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Benzodiazepines
Poisonous Substances
Benzodiazepines
ingested. It may require special attention when the patient has pre-existing chronic obstructive pulmonary disease.
D Nicholas Bateman
Management Generally, the only management required is careful nursing and supportive care. A specific benzodiazepine antagonist (flumazenil) may be given in carefully selected patients, usually to avoid ventilation. Its efficacy is determined clinically from the improvement in consciousness level and respiration. Flumazenil is used more often than is justified by the severity of the poisoning and should be reserved for patients with coma, hypotension or respiratory depression who are known not to be benzodiazepine dependant, not to have epilepsy, and not to have ingested proconvulsants concurrently.3,4 It may precipitate convulsions and cardiac arrhythmias when tricyclic antidepressants have been taken and a normal electrocardiogram (ECG) is mandatory (i.e. no QRS or QT abnormality).5 The usual target group for flumazenil would be patients with obstructive airways disease, or possibly to avoid ventilation in a child (unlicensed). Flumazenil has a short half-life (about 1 hour). Therefore, patients with severe poisoning in whom it is indicated may need repeated doses (0.5 mg intravenously over 1 minute, the same dose repeated if there is no response or only a partial response) or an intravenous infusion (0.1–0.5 mg/hour). Most patients poisoned with benzodiazepines will respond to flumazenil (1 mg). Many benzodiazepines have long half-lives (e.g. diazepam, 36 hours) or active metabolites with long half-lives (e.g. nordiazepam, about 100 hours) and, though major functions return rapidly, it may be several days before patients recover the ability to perform skilled tasks safely. ◆
Abstract Benzodiazepine compounds are rarely fatal if ingested alone however, they potentiate central nervous system depression caused by co-ingested medication. Although an antagonist, flumazenil, is available its use in overdose is associated with significant hazard, including the risk of precipitation of convulsions. Routine use is, therefore, not advised, and indications are restricted to patients who are naive to benziodiazepines, and have not ingested potentially cardiotoxic agents, and to avoid ventilation in children and patients with COPD.
Keywords benzodiazepines; diazepam; flumazenil; zolpidem; zopiclone
Many benzodiazepine compounds are marketed; the main differences relate to their duration of action. Benzodiazepines and the related non-benzodiazepine hypnotic agents (zaleplon, zopiclone and zolpidem) are often taken in overdose with central nervous system (CNS) depressants or ethanol, and potentiate the respiratory depressant effects of the co-ingestants. Combination with opioids appears to be particularly hazardous. However, co-ingestion of benzodiazepines may be beneficial if the other agent taken causes convulsions. For this reason routine use of benzodiazepine antagonists in poisoning as a ‘diagnostic test’ is absolutely contraindicated.
References 1 Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Safety 1991; 6: 247–65. 2 Hojer J, Baechrendtz S, Gustafsson L. Benzodiazepines poisoning: Experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226: 117–22. 3 Kulka PJ, Lauven PM. Benzodiazepine antagonists - an update of their role in the emergency care of overdose patients. Drug Safety 1992; 7: 381–86. 4 Weinbroum A, Rudick V, Sorkine P, et al. Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 1996; 24: 199–206. 5 Mordel A, Winkler E, Almog S, Tirosh M, Ezra D. Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic anti-depressant overdose. Crit Care Med 1992; 20: 1733–34.
Clinical features When taken alone in overdose, all benzodiazepines produce similar clinical features (drowsiness, dizziness, ataxia, dysarthria and nystagmus); less commonly, coma and hypotension develop.1,2 Respiratory depression is a potential complication, particularly when opioids, ethanol and other CNS depressants have also been
D Nicholas Bateman MD FRCP FRCPE FBPharmacolS FBTS is Professor in Clinical Toxicology and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. He is the PastPresident of the European Association of Poison Centres and Clinical Toxicologists. Competing interests: none declared.
MEDICINE 35:11
598
© 2007 Elsevier Ltd. All rights reserved.
