Benzodiazepine Toxicity

Author: Robin Mantooth, MD, FACEP; Chief Editor: Asim Tarabar, MD

Updated: Mar 30, 2012Background

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 use, these drugs have propensity for abuse. In addition,
benzodiazepines frequently are used in overdose, either alone or in association with other
substances.

Pathophysiology
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS.
Benzodiazepines (BZD) exert their action by potentiating the activity of GABA. They
bind to a specific receptor on the GABA A receptor complex, which facilitates the
binding of GABA to its specific receptor site. BZD binding causes increased frequency of
opening of the chloride channel complexed with the GABA A receptor. Chloride channel
opening results in membrane hyperpolarization, which inhibits cellular excitation.
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 and vasodilation. These
changes could have the potential to alter tissue perfusion.
The rate of BZD onset of action is determined by its ability to cross the blood-brain
barrier. The relatively lipophilic BZDs usually produce a faster onset of effect than the
relatively water-soluble BZDs. BZD effects can be potentiated when ethanol is present as
coingestant. Peak blood concentrations of most agents occur within 1-3 hours. After a
single dose, the lipophilic agents can 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). However, diazepam metabolizes to active
intermediates with prolonged half-life extending its therapeutic effects.
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.

Epidemiology
Frequency

United States
In 2010, a total of 81,427 benzodiazepine single-substance exposures were reported to
US poison control centers, of which 337 (0.004%) resulted in major toxicity and 11
(0.0001%) resulted in death.[1]

International
In the 1980s, an overall rate of 5.9 fatalities per million prescriptions for BZDs occurred
in Great Britain, while exposure to temazepam and flurazepam was associated with the
most toxic effects.[2]

Mortality/Morbidity
Benzodiazepines (BZDs) generally are thought to be safe and death is rare.

Mortality and morbidity from a pure oral BZD overdose is rare; it usually occurs
in conjunction with concomitant alcohol ingestion or use of other sedativehypnotics.
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.

History
History should include the time, dose, and intent of the overdose. Determine if coingestants are present and the duration of benzodiazepine (BZD) use.

Dizziness
Confusion
Drowsiness
Blurred vision
Unresponsiveness
Anxiety

Agitation

Physical
Focus the physical examination on the patient's vital signs, cardiorespiratory and
neurologic function. "Classic" isolated BZD overdose presents as coma with normal vital
signs.

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

Differential Diagnoses

Alcohol and Substance Abuse Evaluation

Encephalitis
Hypernatremia
Hypoglycemia
Hyponatremia
Pediatrics, Hypoglycemia
Pediatrics, Meningitis and Encephalitis
Stroke, Hemorrhagic
Stroke, Ischemic
Subarachnoid Hemorrhage
Subdural Hematoma
Toxicity, Alcohols
Toxicity, Antidepressant
Toxicity, Antihistamine
Toxicity, Barbiturate
Toxicity, Carbamazepine
Toxicity, Carbon Monoxide
Toxicity, Clonidine
Toxicity, Ethylene Glycol
Toxicity, Neuroleptic Agents
Toxicity, Sedative-Hypnotics
Toxicity, Valproate

Laboratory Studies

Qualitative screening of urine or blood may be performed but rarely influences

treatment decisions and has no impact on immediate clinical care.
o Immunoassay screening techniques are performed most commonly and
typically detect benzodiazepines (BZDs) that are metabolized to
desmethyldiazepam or oxazepam; thus, a negative screening result does
not rule out the presence of a BZD agent. Overall, the laboratory detection
of BZDs depends upon the screening method used.
Obtain an arterial blood gas (ABG) if respiratory depression is present.
Following an intentional overdose, measure serum electrolytes, glucose, BUN,
creatine clearance, ETOH, and acetaminophen concentration.
Obtain a pregnancy test in women of childbearing age.

