The drug class of benzodiazepines includes many compounds that vary widely in potency, duration of effect, the presence or absence of active metabolites, and clinical use (Table II-14). Three nonbenzodiazepines—eszopiclone, zaleplon, and zolpidem—have similar clinical effects and are included here. In general, death from benzodiazepine overdose is rare unless the drugs are combined with other CNS-depressant agents, such as ethanol, opioids, and barbiturates. Potent, short-acting agents have been considered the sole cause of death in recent forensic cases.

Benzodiazepines enhance the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). They also inhibit other neuronal systems by poorly defined mechanisms. The result is generalized depression of spinal reflexes and the reticular activating system. This can cause coma and respiratory arrest.

1. Respiratory arrest is more likely with potent short-acting benzodiazepines such as triazolam, alprazolam, and midazolam. It has also been reported with zolpidem.
2. Cardiopulmonary arrest has occurred after rapid injection of diazepam, possibly because of CNS-depressant effects or because of the toxic effects of the diluent propylene glycol.
3. Pharmacokinetics. Most of these agents are highly protein bound (80-100%). Time to peak blood level, elimination half-lives, the presence or absence of active metabolites, and other pharmacokinetic values are given in Table II-63.

In general, the toxic-therapeutic ratio for benzodiazepines is very high. For example, oral overdoses of diazepam have been reported in excess of 15-20 times the therapeutic dose without serious depression of consciousness. However, respiratory arrest has been reported after ingestion of 5 mg of triazolam and after rapid IV injection of diazepam, midazolam, and many other benzodiazepines. Also, ingestion of another drug with CNS-depressant properties (eg, ethanol, barbiturates, opioids) probably will produce additive effects.

Onset of CNS depression may be observed within 30-120 minutes of ingestion, depending on the compound. Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Generally, patients with benzodiazepine-induced coma have hyporeflexia and midposition or small pupils. Hypothermia may occur. Serious complications are more likely when potent short-acting agents are involved or when other depressant drugs have been ingested.

Usually is based on the history of ingestion or recent injection. The differential diagnosis should include other sedative-hypnotic agents, antidepressants, antipsychotics, and narcotics. Coma and small pupils do not respond to naloxone but will reverse with administration of flumazenil (see below).

1. Specific levels. Serum drug levels are often available from commercial toxicology laboratories but are rarely of value in emergency management. Urine and blood qualitative screening may provide rapid confirmation of exposure. Immunoassays are sensitive to the benzodiazepines that metabolize to oxazepam (eg, diazepam, chlordiazepoxide, and temazepam), but may not detect newer benzodiazepines (eg. alprazolam, lorazepam, midazolam) or those in low concentrations.
2. Other useful laboratory studies include glucose, arterial blood gases, and/or pulse oximetry.

1. Emergency and supportive measures
   1. Protect the airway and assist ventilation if necessary.
   2. Treat coma, hypotension, and hypothermia if they occur. Hypotension usually responds promptly to supine position and IV fluids.
2. Specific drugs and antidotes. Flumazenil is a specific benzodiazepine receptor antagonist that can rapidly reverse coma. However, because benzodiazepine overdose by itself is rarely fatal, the role of flumazenil in routine management has not been established. It is administered IV with a starting dose of 0.1-0.2 mg, repeated as needed up to a maximum of 3 mg. It has some important potential drawbacks:
   1. It may induce seizures in patients who have co-ingested medications with proconvulsant activity.
   2. It may induce acute withdrawal, including seizures and autonomic instability, in patients who are addicted to benzodiazepines.
   3. Recurrent sedation is common when the drug wears off after 1-2 hours, and repeated dosing or a continuous infusion is often required.
3. Decontamination. Consider activated charcoal if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. There is no role for diuresis, dialysis, or hemoperfusion. Repeat-dose charcoal has not been studied.