title: Safety and efficacy of flumazenil for reversal of iatrogenic benzodiazepine-associated delirium toxicity during treatment of alcohol withdrawal, a retrospective review at one center.
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.
authors.affiliation: Department of Internal Medicine, Harrisburg Hospital, PinnacleHealth, Harrisburg, PA, 17101, USA, pwmoore@pinnaclehealth.org.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Moore
authors.forename: J Ward
authors.initials: JW
authors.lastname: Donovan
authors.forename: Keith K
authors.initials: KK
authors.lastname: Burkhart
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Waskin
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hieger
authors.forename: Audrey R
authors.initials: AR
authors.lastname: Adkins
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wert
authors.forename: David A
authors.initials: DA
authors.lastname: Haggerty
authors.forename: J J
authors.initials: JJ
authors.lastname: Rasimas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000427:Alcohol Deterrents / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D000430:Alcohol Withdrawal Delirium / Q000209:etiology / Q000517:prevention & control; D020270:Alcohol Withdrawal Seizures / Q000209:etiology / Q000517:prevention & control; D000931:Antidotes / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D003693:Delirium / Q000209:etiology / Q000517:prevention & control; D003937:Diagnosis, Differential; D039721:Diagnostic and Statistical Manual of Mental Disorders; D016903:Drug Monitoring; D000431:Ethanol / Q000009:adverse effects; D005260:Female; D005442:Flumazenil / Q000009:adverse effects / Q000627:therapeutic use*; D018757:GABA Modulators / Q000009:adverse effects / Q000627:therapeutic use; D006785:Hospitals, University; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D010414:Pennsylvania; D012189:Retrospective Studies; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000427:Alcohol Deterrents; D000931:Antidotes; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil