title: A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department.
abstract: OBJECTIVE
  To determine if flumazenil, when used in doses higher than those currently recommended, could reverse the effects of a benzodiazepine (BDZ) overdose in patients who might not otherwise respond and whether the higher dose was associated with increased adverse effects.
  
  
  METHODS
  Multicenter, randomized, double-blind, placebo-controlled, balanced, with parallel groups. Open-label flumazenil administration was available if a patient failed to respond or became resedated.
  
  
  METHODS
  Sixteen emergency departments in the United States.
  
  
  METHODS
  Patients presenting to the ED with clinically significant signs and symptoms of a known or suspected BDZ overdose.
  
  
  METHODS
  Patients were randomized to receive 10 mL/min of placebo or flumazenil (1 mg/10 mL) each minute for ten minutes. If there was no response, up to 3 mg of open-label flumazenil could be administered.
  
  
  RESULTS
  Of 170 patients enrolled, 87 received flumazenil and 83 received placebo. The demographic characteristics of both groups were comparable. Ten minutes after the beginning of study drug infusion, patients were evaluated using the Clinical Global Impression Scale (CGIS), Glasgow Coma Scale (GSC), and Neurobehavioral Assessment Scale (NAS). The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. The mean +/- SD dose of flumazenil administered during the double-blind phase was 71.3 +/- 34.2 mL (7.13 mg) compared with 95.06 +/- 16.03 mL of placebo. Of the 39 patients who had BDZ-positive drug screens and received flumazenil, 29 (74%) responded to 3 mg or less. Six additional patients responded to 4 or 5 mg, and one patient responded to 8 mg. The most common adverse effects in patients who received flumazenil were injection site pain (10.3%), agitation (8%), vomiting (3.4%), dizziness (3.4%), headache (3.4%), tachycardia (3.4%), and crying (3.4%). Three patients developed seizures. Two were associated with significant tricyclic antidepressant overdoses and one with propoxyphene ingestion. Two patients had positive drug screens for BDZ.
  
  
  CONCLUSIONS
  Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Most patients will respond to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk for developing seizures.
authors.affiliation: Department of Emergency Medicine, Medical College of Pennsylvania, Philadelphia.
authors.forename: W H
authors.initials: WH
authors.lastname: Spivey
authors.forename: J R
authors.initials: JR
authors.lastname: Roberts
authors.forename: R W
authors.initials: RW
authors.lastname: Derlet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001569:Benzodiazepines / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D062787:Drug Overdose / Q000188:drug therapy; D004636:Emergency Service, Hospital; D005260:Female; D005442:Flumazenil / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests
chemical_list: D001569:Benzodiazepines; D005442:Flumazenil