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GLUTETHIMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Glutethimide is a piperidinedione hypnotic and sedative, used primarily as a nighttime hypnotic.

Specific Substances

    1) Glutarimide, 2-ethyl-2-phenyl-
    2) 2-Ethyl-2-phenylglutarimide
    3) 2-Phenyl-2-ethylglutaric acid imide
    4) alpha-Phenyl-alpha-ethylglutarimide
    5) CC 11511
    6) Molecular Formula: C13-H15-N-O2
    7) CAS 77-21-4

Available Forms Sources

    A) SOURCES
    1) SLANG TERMS: For the combined use of glutethimide and codeine include "sets," "loads," "three's and eight's," and "four doors."
    2) A "set" is usually 1 gram of glutethimide and 240 milligrams of codeine. The source of codeine may contain either acetaminophen or aspirin (Bender et al, 1988).
    3) The synonyms listed below are the street names for codeine and glutethimide:
    1) 3's and 8's
    2) 4 and Doors
    3) Loads
    4) Sets
    B) USES
    1) Glutethimide has primarily been used as a night-time hypnotic. It was transferred from Schedule III to Schedule II of the Controlled Substances Act as of March 21, 1991 (Anon, 1991). The use of this drug has been superseded by other drugs in recent years (Reynolds, 2000).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Glutethimide intoxication results in coma of varying depths and duration, pulmonary edema, respiratory depression, ataxia, and hypotension.
    2) One 500 mg tablet may produce serious toxicity in a small child. Conservative supportive therapy is the treatment of choice.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Blurred vision, papilledema, nystagmus, unilateral fixed dilated pupil, and dilated, sluggishly reactive pupils have been reported.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Hypotension and shock may occur.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Pulmonary edema, respiratory depression and arrest may occur.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Truncal ataxia has been reported in acute intoxication in children.
    2) Ataxia, lethargy, cerebral edema, sudden apnea, tonic muscle spasms, hyperreflexia, intracranial hemorrhage, and absence of deep tendon reflexes, corneal reflexes, pupillary response, and gag reflex have been noted.
    3) Variations in coma do not correlate with plasma glutethimide concentrations.
    4) An isoelectric EEG may occur.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Dry mouth and decreased GI motility may occur.
    B) WITH POISONING/EXPOSURE
    1) Dry mouth and decreased GI motility may occur.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Anuria and renal failure secondary to hypotension have been noted.
    2) Urinary bladder distention and atony may occur.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Erythematous bullae and vesicles ("barb burns") have been reported.
    0.2.20) REPRODUCTIVE
    A) There has been no evidence of teratogenicity in humans at therapeutic doses.
    B) Glutethimide crosses the placenta readily. Neonatal withdrawal symptoms have been reported.
    C) Neonatal respiratory depression and apnea have been reported.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) Abuse, dependence and a withdrawal syndrome have been described.

Laboratory Monitoring

    A) Quantitative plasma glutethimide levels do not correlate with clinical findings because of the presence of an inactive metabolite 4-hydroxyglutethimide that is mistakenly read as parent (active) drug.
    B) Monitor pulse oximetry and/or ABGs in patients with CNS or respiratory depression.
    C) Monitor neurological function for coma or seizure activity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

