DESCRIPTION

The benzodiazepines are used as sedatives, anxiolytics, and muscle relaxants, and include alprazolam (Xanax), brotizolam, chlordiazepoxide (Librium), chlorazepate (Tranxene), clobazam, clonazepam (Clonopin), diazepam (Valium), estazolam (Prosom), flurazepam (Dalmane), halazepam, lorazepam (Ativan), lormetazepam, medazepam, midazolam (Versed), nitrazepam, oxazepam (Serax), prazepam, temazepam (Restoril), triazolam (Halcion).

FORMS AND USES

• Anesthesia and sedation during procedures.
• Prescribed for their hypnotic, anxiolytic, anticonvulsant, and muscle-relaxant properties.
  • Alprazolam. 0.25 to 0.5 mg orally three times per day.
  • Chlordiazepoxide. For anxiety 5 to 25 mg orally four times per day; for alcohol withdrawal 25 to 100 mg intravenously or intramuscularly every 2 to 4 hours.
  • Chlorazepate. 7.5 to 15 mg orally at night or twice per day.
  • Diazepam. 2.5 to 5 mg increments intravenously up to 0.2 mg/kg; 2 to 10 mg orally three or four times per day.
  • Flurazepam. 15 to 30 mg orally at night.
  • Lorazepam. 0.5 to 2 mg intravenously, intramuscularly, or orally every 6 to 8 hours.
  • Midazolam. 5 mg or 0.07 mg/kg intravenously.
  • Oxazepam. 10 to 15 mg orally three or four times per day.
  • Temazepam. 15 to 30 mg orally at bedtime.
  • Triazolam. 0.125 to 0.5 mg orally at bedtime.

PATHOPHYSIOLOGY

• Benzodiazepines bind to the benzodiazepine receptor, augmenting the inhibitory neurotransmitter effect of gamma-aminobutyric acid (GABA).
• Hyperpolarization due to transmembrane chloride ion flux through a GABA-mediated channel produces decreased neuronal excitability.
• Toxic effects are typically mild to moderate.

EPIDEMIOLOGY

• Intentional ingestion is common.
• Death occurs rarely, usually involving coingestant such as ethanol, which accentuates respiratory depression.
• Young children are at increased risk of poisoning.
• The elderly are at risk, usually due to depressed renal and hepatic function.

CAUSES

• Toxic ingestion is usually intentional.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

Toxic effects may be enhanced with coingestion of ethanol, barbiturates, or other CNS depressants.

PREGNANCY AND LACTATION

• Alprazolam, chlordiazepoxide, chlorazepate, diazepam, lorazepam, midazolam, and oxazepam. US FDA Pregnancy Category D. Evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) make use of the drug acceptable despite its risks.
• Flurazepam, temazepam, and triazolam. US FDA Pregnancy Category X. Studies demonstrate fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit.
• Benzodiazepines are secreted in breast milk and can produce sedation in infants.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxicologic causes of respiratory and mental status depression include narcotics, ethanol, barbiturates, numerous sedative-hypnotic drugs, tricyclic antidepressants, and many others.
• Nontoxicologic causes include hypoxia, severe electrolyte abnormality, hypoglycemia, intracranial injury, meningitis, encephalitis, or postictal state, and many others.

SIGNS AND SYMPTOMS

The predominant effects are CNS depression with respiratory depression.

Vital Signs

Hypothermia and hypotension.

HEENT

Nystagmus, miosis, and diplopia.

Cardiovascular

Hypotension, bradycardia; tachycardia may develop as a response to hypotension.

Pulmonary

Respiratory depression; aspiration may occur.

Gastrointestinal

Nausea and vomiting, especially in children.

Musculoskeletal

Pressure injury may produce rhabdomyolysis or skin necrosis.

Neurologic

Impairment of speech and coordination, amnesia, ataxia, somnolence (rarely to the point of coma), confusion, depressed deep tendon reflexes, and dyskinesia.

PROCEDURES AND LABORATORY TESTS

Essential Tests

Testing may not be needed in asymptomatic patients.

