Toxicity, Benzodiazepine: Treatment & Medication

http://emedicine.medscape.com/article/813255-treatment
eMedicine Specialties > Emergency Medicine > Toxicology

Updated: Jan 28, 2010

Introduction

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 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.


Frequency
United States
In 2008, a total of 78,443 benzodiazepine single-substance exposures were reported to US poison control centers, of which 332 (0.004%) resulted in major toxicity and 8 (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 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 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
Toxicity, Antidepressant

Encephalitis
Toxicity, Antihistamine

Hypernatremia
Toxicity, Barbiturate

Hypoglycemia
Toxicity, Carbamazepine

Hyponatremia
Toxicity, Carbon Monoxide

Pediatrics, Hypoglycemia
Toxicity, Clonidine

Pediatrics, Meningitis and Encephalitis
Toxicity, Ethylene Glycol

Stroke, Hemorrhagic
Toxicity, Neuroleptic Agents

Stroke, Ischemic
Toxicity, Sedative-Hypnotics

Subarachnoid Hemorrhage
Toxicity, Valproate

Subdural Hematoma

Toxicity, Alcohols


Workup
Laboratory Studies
Qualitative screening of urine or blood may be performed but rarely influences treatment decisions and has no impact on immediate clinical care.
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.
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 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).
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.
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 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
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.
Flumazenil administration is contraindicated in mixed overdoses (eg, TCAs) because BZD reversal can precipitate seizures and cardiac arrhythmias.
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 ]

Consultations
Toxicologist or a poison control center
Intensive care specialist
Psychiatrist, if suicide attempt
Medication
GI decontaminant
Empirically used to minimize systemic absorption of the toxin.



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.

Dosing
Adult
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

Pediatric
Administer as in adults (typically 12.5-25 g); avoid cathartic in children <2 y

Interactions
May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications
Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions
Protect airway before administration in patients with absent gag reflex or a depressed level of consciousness; when considering repeat dosing, monitor for active bowel sounds to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

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.



Flumazenil (Romazicon)
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.

Dosing
Adult
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

Pediatric
0.002-0.02 mg/kg IV q1min

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

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

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

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

Follow-up
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 excellent patient education resources, visit eMedicine's Poisoning - First Aid and Emergency Center, Mental Health and Behavior Center, and Substance Abuse Center. Also, see eMedicine's patient education articles Benzodiazepine Abuse, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.
Miscellaneous
Medicolegal Pitfalls
Unmasking an underlying disorder, specifically seizures, with indiscriminate use of flumazenil
Administration of full dose of naloxone (0.4 mg or more) and precipitation of opioid withdrawal in patients with mixed overdose resulting in aspiration of gastric content
Administration of charcoal in patients with unprotected airway
Failure to anticipate withdrawal in a patient with chronic benzodiazepine (BZD) use
Failure to consider the possibility of co-ingestant use or secondary causes of treatable altered mental status (eg, hypoglycemia, meningitis)
References
Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila). Dec 2009;47(10):911-1084. [Medline]. [Full Text].

Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980s. Br J Psychiatry. Sep 1993;163:386-93. [Medline].

[Guideline] Kleber HD, Weiss RD, Anton RF, et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry. Aug 2006;163(8 Suppl):5-82. [Medline]. [Full Text].

[Guideline] National Collaborating Centre for Mental Health. Self-harm: the short-term physical and psychological management and secondary prevention of self-harm in primary and secondary care. London (UK): National Institute for Clinical Excellence (NICE). 2004;199. [Full Text].

Bosse GM. Benzodiazepines. In: Emergency Medicine: A Comprehensive Study Guide. 4th ed. McGraw-Hill; 1996:759-61.

Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ. Jan 28 1995;310(6974):219-21. [Medline].

Cairns C. Benzodiazepine overdose and withdrawal. In: Emergency Medicine: Concepts and Clinical Practice. 3rd ed. Mosby-Year Book; 1992:2684-9.

Drummer OH, Syrjanen ML, Cordner SM. Deaths involving the benzodiazepine flunitrazepam. Am J Forensic Med Pathol. Sep 1993;14(3):238-43. [Medline].

Hoffman RS, Wipfler MG, Maddaloni MA, Weisman RS. Has the New York State triplicate benzodiazepine prescription regulation influenced sedative-hypnotic overdoses?. N Y State J Med. Oct 1991;91(10):436-9. [Medline].

Longmire AW, Seger DL. Topics in clinical pharmacology: flumazenil, a benzodiazepine antagonist. Am J Med Sci. Jul 1993;306(1):49-52. [Medline].

Mullins ME. First-degree atrioventricular block in alprazolam overdose reversed by flumazenil. J Pharm Pharmacol. Mar 1999;51(3):367-70. [Medline].

Verghese J, Merino J. Temazepam overdose associated with bullous eruptions. Acad Emerg Med. Oct 1999;6(10):1071. [Medline].

Keywords
BZD toxicity, sedative-hypnotic toxicity, benzodiazepine toxicity, benzodiazepine treatment, flumazenil, benzodiazepine exposure, BZD exposure, seizure control, anxiety, alcohol withdrawal, alprazolam, flunitrazepam, chlordiazepoxide, diazepam, triazolam, temazepam, flurazepam, bromazepam, clorazepate, oxazepam, nitrazepam, alprazolam, lormetazepam, lorazepam, benzodiazepine overdose

Contributor Information and Disclosures
Author
Robin Mantooth, MD, FACEP, Consulting Staff, Department of Emergency Medicine, Norman Regional Health System; Adjunct Clinical Assistant Professor, Family Medicine, Oklahoma State University; Consulting Staff, Department of Emergency Medicine, Integris Southwest Medical Center; Consulting Staff, Department of Emergency Medicine, Oklahoma University Medical Center; Consulting Staff, Department of Emergency Medicine, Integris Canadian Valley Health Center; Consulting Staff, Department of Emergency Medicine, Saint Anthony Hospital; Consulting Staff, Department of Emergency Medicine, Commanche County Medical Center; Consulting Staff, Department of Emergency Medicine, Claremore Medical Center
Robin Mantooth, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Medical Editor
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor
Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor
John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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