AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Since initial development in the 1950s, benzodiazepine has become popular in the treatment of various medical disorders and as a drug of abuse. Benzodiazepine overdoses (usually combined with alcohol) are commonly observed in emergency departments (EDs) and intensive care units (ICUs).

Pathophysiology

Ingested benzodiazepines are rapidly absorbed. In the serum, more than 70% of the drug is protein bound and thus unavailable to produce a clinical affect. The unbound fraction crosses the blood-brain barrier and interacts with neuronal benzodiazepine receptors in the CNS.

In the CNS, benzodiazepines exert their clinical effect by enhancing the activity of the inhibitory neurotransmitter GABA. GABA receptors, located on postsynaptic neurons, cause an influx of negatively charged chloride ions into the neuron when stimulated by GABA. This influx of negative charge causes a hyperpolarization of the cell membrane and therefore inhibits depolarization. The binding of a benzodiazepine molecule to a site on the GABA receptor complex potentiates the inhibitory effect of GABA by increasing the frequency of chloride channel opening.

Duration of the clinical effect is proportional to the drug concentration in the CNS. Benzodiazepines that quickly diffuse from the CNS (more lipophilic) have a relatively short duration of action yet may have a long half-life. The clinical effects of GABA release and binding of the GABA receptor include sleep induction and excitement inhibition.

Frequency

United States

In 1998, 40,004 benzodiazepine overdoses and 53 deaths were reported.

Mortality/Morbidity

Benzodiazepine overdose in itself is remarkably safe. Numerous studies have demonstrated that most patients with benzodiazepine overdose can be managed in the ED and released home after appropriate care. When combined with other sedatives (most frequently alcohol), patients with benzodiazepine overdose can present with profoundly depressed levels of consciousness.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

History should include the time, dose, intent of the overdose, and if possible, the type of benzodiazepine, as some may be more toxic than others. Determine the presence of co-ingestants and the duration of benzodiazepine use. Benzodiazepine's main effect is CNS depression, thus patients' complaints center on decreased neurologic function. Complaints may include blurred vision, dizziness, confusion, drowsiness, anxiety, agitation, and unresponsiveness or coma.

Physical

Physical examination should focus on vital signs and cardiorespiratory and neurologic function.

• Vital signs
• • Decreased respiratory rate
  • Hypotension
  • Decreased oxygen saturation level
• Central nervous system
• General
  • Hallucinations
  • Slurred speech
  • Ataxia
• Altered mental status
  • Coma
  • Impairment of cognition
• Examination
• Nystagmus
• Hypotonia
• Weakness
• Respiratory depression
• Cardiovascular system (CVS) - Hypotension

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The differential diagnosis is wide and includes the many causes of altered mental status. Remember that patients with benzodiazepine overdoses commonly ingest other toxic substances, whose signs and symptoms may be masked. A thorough search for all possible co-ingestants is warranted.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Patients referred to an ICU usually have significant instability or altered mental status. Although benzodiazepines can lead to respiratory depression and cardiac instability, a thorough search for other contributing illnesses and factors is warranted.
• CBC count: Search for possible sepsis (high WBC count) and anemia (decreased hemoglobin level), which may contribute to the presentation.
• Electrolytes: Some electrolyte abnormalities can affect the functioning of the CNS and thus contribute to the presentation. Specifically, measure sodium, calcium, magnesium, and phosphate levels.
• Urea and creatinine: Significant dysfunction of the kidney can affect the functioning of the CNS.
• Blood glucose: Hyperglycemia and hypoglycemia can affect the functioning of the CNS.
• Cardiac enzymes: This test is warranted in patients with significant cardiovascular instability.
• Myoglobin: This test is warranted in patients who may be at risk for the development of rhabdomyolysis.
• Toxicologic screen: Benzodiazepines can be easily identified in routine urine toxicologic screens, but this may not aid in treatment, as cause and effect cannot be demonstrated. Other drugs may be identified, which can confound the presentation of a patient with benzodiazepine overdose.

