Abstract
Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10–530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics (n = 57), opioids (n = 27), clonidine (n = 35), and phenobarbital (n = 23). Average time of flumazenil administration was 4.7 days (1–11 days) after abstinence, and average dose was 0.5 mg (0.2–1 mg). At the time of flumazenil administration, delirium was described as hypoactive (n = 21), hyperactive (n = 15), mixed (n = 41), or not specified (n = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.
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References
Short TG, Young KK, Tan P, Tam YH, Gin T, Oh TE (1994) Midazolam and flumazenil pharmacokinetics and pharmacodynamics following simultaneous administration to human volunteers. Acta Anaesthesiol Scand 38:350–356
Ma JD, Lawendy NM, Fullerton T, Snyder PJ, Nafziger AN, Bertino JS Jr (2009) Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe. Int J Clin Pharmacol Ther 47:111–119
Jones RD, Chan K, Roulson CJ, Brown AG, Smith ID, Mya GH (1993) Pharmacokinetics of flumazenil and midazolam. Br J Anaesth 70:286–292
Oliver FM, Sweatman TW, Unkel JH, Kahn MA, Randolph MM, Arheart KL et al (2000) Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon) in an animal model. Pediatr Dent 22:489–493
Mandema JW, Gubbens-Stibbe JM, Danhof M (1991) Stability and pharmacokinetics of flumazenil in the rat. Psychopharmacology (Berlin) 103:384–387
Kretz FJ, Loscher W, Peisdersky B, Kraft A, Eyrich K (1990) Flumazenil (Anexate): pharmacodynamics, pharmacokinetics, indications and contraindications. Med Klin (Munich) 85:156–162, 69
Klotz U, Kanto J (1988) Pharmacokinetics and clinical use of flumazenil (Ro 15–1788). Clin Pharmacokinet 14:1–12
Klotz U (1988) Drug interactions and clinical pharmacokinetics of flumazenil. Eur J Anaesthesiol Suppl 2:103–108
Kim YJ, Lee H, Kim CH, Lee GY, Baik HJ, Han JI (2012) Effect of flumazenil on recovery from anesthesia and the bispectral index after sevoflurane/fentanyl general anesthesia in unpremedicated patients. Korean J Anesthesiol 62:19–23
Karakosta A, Andreotti B, Chapsa C, Pouliou A, Anastasiou E (2010) Flumazenil expedites recovery from sevoflurane/remifentanil anaesthesia when administered to healthy unpremedicated patients. Eur J Anaesthesiol 27:955–959
Henthorn KM, Dickinson C (2010) The use of flumazenil after midazolam-induced conscious sedation. Br Dent J 209:E18
Potokar J, Coupland N, Glue P, Groves S, Malizia A, Bailey J et al (1997) Flumazenil in alcohol withdrawal: a double-blind placebo-controlled study. Alcohol Alcohol 32:605–611
Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP (2012) Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. Emerg Med J 29:565–569
Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA (2012) A poison center's ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med
The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group (1992) Treatment of benzodiazepine overdose with flumazenil. Clin Ther 14:978–995
Weinbroum A, Rudick V, Sorkine P, Nevo Y, Halpern P, Geller E et al (1996) Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 24:199–206
Soleimanpour H, Ziapour B, Negargar S, Taghizadieh A, Shadvar K (2010) Ventricular tachycardia due to flumazenil administration. Pak J Biol Sci PJBS 13:1161–1163
Rasimas JJ, Smolcic EE, Cressell A, Sachdeva K, Donovan JW (2010) Bedside toxicologic experience with physostigmine and flumazenil. Clin Toxicol Abstract
Ngo AS, Anthony CR, Samuel M, Wong E, Ponampalam R (2007) Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation 74:27–37
Dunton AW, Schwam E, Pitman V, Leese P, Siegel J (1988) The relationship between dose and duration of action of intravenous flumazenil in reversing sedation induced by a continuous infusion of midazolam. Eur J Anaesthesiol Suppl 2:97–102
Camus V, Gonthier R, Dubos G, Schwed P, Simeone I (2000) Etiologic and outcome profiles in hypoactive and hyperactive subtypes of delirium. J Geriatr Psychiatry Neurol 13:38–42
Camus V, Burtin B, Simeone I, Schwed P, Gonthier R, Dubos G (2000) Factor analysis supports the evidence of existing hyperactive and hypoactive subtypes of delirium. Int J Geriatr Psychiatry 15:313–316
Stagno D, Gibson C, Breitbart W (2004) The delirium subtypes: a review of prevalence, phenomenology, pathophysiology, and treatment response. Palliat Support Care 2:171–179
Khan BA, Guzman O, Campbell NL, Walroth T, Tricker J, Hui SL et al (2012) Comparison and agreement between the Richmond agitation-sedation scale and the Riker sedation-agitation scale in evaluating patients’ eligibility for delirium assessment in the ICU. Chest 142:48–54
Riker RR, Picard JT, Fraser GL (1999) Prospective evaluation of the sedation-agitation scale for adult critically ill patients. Crit Care Med 27:1325–1329
Riker RR, Fraser GL (2001) Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Sem Respir Crit Care Med 22:189–198
Mancuso CE, Tanzi MG, Gabay M (2004) Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy 24:1177–1185
Maldonado JR (2010) An approach to the patient with substance use and abuse. Med Clin N Am 94:1169–1205, x-i
Lheureux P, Vranckx M, Leduc D, Askenasi R (1992) Flumazenil in mixed benzodiazepine/tricyclic antidepressant overdose: a placebo-controlled study in the dog. Am J Emerg Med 10:184–188
Gilbert EH, Lowenstein SR, Koziol-McLain J, Barta DC, Steiner J (1996) Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med 27:305–308
Worster A, Bledsoe RD, Cleve P, Fernandes CM, Upadhye S, Eva K (2005) Reassessing the methods of medical record review studies in emergency medicine research. Ann Emerg Med 45:448–451
Acknowledgments
The authors thank Helen Houpt MSLS, AHIP, for assistance with editing and manuscript preparation, Elizabeth Morgan for general library services and assistance obtaining specified references, and Betty Ruppert and Amanda Cresswell RN, MSN, CMSRN, for assistance with study coordination and chart review.
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Moore, P.W., Donovan, J.W., Burkhart, K.K. et al. Safety and Efficacy of Flumazenil for Reversal of Iatrogenic Benzodiazepine-Associated Delirium Toxicity During Treatment of Alcohol Withdrawal, a Retrospective Review at One Center. J. Med. Toxicol. 10, 126–132 (2014). https://doi.org/10.1007/s13181-014-0391-6
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DOI: https://doi.org/10.1007/s13181-014-0391-6