Benzodiazepines
ingested. It may require special attention when the patient has pre-existing chronic obstructive pulmonary disease.
D Nicholas Bateman
Management Generally, the only management required is careful nursing and supportive care. A specific benzodiazepine antagonist (flumazenil) may be given in carefully selected patients, usually to avoid ventilation. Its efficacy is determined clinically from the improvement in consciousness level and respiration. Flumazenil is used more often than is justified by the severity of the poisoning and should be reserved for patients with coma, hypotension or respiratory depression who are known not to be benzodiazepine dependant, not to have epilepsy, and not to have ingested proconvulsants concurrently.3,4 It may precipitate convulsions and cardiac arrhythmias when tricyclic antidepressants have been taken and a normal electrocardiogram (ECG) is mandatory (i.e. no QRS or QT abnormality).5 The usual target group for flumazenil would be patients with obstructive airways disease, or possibly to avoid ventilation in a child (unlicensed). Flumazenil has a short half-life (about 1 hour). Therefore, patients with severe poisoning in whom it is indicated may need repeated doses (0.5 mg intravenously over 1 minute, the same dose repeated if there is no response or only a partial response) or an intravenous infusion (0.1–0.5 mg/hour). Most patients poisoned with benzodiazepines will respond to flumazenil (1 mg). Many benzodiazepines have long half-lives (e.g. diazepam, 36 hours) or active metabolites with long half-lives (e.g. nordiazepam, about 100 hours) and, though major functions return rapidly, it may be several days before patients recover the ability to perform skilled tasks safely. ◆
Abstract Benzodiazepine compounds are rarely fatal if ingested alone however, they potentiate central nervous system depression caused by co-ingested medication. Although an antagonist, flumazenil, is available its use in overdose is associated with significant hazard, including the risk of precipitation of convulsions. Routine use is, therefore, not advised, and indications are restricted to patients who are naive to benziodiazepines, and have not ingested potentially cardiotoxic agents, and to avoid ventilation in children and patients with COPD.
Keywords benzodiazepines; diazepam; flumazenil; zolpidem; zopiclone
Many benzodiazepine compounds are marketed; the main differences relate to their duration of action. Benzodiazepines and the related non-benzodiazepine hypnotic agents (zaleplon, zopiclone and zolpidem) are often taken in overdose with central nervous system (CNS) depressants or ethanol, and potentiate the respiratory depressant effects of the co-ingestants. Combination with opioids appears to be particularly hazardous. However, co-ingestion of benzodiazepines may be beneficial if the other agent taken causes convulsions. For this reason routine use of benzodiazepine antagonists in poisoning as a ‘diagnostic test’ is absolutely contraindicated.
References 1 Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Safety 1991; 6: 247–65. 2 Hojer J, Baechrendtz S, Gustafsson L. Benzodiazepines poisoning: Experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226: 117–22. 3 Kulka PJ, Lauven PM. Benzodiazepine antagonists - an update of their role in the emergency care of overdose patients. Drug Safety 1992; 7: 381–86. 4 Weinbroum A, Rudick V, Sorkine P, et al. Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 1996; 24: 199–206. 5 Mordel A, Winkler E, Almog S, Tirosh M, Ezra D. Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic anti-depressant overdose. Crit Care Med 1992; 20: 1733–34.
Clinical features When taken alone in overdose, all benzodiazepines produce similar clinical features (drowsiness, dizziness, ataxia, dysarthria and nystagmus); less commonly, coma and hypotension develop.1,2 Respiratory depression is a potential complication, particularly when opioids, ethanol and other CNS depressants have also been
D Nicholas Bateman MD FRCP FRCPE FBPharmacolS FBTS is Professor in Clinical Toxicology and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. He is the PastPresident of the European Association of Poison Centres and Clinical Toxicologists. Competing interests: none declared.
MEDICINE 35:11
598
© 2007 Elsevier Ltd. All rights reserved.