Recommended Tests

• Serum electrolytes, BUN, and creatinine to assess causes of altered mental status.
• Pulse oximetry for assessment of altered mental status.
• Electrocardiogram, serum acetaminophen, aspirin, and ethanol levels in overdose setting to detect occult overdose.
• Urinalysis and serum creatine kinase if comatose to evaluate for rhabdomyolysis.
• Head CT, lumbar puncture, and chest radiographs as needed to evaluate respiratory complications and assess other causes of CNS depression.

Not Recommended Tests

Quantitative benzodiazepine levels are not clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

DIRECTING PATIENT COURSE

• Treatment should focus on gastrointestinal decontamination and airway management.
• Supportive care with appropriate airway management is vital; endotracheal intubation may be needed to protect the airway.
• Dose and time of exposure should be determined for all substances involved.

The health-care professional should call the poison control center when:

• Significant CNS or respiratory depression, or other severe effects are present.
• Signs and symptoms are not consistent with benzodiazepine poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or CNS effects are present.
• Patient or caregiver seem unreliable.
• Any toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted if persistent respiratory or CNS effects are present.

DECONTAMINATION

Out of Hospital

Emesis should not be induced due to potential for rapid deterioration.

In Hospital

• Emesis should not be induced.
• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Flumazenil (Romazicon) is a specific antidote for benzodiazepine intoxication.

• Indications. Reversal of benzodiazepine effects including profound sedation, respiratory depression, and coma.
• Contraindications. Seizures, known allergy to flumazenil, concurrent overdose of tricyclic antidepressant drugs, or use of cocaine or other seizure producing agents.
• Method of administration
  • Adult dose is 0.1 to 0.2 mg intravenous push every 1 to 2 minutes until clinical effect or 1 to 2 mg given; if resedation occurs, may give 1 mg every 20 minutes to a maximum of 3 mg/h.
  • Pediatric dose is 10 µg/kg intravenous push, titrated to effect.
  • Caution: Resedation is possible 30 to 60 minutes after administration.
• Potential adverse effects. Agitation, vomiting, confusion, seizures, dysrhythmia, and flushing; may induce withdrawal.

ADJUNCTIVE TREATMENT

• Hemodialysis is not effective.
• Following decontamination, treatment is primarily supportive.
• Hypotension
  • Patient should receive an intravenous infusion of 10 to 20 ml/kg 0.9% NaCl and be placed in the Trendelenburg position.
  • Guide further fluid therapy by monitoring central pressure to avoid volume overload.
• If hypotension is unresponsive, a vasopressor should be administered.
  • Dopamine. Patient should receive 2 to 5 µg/kg/min, titrated upward to desired effect; rates above 20 µg/kg/min are unlikely to provide further benefit.
  • Norepinephrine. An infusion of 0.1 to 0.2 µg/kg/min intravenously, titrated to desired effect, should be given. High infusion rates may cause tissue ischemia.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

Patients should have continuous respiratory and hemodynamic monitoring.

EXPECTED COURSE AND PROGNOSIS

• Patients usually regain consciousness within 24 hours.
• Most patients recover completely unless hypoxia intercedes.
• In one study, only 5 of 702 poisoning patients died (a mortality rate of 0.007) and those cases were usually complicated by a coingestion.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Asymptomatic patients may be discharged after decontamination, a 6-hour observation period, and psychiatric evaluation, if needed.
• From the hospital. Patients may be discharged when vital signs and mental status become normal and after psychiatric evaluation, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

Signs and symptoms of benzodiazepine overdose may closely resemble other conditions (both other ingestions and nontoxicologic conditions), resulting in misdiagnosis.

TREATMENT

Agents with long half-lives may require extended observation and care.

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by psychotropic agents: benzodiazepine-based tranquilizers.

See Also: SECTION II, Hypotension chapter; SECTION III, Flumazenil chapter; and SECTION IV, Sedative-Hypnotic Agents chapter.

RECOMMENDED READING

Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ 1995;310:219-221.

POISINDEX Editorial Staff. Benzodiazepines (management/treatment protocol). In: Rumack BH, Hess AJ, Gelman CR, eds. POISINDEX system. Englewood, CO: Micromedex, Inc. (edition expires August 31, 1997).

Author: Brian T. Williams

Reviewer: Richard C. Dart