Treatment of Benzodiazepine Toxicity and the Use of Flumazenil
Substance Use, Toxicology
First 5 Minutes
- Focus on airway and breathing. Patient may require intubation and ventilation, especially given the high likelihood of co-ingestion of contamination of benzodiazepines with opioids.
- Administer activated charcoal if ingestion is less than one hour.
- Rule out co-ingestion of other substances.
- Flumazenil can be considered if known benzodiazepine overdose in the absence of coma NYD, mixed overdoses, and patients with benzodiazepine dependence (controversial).
Context
Benzodiazepines are GABA-potentiating substances that have anxiolytic, sedative, anticonvulsant, and muscle-relaxing effects.
In overdose/toxicity, benzodiazepines cause CNS depression, but death is rare and usually attributed to co-ingestion of other drugs or alcohol. Adulteration of benzodiazepines in British Columbia makes resuscitation complex.
Examples include alprazolam (Xanax®), clobazam, clonazepam, diazepam (Valium®), lorazepam (Ativan®), midazolam, oxazepam, temazepam (Restoril®), and etizolam.
“Z-drugs” (e.g. zopiclone, zolpidem) are structurally unrelated to benzodiazepines, but have similar pharmacological and toxic effects.
Street drugs including benzodiazepines in BC vary significantly from the expected substance. Data from BCCSU (2022) indicated only 54% of Xanax® samples contained benzodiazepines and between 4% and 22% of benzodiazepine samples contained fentanyl.
Diagnostic Process
Diagnosis is clinical and based on history of benzodiazepine ingestion and the presence of several clinical features:
- CNS depression (e.g. drowsiness, ataxia, confusion, slurred speech, sedation).
- Paradoxical agitation, hyperexcitability, hyperactivity, disinhibition, or aggression
- Coma (uncommon with benzodiazepines alone).
- Death is rare. Benzodiazepines have a wide therapeutic index. Death usually occurs due to co-ingestion with other drugs or alcohol.
Recommended Treatment
Treatment is largely supportive. If patients are asymptomatic, they should be observed for several hours.
Symptomatic patients require supportive management and observation until symptoms resolve.
- Assess airway. Ensure patient is protecting airway. Intubate and ventilate if required.
- If ingestion was recent, administer activated charcoal.
- Monitor vital signs.
- Consider administration of flumazenil. Do not rely on flumazenil for treatment of respiratory function. Standard supportive measures should be utilized.
- Avoid forced diuresis or hemodialysis.
Flumazenil Information and Dosing
Flumazenil is the antidote for benzodiazepines. It is a competitive antagonist at benzodiazepine receptors in the CNS.
It has action against benzodiazepines and “Z-drugs”.
It reverses sedative, amnestic, anticonvulsant, anxiolytic, and muscle relaxant effects of benzodiazepines. It may reverse paradoxical agitation effects as well. It has a benefit for ventilation, but this is poorly understood.
Flumazenil is controversial in benzodiazepine toxicity as it may increase the risk of ventricular dysrhythmias and seizures, the latter of which may be difficult to treat.
Indications
- Reversal of iatrogenic sedation.
- Severe paradoxical reactions.
- Limited role in benzodiazepine and “Z-drug” toxicity.
Contraindications
- Patients with seizure disorders.
- Coma NYD.
- Mixed overdose (especially with TCAs or substances that may cause seizure or cardiac dysrhythmias).
- Patients with benzodiazepine dependence (controversial).
Not Recommended
- Patients with anticholinergic symptoms (e.g., tachycardia, hypotension, hypoxia, ECG changes, hyperreflexia, increased muscle tone, dyskinesias).
Dosing
- 0.2-0.3mg IV over 30 seconds. Repeat in 60-second intervals until desired effect. Typical response with 1-3mg IV or less. Unlikely to achieve benefit >5mg.
- If initial benefit, maintenance dose may be considered. Continuous IV infusion suggested rate 0.1-0.5mg/hr IV up to 1.5mg/hr IV. Stop infusion and reassess every 6-12 hours.
- Children (limited data) initial loading 0.01mg/kg IV (max 0.2mg) give over 30 seconds. Repeat every minute until target effect achieved. Maximum 1mg total.
- Safe in pregnancy.
Monitoring
- Cardiac monitoring.
- Vital signs.
- Maintain IV access.
- Observe every hour for re-sedation as half-life ~1 hour.
Criteria For Hospital Admission
Not well defined in literature.
Criteria For Transfer To Another Facility
In cases of isolated benzodiazepine toxicity, management will be primarily supportive, and few patients will require transfer.
Criteria For Close Observation And/or Consult
Asymptomatic patients will require observation for several hours. Symptomatic patients will require supportive care and observation until symptoms resolve.
Physicians should contact BC Poison Control Centre for consideration of the use of flumazenil in patients with benzodiazepine toxicity.
Criteria For Safe Discharge Home
Asymptomatic patients may be discharged after a period of observation. Initially symptomatic patients may be discharged after supportive care and resolution of symptoms.
Quality Of Evidence?
High
We are highly confident that the true effect lies close to that of the estimate of the effect. There is a wide range of studies included in the analyses with no major limitations, there is little variation between studies, and the summary estimate has a narrow confidence interval.
Moderate
We consider that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. There are only a few studies and some have limitations but not major flaws, there are some variations between studies, or the confidence interval of the summary estimate is wide.
Low
When the true effect may be substantially different from the estimate of the effect. The studies have major flaws, there is important variations between studies, of the confidence interval of the summary estimate is very wide.
Justification
Benzodiazepine Toxicity at High Doses
Information regarding toxicity at high doses is based primarily on case reports through the BC Drug and Poison Information Centre.
Flumazenil as a Cause of Seizures and Ventricular Dysthymias
The recommendation to avoid flumazenil in benzodiazepine overdose is based on opinion from the BC Centre for Substance Use.
Recommendations Regarding Supportive Management
Recommendations are based on monographs from BC Drug and Poison Information Centre. Information lacks citation and evidence base. Several references to case studies are noted throughout the monograph.
Recommendations Regarding Flumazenil Dosing
Recommendations are based on monographs from BC Drug and Poison Information Centre. Information lacks citation and evidence base.
Related Information
Reference List
Russell R, Buxton J, Godwin J, Moe J. Potent sedatives in opioids in BC: Implications for resuscitation, and benzodiazepine and etizolam withdrawal. BC Med J. 2021;63(4):177-178.
Poison Management Manual. Flumazenil – Antidote. BC Drug and Poison Information Centre; 2015. Accessed November 29, 2022. http://dpic.org/
Poison Management Manual. Benzodiazepines and Related Drugs. BC Drug and Poison Information Centre; 2015. Accessed November 29, 2022. http://dpic.org/
Knill A, Tobias S, Matthews J, Ti L. A Report on British Columbia’s Unregulated Drug Supply. British Columbia Centre on Substance Use. 2022. Accessed November 29, 2022. https://www.bccsu.ca/
RESOURCE AUTHOR(S)
DISCLAIMER
The purpose of this document is to provide health care professionals with key facts and recommendations for the diagnosis and treatment of patients in the emergency department. This summary was produced by Emergency Care BC (formerly the BC Emergency Medicine Network) and uses the best available knowledge at the time of publication. However, healthcare professionals should continue to use their own judgment and take into consideration context, resources and other relevant factors. Emergency Care BC is not liable for any damages, claims, liabilities, costs or obligations arising from the use of this document including loss or damages arising from any claims made by a third party. Emergency Care BC also assumes no responsibility or liability for changes made to this document without its consent.
Last Updated Dec 27, 2022
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