BENZODIAZEPINES INTOXICATION

BENZODIAZEPINES INTOXICATION

Background

Benzodiazepines (BZDs) are sedative-hypnotic agents that were first introduced in 1960. BZDs commonly are used for a variety of situations that include seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants, and as preanesthetic agents. They also are combined frequently with other medications for procedural sedation.

Because of their widespread popularity, these drugs commonly are abused. In addition, BZDs frequently are used in overdose, either alone or in association with other substances.( alprazolam,, chlordiazepoxide, diazepam, triazolam, temazepam, flurazepam, bromazepam, clorazepate, oxazepam, nitrazepam, loprazolam, lormetazepam, lorazepam)

Pathophysiology

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. BZDs exert their action by potentiating the activity of GABA.

Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility, vasodilation, and enhanced perfusion.

The rate of BZD onset of action is determined by rate of BZD absorption from the GI tract. The relatively lipophilic BZDs usually are absorbed more rapidly and produce a faster onset of effect than the relatively water-soluble BZDs. BZD absorption is especially rapid when ethanol is present and the stomach is empty. Peak blood concentrations of most agents occur within 1-3 hours. After a single dose, the lipophilic agents have a shorter duration of action (shorter CNS effect) than water-soluble agents because rapid redistribution from the CNS to peripheral sites (eg, adipose tissue); thus, lorazepam (water soluble) has a longer CNS duration of action than diazepam (lipophilic).

BZDs are metabolized predominantly in the liver by oxidation and/or conjugation. Most BZDs are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.

Frequency

United States

In 2005, a total of 67,593 BZD exposures were reported to US poison control centers, of which 3018 (0.04%) resulted in major toxicity and 243 (0.003%) resulted in death. From 1995-2002, the frequency of ED visits involving BZD increased by 41%.

International

In the 1980s, an overall rate of 5.9 fatalities per million prescriptions for BZDs occurred in Great Britain; temazepam and flurazepam appeared to be the most toxic.

Mortality/Morbidity

BZDs generally are thought to be safe and death is rare.

• Mortality from a pure BZD overdose is rare; it usually occurs in conjunction with concomitant alcohol ingestion or use of other sedative-hypnotics. Intravenous administration or overdose of ultrashort-acting BZDs (eg, triazolam [Halcion]) is more likely to result in apnea and death. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of BZDs than people in other age groups.
• Intravenous administration is associated with greater degrees of hypotension than other routes of administration and occasional cardiac and respiratory arrest.

Age

The most reported BZD use is in persons older than 19 years.

CLINICAL

History

History should include the time, dose, and intent of the overdose. Determine if co-ingestants are present and the duration of BZD use.

• Dizziness
• Confusion
• Drowsiness
• Blurred vision
• Unresponsiveness
• Anxiety
• Agitation

Physical

Focus the physical examination on the patient's vital signs and cardiorespiratory and neurologic function.

• Nystagmus
• Hallucinations
• Slurred speech
• Ataxia
• Coma
• Hypotonia
• Weakness
• Altered mental status, impairment of cognition
• Amnesia
• Paradoxical agitation
• Respiratory depression
• Hypotension

DIFFERENTIALS

Encephalitis
Hypernatremia
Hypoglycemia
Hyponatremia
Stroke, Hemorrhagic
Stroke, Ischemic
Subarachnoid Hemorrhage
Subdural Hematoma
Toxicity, Alcohols
Toxicity, Antidepressant
Toxicity, Antihistamine
Toxicity, Barbiturate
Toxicity, Carbon Monoxide
Toxicity, Clonidine
Toxicity, Ethylene Glycol
Toxicity, Neuroleptic Agents

Lab Studies

• Qualitative screening of urine or blood may be performed but rarely influences treatment. Overall, the laboratory detection of BZDs depends upon the screening method used.
• Obtain an arterial blood gas if respiratory depression is present.
• Following an intentional overdose, measure serum electrolytes, glucose, BUN, creatine clearance, and acetaminophen concentration.

Imaging Studies

• Obtain a chest x-ray if respiratory compromise is present.

