-systemic encephalopathy.
    B) THERAPEUTIC DOSES: ADULTS: Constipation: 15 to 30 mL (10 to 20 grams lactulose) orally once daily for 24 to 48 hours; may increase to 60 mL (40 grams lactulose)/day if needed. CHILDREN: 6 months to 3 years: 5 to 10 mL (3.33 to 6.66 grams lactulose) orally daily. Higher doses are used for hepatic encephalopathy: ADULTS: up to 45 mL every hour until laxative effect, then 3 to 4 times daily; CHILDREN: infants: 2.5 to 10 mL in divided doses; older children and adolescents: up to 90 mL/day.

Therapeutic Dose

    7.2.1) ADULT
    A) LACTULOSE
    1) CONSTIPATION: 15 to 30 mL (10 to 20 grams lactulose) orally once daily for 24 to 48 hours; may increase to 60 mL (40 grams lactulose)/day if needed (Prod Info lactulose oral solution, 2007)
    2) HEPATIC ENCEPHALOPATHY: 30 to 40 mL (containing 20 to 30 grams lactulose) orally every 1 hours at first and then 3 to 4 times daily; then lactulose 300 mL mixed with 700 mL water or normal saline and retained rectally for 30 to 60 min and repeated every 4 to 6 hr as a retention enema via a rectal balloon catheter (Prod Info lactulose oral, rectal solution, 2006).
    7.2.2) PEDIATRIC
    A) LACTULOSE
    1) CONSTIPATION: (6 months to 3 years) 5 to 10 mL (3.33 to 6.66 grams lactulose) orally daily (Dupont et al, 2005)
    2) HEPATIC ENCEPHALOPATHY: (infants) initial, 2.5 to 10 mL/day orally in divided doses to achieve 2 to 3 soft formed stools daily (Prod Info lactulose oral, rectal solution, 2006)
    3) HEPATIC ENCEPHALOPATHY: (children and adolescents) 40 to 90 mL/day orally in divided doses to achieve 2 to 3 soft formed stools daily (Prod Info lactulose oral, rectal solution, 2006)

Maximum Tolerated Exposure

    A) Doses of lactulose solution in excess of 100 mL/day may be associated with diarrhea and hypernatremia.
    B) CASE REPORT: Administration of 30 mL of lactulose every 4 hours was associated with the development of lactic acidosis in a man with hepatic encephalopathy and adynamic ileus (Mann et al, 1985).
    C) CASE REPORT: A patient developed pneumatosis coli after receiving lactulose 240 mL/day for the early manifestations of portal-systemic encephalopathy (Zimmerman et al, 1979).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) DEHYDROCHOLIC ACID
    1) LD50- (ORAL)MOUSE:
    a) 3.1 g/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 4 g/kg (RTECS , 2001)
    B) LACTULOSE
    1) LD50- (ORAL)MOUSE:
    a) 31 g/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 48.8 mL/kg (Prod Info lactulose oral solution, 2007)
    3) LD50- (ORAL)RAT:
    a) Greater than 30 mL/kg (Prod Info lactulose oral solution, 2007)
    4) LD50- (ORAL)RAT:
    a) 1860 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Lactulose is a synthetic disaccharide used for the treatment of constipation. Bacteria in the colon degrade lactulose into lactic acid, acetic acid, and formic acid resulting in an increase in osmotic pressure and acidification of intestinal contents which in turn, softens the stool by promoting stool water content (Prod Info lactulose oral solution, 2007).

Toxicologic Mechanism

    A) HYPERNATREMIA: LACTULOSE: Since stool water increases proportionately greater than stool sodium excretion, hypernatremia can result (Nelson et al, 1983).

References

General Bibliography

    1) Avery GS, Davies EF, & Brogden RN: Lactulose: A review of its therapeutic and pharmacological properties with particular reference to ammonia metabolism and its mode of action in portal systemic encephalopathy. Drugs 1972; 4:7-48.
    2) Barkin RM & Rosen P: Emergency Pediatrics, CV Mosby, St Louis, MO, 1986.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
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