Range Of Toxicity

    A) One 500 mg tablet may cause severe toxicity in a small child. Death has been reported with 5 grams yet survival has also been reported following 28 grams. Clinical findings should be used to determine severity.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Glutethimide intoxication results in coma of varying depths and duration, pulmonary edema, respiratory depression, ataxia, and hypotension.
    2) One 500 mg tablet may produce serious toxicity in a small child. Conservative supportive therapy is the treatment of choice.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA has been reported (Ozdemir & Tannenberg, 1972).
    2) FEVER following hypothermia has been reported (Skoutakis & Acchiardo, 1982).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Blurred vision, papilledema, nystagmus, unilateral fixed dilated pupil, and dilated, sluggishly reactive pupils have been reported.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) AMBLYOPIA - Blurred vision may occur (Skoutakis & Acchiardo, 1982).
    2) MYDRIASIS - Widely dilated pupils, sluggishly reactive to light, are common following severe intoxication (Wright & Roscoe, 1970; (Skoutakis & Acchiardo, 1982; Grant & Schuman, 1993). Fixed dilated pupils were reported in one patient (Brown & Hammil, 1971).
    3) NYSTAGMUS - Horizontal and vertical nystagmus have been reported following overdose (Huttenlocher, 1963; Grant & Schuman, 1993).
    4) PAPILLEDEMA - has been reported (Wright & Roscoe, 1970).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension and shock may occur.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension is frequently reported following severe overdose (Chazan & Cohen, 1969; Chazan & Garella, 1971) Wright & Roscoe, 1970) and may be unresponsive to fluid therapy. Circulatory failure following glutethimide overdose is generally more severe than with the barbiturates (Reynolds, 2000).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Pulmonary edema, respiratory depression and arrest may occur.
    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Intermittent apnea and respiratory arrest may occur following moderate to severe (stage 3 to 4 coma) intoxication (Chazan & Garella, 1971) Wright & Roscoe, 1970). Respiratory depression is generally less severe than with the barbiturates (Reynolds, 2000).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema may commonly complicate the clinical findings (Wright & Roscoe, 1970).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Truncal ataxia has been reported in acute intoxication in children.
    2) Ataxia, lethargy, cerebral edema, sudden apnea, tonic muscle spasms, hyperreflexia, intracranial hemorrhage, and absence of deep tendon reflexes, corneal reflexes, pupillary response, and gag reflex have been noted.
    3) Variations in coma do not correlate with plasma glutethimide concentrations.
    4) An isoelectric EEG may occur.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Severe intoxication is associated with coma marked by variations in both depth and duration (Chazan & Garella, 1971; Reynolds, 2000).
    b) Waxing and waning in the level of consciousness are not uncommon (Comstock, 1971) and duration of coma may approach 100 hours (Chazan & Garella, 1971).
    c) Variations in coma do not correlate with plasma glutethimide concentration (Chazon & Garella, 1971; Wright & Roscoe, 1970; (Curry et al, 1987).
    d) Absence of deep tendon reflexes (DTRs), corneal reflexes, gag reflex, pupillary response and sudden apnea have been reported with acute intoxication (Brown & Hammill, 1971; Skoutakis & Acchiardo, 1982; Curry et al, 1987).
    B) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Tonic muscle spasms and hyperreflexia have been noted with acute intoxication as well (Skoutakis & Acchiardo, 1982).
    C) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy (Nover, 1967) and diplopia (Salatich, 1965) have been reported with chronic intoxication.
    D) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) Cerebral edema associated with papilledema is not uncommon in the deeply comatose patient (Wright & Roscoe, 1970).
    E) PARASYMPATHOLYTIC POISONING
    1) WITH POISONING/EXPOSURE
    a) CNS anticholinergic effects include irritability and seizures (Johnson & Van Buren, 1962).
    F) INTRACRANIAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Intracranial hemorrhage with increased intracranial pressure has been noted (Skoutakis & Acchiardo, 1982).
    G) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Truncal ataxia has been reported in acute intoxication in children (Huttenlocher, 1963). Overdoses have resulted in cerebellar ataxia with horizontal and vertical nystagmus, and widely dilated poorly reactive pupils (Grant & Schuman, 1993).
    H) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) EEG abnormalities may consist of diffuse fast wave activity (20 to 30 per second) (Huttenlocher, 1963). There has been a report of an isoelectric encephalogram in a patient who received intensive supportive care and subsequently recovered without residual injury (Comstock, 1971).
    I) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Mild intoxications are characterized by drowsiness, lethargy, slurred speech and ataxia (Reynolds, 2000).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dry mouth and decreased GI motility may occur.
    B) WITH POISONING/EXPOSURE
    1) Dry mouth and decreased GI motility may occur.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED ILEUS
    1) WITH POISONING/EXPOSURE
    a) Decreased GI motility may lead to a cyclic coma if gastrointestinal decontamination is not achieved (Comstock, 1971). Gastrointestinal atony, due to parasympatholytic activity, is likely (Chazan & Garella, 1971) and may result in delayed and continued absorption of drug (Comstock, 1971).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Chronic abuse can present as dysphagia (Emerg Med, Dec 15, 1981).
    2) WITH POISONING/EXPOSURE
    a) Dry mouth and decreased GI motility may occur as anticholinergic effects of overdose (Reynolds, 2000).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Anuria and renal failure secondary to hypotension have been noted.
    2) Urinary bladder distention and atony may occur.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Worsening renal function with anuria and renal failure has been described in a patient with hypotension following an overdose (Chartier, 1983).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Persistent acidosis can occur in severe intoxications (Skoutakis & Acchiardo, 1982).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Megaloblastic anemia and aplastic anemia have been reported in chronic intoxications (Pearson, 1965).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported with chronic intoxication (Pearson, 1965).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with chronic use (Pearson, 1965).
    D) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Development of significant methemoglobinemia has been reported (Filipini, 1965) but is uncommon following overdose.