Imaging Studies

• CNS: Perform CT scanning or MRI in a patient with significant decreased level of consciousness in order to exclude other intracerebral pathology.
• CVS: ECG is useful in any unstable patient as a baseline and as a diagnostic tool in patients who have coexisting electrolyte abnormalities (potassium) or who have co-ingested other agents (ie, tricyclic antidepressants [TCAs]).
• Respiratory: Obtain a chest x-ray of patients with significant respiratory depression to identify lung pathologies (eg, aspiration pneumonia).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• General care: The most important aspect of the management of benzodiazepine overdoses is good supportive care.
• Airway and breathing
  • The airway must be controlled in any patient with significantly decreased level of consciousness or respiratory insufficiency.
  • Supplementary oxygen may be all that is needed if patients are alert enough to protect the airway (gag reflex) and to breathe on their own. Endotracheal intubation is warranted if patients cannot maintain airways and breathing on their own.
  • Cardiac, noninvasive blood pressure, and pulse oximetry monitoring are required for all patients.
• Circulation
  • Intravenous access is needed for all patients.
  • Significant cardiovascular instability may warrant central venous access in order to provide medications, fluids, and invasive monitoring data.
• Monitoring: Continuous monitoring is needed in all unstable patients.
• Limitation of toxic exposure
  • As with any overdose, an attempt to minimize toxicologic effects is warranted.
  • Agents that have been orally ingested may be absorbed by activated charcoal. Activated charcoal is beneficial if it can be administered within 2-4 hours of ingestion and if the risk of aspiration is minimal.
• Dialysis: Dialysis is not useful because of benzodiazepine's large volume of distribution and high level of protein binding.
• Antidote
  • Flumazenil is a competitive antagonist of the GABA receptor and therefore is a specific antidote for benzodiazepine overdoses; however, use of flumazenil for benzodiazepine overdoses is controversial. Significant adverse effects, such as seizures and acute benzodiazepine withdrawal, have been reported.
  • Use of flumazenil causes a decrease in the seizure threshold by blocking the binding of GABA. Flumazenil use in overdoses with co-ingestion of substances that tend to induce seizures (eg, TCAs) may actually precipitate seizure activity.
  • In the authors' view, flumazenil should be used cautiously, if at all. The most important indication is to reverse iatrogenic oversedation with benzodiazepines during procedural sedation.
  • Flumazenil should not be used routinely or as part of a "coma cocktail."

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce absorption of the drug, prevent complications, and reduce morbidity.

Drug Category: Antidote, benzodiazepine

A selective competitive antagonist of the GABA receptor and the only available specific antidote for benzodiazepines. Reversal may result in seizure or status epilepticus.

Drug Category: Antidote, adsorbent

Empirically used to minimize systemic absorption of the ingested toxin.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit all patients in unstable condition to the ICU for ongoing care. A pure benzodiazepine overdose can be managed with supportive care. Elimination of all unnecessary potential CNS depressants is advisable.
• The use of multidose activated charcoal is not indicated because it is not beneficial.
• Evaluation by a psychiatrist is advisable prior to discharge for any patient whose overdose is intentional.

Complications

• CNS depression - Aspiration, respiratory compromise, anoxic brain injury, coma
• Complications of intubation
• Rhabdomyolysis
• Death: Due to prolonged apnea or co-ingestants

Prognosis

• Overall prognosis is good if adequate supportive care is instituted.

Patient Education

• For excellent patient education resources, visit emedicine's Substance Abuse Center. Also, see eMedicine's patient education articles Benzodiazepine Abuse and Substance Abuse.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider possible co-ingestants
• Failure to provide adequate supportive care
• Use of activated charcoal in patients with a compromised airway or in patients who have ingested a benzodiazepine more than 2-3 hours earlier
• Indiscriminate use of flumazenil
• Failure to provide adequate psychological evaluation after resuscitation

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bledsoe BE. No more coma cocktails. Using science to dispel myths and improve patient care. JEMS. 2002;Nov;27(11):54-60. [Medline].
• Bosse GM. Benzodiazepines. In: Emergency Medicine: A Comprehensive Study Guide. 2000. McGraw-Hill Book Co.
• Buckley NA, Dawson AH, Whyte IM. Relative toxicity of benzodiazepines in overdose. BMJ. Jan 28 1995;310(6974):219-21. [Medline].
• Farrell SE, Roberts JR. Benzodiazepines. In: Clinical Management of Poisoning and Overdose. W B Saunders Co. 1998;609-628.
• Fraser AD. Use and abuse of benzodiazepines. Ther Drug Monit. 1998;Oct;20(5):481-9.
• Isbister GK, O'Regan L, Sibbritt D. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. Jul 2004;58(1):88-95. [Medline].
• Litovitz TL, Klein-Schwartz W, Caravati EM, et al. 1998 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1999;17(5):435-87. [Medline].
• Maxa JL, Ogu CC, Adeeko MA. Continuous-infusion flumazenil in management of chlordiazepoxide toxicity. Pharmacotherapy. 2003;Nov;23(11):1513-6. [Medline].
• Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Ann Emerg Med. Dec 1993;22(12):1813-21. [Medline].
• Weinbroum AA, Flaishon R, Sorkine P, et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf. Sep 1997;17(3):181-96. [Medline].

Article Last Updated: May 19, 2006