Benzodiazepine Toxicity

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.