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Erythematous bullae and vesicles ("barb burns") have been reported.
    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Lesions resembling burns similar to those seen with barbiturate overdose, have been described (Burdon & Cade, 1979).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rashes may include erythematous vesicles and bullae with irregularly shaped lesion and dermographism and a persistent erythematous line that follows the dermographism (Leavell et al, 1972). Exfoliative dermatitis has been reported, but is rare (Reynolds, 2000).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) OSTEOMALACIA
    1) WITH THERAPEUTIC USE
    a) Osteomalacia has been reported after prolonged administration (Greenwood, 1973).

Reproductive

    3.20.1) SUMMARY
    A) There has been no evidence of teratogenicity in humans at therapeutic doses.
    B) Glutethimide crosses the placenta readily. Neonatal withdrawal symptoms have been reported.
    C) Neonatal respiratory depression and apnea have been reported.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) HUMANS - In therapeutic doses, there has been no evidence of teratogenicity in humans (Kurtz et al, 1966; Graupner, 1965).
    2) OVERDOSE EXPOSURE
    a) CASE SERIES - The children of 16 women who attempted suicide with large ingestions of glutethimide (dose range 1000 to 15,000 mg; mean 4234 mg) during their pregnancy were examined for congenital abnormalities (CA). Eight of the ingestions involved glutethimide plus other drugs. Three (18.8%) of the exposed children had a CA (atrial septal defect type II, pectus carinatum, fetal alcohol syndrome), but compared to the rate of CAs for the control group of unexposed sib pairs (2 children had a CA), this was not significant. Based on this result and confounders of the study mothers, the authors concluded large doses of glutethimide did not produce teratogenic or fetotoxic effects (Petik et al, 2008).
    B) ANIMAL STUDIES
    1) A single intraperitoneal injection of glutethimide 300 mg/kg in mice resulted in congenital abnormalities in 16% of the surviving embryos; primarily orofacial clefts (Petik et al, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) WITHDRAWAL SYNDROME
    1) NEONATAL EFFECTS - Glutethimide crosses the placenta readily. Neonatal withdrawal symptoms have been reported (Reveri et al, 1977; Kurtz et al, 1966).
    a) Neonatal respiratory depression and apnea have been reported (Asnes & Lamb, 1969).
    B) ANIMAL STUDIES
    1) A single intraperitoneal injection of glutethimide 300 mg/kg in mice resulted in an embryo mortality rate of 65% (Petik et al, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) A peak level of 270 ng/mL in breast milk at 8 to 12 hours after a maternal dose of 500 mg has been reported (Curry et al, 1971).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Quantitative plasma glutethimide levels do not correlate with clinical findings because of the presence of an inactive metabolite 4-hydroxyglutethimide that is mistakenly read as parent (active) drug.
    B) Monitor pulse oximetry and/or ABGs in patients with CNS or respiratory depression.
    C) Monitor neurological function for coma or seizure activity.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Mild intoxication has been associated with glutethemide concentrations of between 0.5 and 5.6 mg%. Severe intoxication is reported between 1.8 mg% and 12 mg%.
    2) BLOOD LEVEL/CLINICAL EFFECT CORRELATION - The above correlations appear only to be valid before the glutethimide is metabolized to the inactive metabolite 4-hydroxyglutethimide (Curry et al, 1987).
    a) The inactive metabolite 4-hydroxyglutethimide accumulated levels will not decline as the patient awakens (Curry et al, 1987).
    b) There is an overlap between blood levels and degree of intoxication. There is no correlation between initial glutethimide levels and length of coma.
    c) Levels at the end of the comatose period may be the same, greater or lesser than the level on admission (Chazan & Garella, 1971).
    3) MULTIPLE DRUG INGESTIONS - Because glutethimide is often ingested with acetaminophen and codeine, it would be appropriate to determine the acetaminophen level at 4 hours after the ingestion.
    B) ACID/BASE
    1) Monitor ABGs and/or pulse oximetry in patients with respiratory or CNS depression.