Imaging Studies

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

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

Other Tests

Obtain an electrocardiogram (ECG) to evaluate for co-ingestants, particularly

cyclic antidepressants.

Prehospital Care

Cardiac monitoring
Supplemental oxygen and airway support
Intravenous access
Rapid glucose determination (finger stick) and administration of D50 if necessary
Naloxone can be administered at a very low dose (0.05 mg with gradual increase
in dose if needed), if the diagnosis is unclear and an opiate co-ingestion is
suspected (eg, evidence of severe respiratory depression).
o CAVEAT: Administration of 0.4 mg of naloxone will reverse respiratory
depression in most opioid overdoses; however, it will also result in severe
withdrawal symptoms (nausea, vomiting) in opioid-dependent individuals.
This can be detrimental in patients who are still unable to protect their
airway due to BZD effect (sedation) and can suffer from aspiration of
gastric contents.

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.
o 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.
o Single-dose activated charcoal is recommended for GI decontamination in
patients with protected airway who present within 4 hours of ingestion. It
is important to remember that isolated oral BZD overdose is relatively
benign exposure (eg, prolonged sedation), and aspiration of activated
charcoal can significantly worsen clinical outcome, sometimes resulting
even in death.
Respiratory depression may be treated with assisted ventilation.
Flumazenil
o Flumazenil is a competitive BZD receptor antagonist and should be used
cautiously because it has potential to precipitate BZD withdrawal in
chronic users, resulting in seizures.
o Flumazenil administration is contraindicated in mixed overdoses (eg,
TCAs) because BZD reversal can precipitate seizures and cardiac
arrhythmias.
o Ideal indication for flumazenil use is isolated BZD overdose in BZD-naive
patients, particularly if overdose is iatrogenic in nature (eg, during
conscious sedation on BZD-naive patient).
The American Psychiatric Association and the National Institute of Clinical
Excellence have treatment and diagnostic guidelines available for cases of
substance abuse and self-harm.[3, 4]
o

Consultations

Toxicologist or a poison control center

Intensive care specialist
Psychiatrist, if suicide attempt

GI decontaminant
Class Summary
Empirically used to minimize systemic absorption of the toxin.
View full drug information

Activated charcoal (Liqui-Char)

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. Dangerous fluid and electrolyte shifts have occurred when
cathartics are used in small children.
When the ingested dose is known, charcoal may be administered at 10 times ingested
dose of agent over 1 or 2 doses.

Antagonist
Class Summary
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.
View full drug information

Flumazenil (Romazicon) Dosing & Uses

AdultPediatric

Dosing Forms & Strengths

Benzodiazepine Reversal
0.2 mg IV inj over 15-30 sec
If no response: then 0.3 mg over 15-30 sec 1 min later, if no response then again 0.5 mg
IV over 15-30 sec to max cumulative dose of 3 mg/hr

Rarely pt may require titration up to total dose 5 mg; if no response after 5 min, sedation
unlikely to be 2ndary to benzodiazepines
Slow infusion of lowest dose required decr to adverse events
Indicated for reversal of benzodiazepine use during procedure, OR known isolated
benzodiazepine overdose in pt not taking benzodiazepines chronically

DOC to reverse effects of BZDs in an overdose by selectively antagonizing GABA/BZD

receptor complex.
If overdosed patient has not responded after 5 min of 5 mg cumulative dose, cause of
sedation is not likely to be BZDs.

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 benzodiazepines
(BZDs) chronically before overdose.

Further Outpatient Care

Patients may be discharged if they remain asymptomatic at least 6 hours post

ingestion. Those with mild toxicity may be observed in the emergency department
until they recover. Patients with intentional overdoses have to be evaluated by a
psychiatrist.

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
For patient education resources, see the Poisoning - First Aid and Emergency Center,
Mental Health and Behavior Center, and Substance Abuse Center, as well as
Benzodiazepine Abuse, Drug Overdose, Activated Charcoal, and Poison Proofing Your
Home.