• Evaluate for aspiration.
• Evaluate for acute respiratory distress syndrome (ARDS).

Other Tests

• Obtain an electrocardiogram (ECG) to evaluate for co-ingestants, particularly cyclic antidepressants.

TREATMENT

Prehospital Care

• Cardiac monitoring
• Supplemental oxygen
• Intravenous access
• Rapid glucose determination
• Naloxone, if the diagnosis is unclear or an opiate co-ingestion is suspected

Emergency Department Care

Continue supportive care and monitoring (eg, cardiac monitoring, IV, oximetry, vital signs).

• Decontamination

• Ipecac syrup is contraindicated for prehospital or hospital use because of the risk for CNS depression and subsequent aspiration with emesis.
• Gastric lavage is not recommended but may be considered if the presence of a lethal co-ingestant is suspected and the patient presents within 1 hour of ingestion.
• Single-dose activated charcoal is recommended for GI decontamination in patients who present within 4 hours of ingestion or in symptomatic patients when the time of ingestion is unknown.
• Respiratory depression may be treated with assisted ventilation.

Consultations

• Toxicologist or a poison control center
• Intensive care specialist
• Psychiatrist, if suicide attempt

MEDICATION

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin.

Activated charcoal

Most useful if administered within 1-2 h of ingestion. Repeat doses may be used, especially with ingestion of sustained release agents. Limited outcome studies exist, especially when administration is more than 1 h of ingestion.
Administration of charcoal by itself (in aqueous solution), as opposed to coadministration with a cathartic is becoming the current practice standard. Studies have not shown benefit from cathartics, and, while most drugs and toxins are absorbed within 30-90 min, laxatives take hours to work

Dose:1 g/kg PO/NG (typically 50-75 g); cathartic optional but not routinely recommended; repeat dose of 0.5 g/kg PO/NG if desired; do not use cathartic with repeat doses

Drug Category: Antagonist

Flumazenil is a selective competitive antagonist of the GABA receptor and the only available specific antidote for BZDs; it will reverse effects of BZDs but must be used with caution. If BZDs are being used to treat a potentially life-threatening condition (eg, seizure disorder), antagonists may exacerbate the underlying disorder.

Additionally, co-ingestion commonly occurs with agents that lower the seizure threshold (eg, cyclic antidepressants) and reversal may result in seizure or status epilepticus; therefore, antagonists are not recommended for use by prehospital personnel or for indiscriminate use before a complete evaluation.

In overdose situations, flumazenil may be used for patients with pure BZD overdose who are verbally unresponsive and have no history of long-term BZD use or seizure disorder. Perform an ECG should be performed before use to confirm the absence of cardiac conduction disturbances (which would suggest the presence of cyclic antidepressants). Use as a diagnostic and therapeutic agent for unsubstantiated drug-associated coma is controversial. A positive response to small titratable doses may obviate the need for endotracheal (ET) intubation and the search for other causes of coma.

Dose:0.1-0.2 mg IV q1min to a total dose of 1 mg at one time or 3 mg in 1 h; infusion rates of 0.1 mg/min decrease disconcerting rapid arousal

Contraindications:Documented hypersensitivity; serious cyclic-antidepressant overdosage; patients using BZDs to control a potentially life-threatening condition (eg, intracranial pressure, status epilepticus); chronic BZD use

Interactions: Caution with mixed drug overdose; toxic effects due to other drugs taken in overdose (eg, cyclic antidepressants) may occur with reversal of BZD effects

Precautions Patients on BZDs for prolonged periods may experience seizures; monitor for resedation and unmasking of seizures

Further Inpatient Care

• Admit patients with hemodynamic instability, coma, or respiratory depression to the ICU.
• Watch for signs of withdrawal in patients who have been taking BZDs chronically before overdose.

Further Outpatient Care

• Patients may be discharged if they remain asymptomatic 4-6 hours postingestion. Those with mild toxicity may be observed in the emergency department until they recover.

Transfer

• Transfer patients who may require more advanced care than is available in either the ED or inpatient setting.

Complications

• Aspiration pneumonia
• Rhabdomyolysis
• Fatality (rare)

Patient Education