Methods

    A) OTHER
    1) METABOLITE INTERFERENCE - Quantitative plasma glutethimide levels do not correlate with clinical findings because of the presence of an inactive metabolite 4-hydroxyglutethimide that is mistakenly read as parent (active) drug.

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) Due to a wide range of doses to produce a given effect, irregular absorption and lack of reliable prognostic value of blood levels, individual case assessment is paramount.
    B) Patients who are symptomatic or whose history suggests glutethimide overdose should be admitted.
    C) Progressively decreasing levels of consciousness or unconsciousness are indications for admission to an intensive care unit.

Monitoring

    A) Quantitative plasma glutethimide levels do not correlate with clinical findings because of the presence of an inactive metabolite 4-hydroxyglutethimide that is mistakenly read as parent (active) drug.
    B) Monitor pulse oximetry and/or ABGs in patients with CNS or respiratory depression.
    C) Monitor neurological function for coma or seizure activity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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).
    3) Multiple-dose activated charcoal has been shown to enhance elimination of glutethimide in human volunteers (Hayden & Comstock, 1975) but has not been shown to affect outcome after overdose. Routine use of multiple dose activated charcoal is not recommended.
    B) GASTRIC LAVAGE
    1) Glutethimide's anticholinergic properties may allow tablets to remain in the stomach for a longer time than would normally be anticipated. Treatment may be complicated by irregular absorption and storage in fat depots (Reynolds, 2000).
    a) If the glutethimide is combined with codeine, gastric emptying may become further delayed (Chazan & Garella, 1971; Bertino & Reed, 1986).
    b) Gastric lavage may be useful if performed within several hours after ingestion.
    2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    3) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    4) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    5) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    6) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) GASTRIC EMPTYING
    1) Emptying of gastrointestinal tract is imperative to prevent cyclic coma (Comstock, 1971).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Conservative supportive therapy appears to be the treatment of choice. In one study (Chazan & Garella, 1971) the mortality rate was about 1% (1 out of 70) when patients were treated conservatively without dialysis.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    E) CEREBRAL EDEMA
    1) Papilledema indicates probable cerebral edema (Wright & Roscoe, 1970).
    2) If the patient demonstrates papilledema or other signs of increased intracranial pressure, administer intravenous mannitol 0.25 gram/kilogram intravenous push repeated at 5 minute intervals as needed to control intracranial hypertension.
    3) CLINICAL IMPLICATIONS
    a) Cerebral edema and elevated intracranial pressure (ICP) may occur. Emergent management includes head elevation and administration of mannitol; hyperventilation should be performed if there is evidence of impending herniation.
    4) MONITORING
    a) Patients will usually require endotracheal intubation and mechanical ventilation. Monitor intracranial pressure, cerebral perfusion pressure and cerebral blood flow.
    5) TREATMENT
    a) Most information on the treatment of cerebral edema is derived from studies of traumatic brain injury.
    6) MANNITOL
    a) ADULT/PEDIATRIC DOSE: 0.25 to 1 gram/kilogram intravenously over 10 to 15 minutes (None Listed, 2000).
    b) AVAILABLE FORMS: Mannitol injection (5%, 10%, 15%, 20%, 25%).
    c) MAJOR ADVERSE REACTIONS: Congestive heart failure, hypernatremia, hyponatremia, hyperkalemia, renal failure, pulmonary edema, and allergic reactions.
    d) PRECAUTIONS: Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia. Do not add to whole blood for transfusions; enhanced neuromuscular blockade has occurred with tubocurarine. Keep serum osmolarity below 320 mOsm.
    e) MONITORING PARAMETERS: Renal function, urine output, fluid balance, serum potassium levels, serum osmolarity, and CVP.
    7) HYPERTONIC SALINE
    a) Preliminary studies suggest that hypertonic saline (7.5% saline/6% dextran) 100 ml reduced ICP more effectively than 200 mL of 20% mannitol in adults with elevated ICP after traumatic brain injury(Battison et al, 2005).
    8) ELEVATION
    a) Elevation of the head of the bed to approximately 30 degrees decreases ICP and improves cerebral perfusion pressure (Meixensberger et al, 1997; Schneider et al, 1993; Feldman et al, 1992).
    9) MECHANICAL DECOMPRESSION
    a) Early surgical decompression, ventriculostomy with CSF drainage, or craniectomy may be useful in patients with persistent elevation of ICP (Sahuquillo & Arikan, 2006; Sakai et al, 1998; Polin et al, 1997; Taylor et al, 2001). Most experience with these modalities has been in patients with traumatic brain injury.
    10) HYPERVENTILATION
    a) SUMMARY: Hyperventilation has been associated with adverse outcomes and should not be performed routinely (Muizelaar et al, 1991). It is indicated in patients who have clinical evidence of herniation or if there is intracranial hypertension refractory to sedation, paralysis, CSF drainage and osmotic diuretics (None Listed, 2000a).
    b) RECOMMENDATION:
    1) The PCO2 must be controlled in the range of 25 torr; further lowering of PCO2 may create undesirable effects secondary to local tissue hypoxia.
    2) End-tidal CO2 tension, correlated with an initial ABG measurement, provides a noninvasive means of monitoring PCO2 (Mackersie & Karagianes, 1990).
    3) Most authorities advise that hyperventilation should be considered a temporizing measure only; SUSTAINED hyperventilation should be avoided (Am Acad Neurol, 1997; Bullock et al, 1996; Kirkpatrick, 1997).
    F) MONITORING OF PATIENT
    1) Monitor blood gases regularly while supporting respiration in the severely intoxicated patient.
    G) DRUG WITHDRAWAL
    1) Phenobarbital is considered the drug of choice for these seizures (Vestal & Rumack, 1974). Benzodiazepines have also been used (Lucas & Montgomery, 1992).
    2) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    3) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    6) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    7) Because glutethimide is often concurrently abused with codeine, both methadone and phenobarbital may be necessary to treat withdrawal symptoms (Sramek & Klajawall, 1981).

Enhanced Elimination

    A) DIURESIS
    1) Forced diuresis is considered ineffective for increasing excretion since only 2 percent of glutethimide is excreted in the urine unchanged (Keberle et al, 1962).
    2) In view of potential for pulmonary edema, diuresis may be dangerous (Wright & Roscoe, 1970).
    B) HEMODIALYSIS
    1) Hemodialysis does not appear to alter the course of intoxication.
    2) Conservative supportive therapy is generally all that is required following overdose (Chazan & Garella, 1971; Comstock, 1971) Wright & Roscoe, 1970).
    3) CASE REPORT
    a) In one study there was no significant change in duration of coma and associated complications when hemodialysis was compared to conservative supportive therapy (Chazen & Cohen, 1969).
    b) A 21-year-old pregnant woman was treated with hemodialysis for 10 hours for acute glutethimide intoxication. She was in her 23rd to 24th week of gestation.
    1) She developed hypotension, tachycardia and decreased clotting time (requiring the administration of heparin) during dialysis.
    2) Immediately following dialysis, uterine contractions developed for four hours, and the patient developed acute renal failure lasting five days.
    3) Fetal heart tones heard on admission were not audible during dialysis or for fourteen hours after dialysis, but returned thirty hours after admission.
    4) The patient delivered a normal, full-term, viable baby with a normal neurological examination 4 months after discharge (Kurtz et al, 1966).
    C) HEMOPERFUSION
    1) Charcoal hemoperfusion does not appear to alter the depth of coma despite clearances of 100 milliliters/minute (Koffler et al, 1978). Little change was noted in the blood glutethimide concentration during the procedure.
    2) Resin hemoperfusion (Amberlite XAD-4) does not appear to be able to significantly alter the removal of glutethimide. Following 4 consecutive resin hemoperfusion runs, levels rebounded to near pre-perfusion levels (Raja, 1986).

Range Of Toxicity

Summary

    A) One 500 mg tablet may cause severe toxicity in a small child. Death has been reported with 5 grams yet survival has also been reported following 28 grams. Clinical findings should be used to determine severity.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Normal adult hypnotic dose is 250 to 500 milligrams orally at bedtime (USPDI , 2002). Individualize dose as needed.
    7.2.2) PEDIATRIC
    A) GENERAL
    1) Not recommended for use in children (USPDI , 2002).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) As in most ingestions, estimates of minimum lethal doses are unreliable. The symptomatology is so evident that if there is any question of ingestion, a period of observation should determine if toxicity will occur.
    2) Absorption may be quite erratic and intact tablets may be found for days following severe ingestion.
    B) CASE REPORTS
    1) SINGLE CASES -
    a) One 500 milligram tablet may produce severe toxicity in a small child (Huttenlocher, 1963).
    b) Death has been reported with 5 grams.
    c) The lethal dose has been reported as 10 to 20 grams (Skoutakis & Acchiardo, 1982).
    2) CASE SERIES -
    a) Nine fatalities in the area of Erie, Pennsylvania from 1985 to 1987 were reported due to acute toxicity of glutehimide/codeine combination ("sets") in adults (18 to 37 years of age). All 9 were known chronic abusers (Bender et al, 1988).
    C) ADULT
    1) RTECS (2000) reports an LDLo (lowest published lethal dose) in a human adult of 147 milligrams/kilogram.

Maximum Tolerated Exposure

    A) ACUTE
    1) A patient that ingested 28 grams survived.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 208 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 360 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 600 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Glutethimide is metabolized almost entirely in the liver. It has a high lipid solubility. While enterohepatic circulation was once suggested as being responsible for cyclical coma seen with this drug it is now known not to be the case.
    B) Accumulation of a toxic, active metabolite 4-hydroxy-2-ethyl-2-phenylglutarimide may be the cause of the prolonged coma noted in these patients (Hansen et al, 1975).
    1) There is some controversy concerning this; some authors suggest that the role of this metabolite has been overemphasized (Curry et al, 1987).
    C) Cyclical coma, also a feature of glutethimide poisoning, seems to occur as a result of continued absorption from the gut (Comstock, 1971).
    D) GI EFFECTS - The anticholinergic and/or CNS depressant effects of this drug decrease bowel motility until it has been metabolized at which time bowel motility returns, more drug is absorbed and coma once again ensues, completing the cyclical pattern.

Physicochemical

Physical Characteristics

    A) Glutethimide is available as colorless crystals or white to almost white crystalline powder. It has a melting point of 86 to 89 degrees. It is almost insoluble in water, but freely soluble in alcohol, methyl alcohol, acetone, chloroform, ether, and ethyl acetate. When in a saturated water solution, it is reported to be acid to litmus (Budavari, 1996; Reynolds, 2000).

Molecular Weight

    A) 217.27 (Budavari, 1996)

References

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