Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised controlled study.

Abstract

Objective-To assess the diagnostic value and safety of the benzodiazepine antagonist flumazenil in patients with coma ofunclear origin with suspected poisoning.Design-Double blind, placebo controlled, randomised study.Setting-Intensive care unit at a major teaching hospital.Patients-105 Unconscious adults admitted consecutively with suspected drug overdosage during 18 months from a total of 362 cases of poisoning. Exclusion criteria were pregnancy, epilepsy, obvious poisoning with drugs identified unequivocally from information from relatives or others as other than benzodiazepines, and coma score >10 on a scale graded from 4 to 20. Patients were allocated randomly to receive flumazenil (21 men and 32 women) or placebo (25 men and 27 women).Interventions -Intravenous injection offlumazenil (10 ml, 0-1 mg/ml) or placebo (10 ml vehicle alone) given double blind over three minutes.Main outcome measures -Serum and urine concentrations ofbenzodiazepines, antidepressants, and several other agents; blood gas tensions; standardised evaluation on admission and five minutes after the injection by means of coma scale score and urgent diagnostic or therapeutic interventions indicated according to the history and clinical examination; standardised interview after the injection to try to ascertain further information; and adverse reactions.Results-Benzodiazepines were found in the serum in 36 of the 53 patients in the flumazenil group and in 37 of the 52 who received placebo. The average coma scale score increased significantly after injection in the flumazenil group (6-4 v 12-1, p<0-001) but not in the placebo group. In the flumazenil group several interventions were rendered unnecessary by the injection: gastric lavage and urinary catheterisation (19 patients each), intubation (21), artificial ventilation and computed tomography of the brain (three patients each), blood culture and lumbar puncture (one patient each), and electroencephalography (two). In the placebo group the indications for these procedures did not change in any patient after injection. The 95% confidence interval for the difference in reduction of the frequency ofindications for gastric lavage after injection between the two groups was 21% to 51%, that for intubation 25% to 55%, and that for urinary catheterisation 21% to 51%. In the flumazenil group 21 patients gave valuable information on their drug ingestion within 10 minutes after injection compared with only one in the placebo group (p<0-001). Nine adverse reactions were recorded in the flumazenil group, eight of which were graded as mild and one severe.

Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta‐analysis

“…Flumazenil is usually used for the diagnosis of suspected poisoning in emergency situations and for the treatment of benzodiazepine intoxication 31 . This antagonist property has been proposed in the treatment of hepatic encephalopathy.…”

Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: An italian multicenter double-blind, placebo-controlled, cross-over study

“…It is difficult to affirm whether the rate of response to flumazenil represents a specific effect of the drug on HE or a nonspecific excitation of the central nervous system, as it is possible to observe in poisoning or metabolic coma. 3,4 In our study, the efficacy of flumazenil was not related to the presence or absence of benzodiazepines in the blood, because improvement of neurological and EEG scores occurred, respectively, in 91.5% (93.4% in the grade III group and 89.7% in the grade IVa group) and in 94.3% (95.8% in the grade III group and 92.9% in the grade IVa group) of responders with no detectable blood levels of benzodiazepines. These findings, which are in agreement with those reported by Pomier-Layrargues et al 8 and by us in a previous preliminary trial, 10 suggest that mechanisms alternative to the action on blood-borne benzodiazepines must be invoked, such as the action of flumazenil on benzodiazepine receptor agonist ligands synthesized in situ in brain in liver failure or some other intrinsic action of flumazenil.…”

“…These findings, which are in agreement with those reported by Pomier-Layrargues et al 8 and by us in a previous preliminary trial, 10 suggest that mechanisms alternative to the action on blood-borne benzodiazepines must be invoked, such as the action of flumazenil on benzodiazepine receptor agonist ligands synthesized in situ in brain in liver failure or some other intrinsic action of flumazenil. 8,10,28 When used in the treatment of benzodiazepine overdose, the drug works within minutes 3,4,17 ; late improvement in hepatic coma most likely represents spontaneous evolution rather than drug efficacy. [8][9][10] The time of administration of the drug may justify the difference observed in the rate of clinical response between patients receiving flumazenil directly after randomization and those receiving it during the cross-over period.…”

“…1,2 Flumazenil, a specific benzodiazepine antagonist, has been used in the treatment of intoxication patients with coma 3 and has shown diagnostic utility in coma patients with suspected poisoning. 4 Contrasting opinions exist on the therapeutic efficacy of flumazenil in the treatment of HE and on the applicability of this treatment to unselected patients with a different HE grade. [5][6][7][8][9][10] Our study was planned to assess the efficacy of flumazenil in cirrhotic patients with severe HE admitted to Intensive Care Units over a 5-year period.…”

Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication – A Systematic Review with Meta‐Analyses of Randomised Trials

“…Initially, flumazenil was considered a safe antidote with no intrinsic activity and was not only recommended to reverse coma due to benzodiazepine overdose but also as a diagnostic tool in comatose patients in the emergency department . Over the years, serious adverse events (SAEs) such as seizures and cardiac arrhythmias have been reported in patients treated with flumazenil , and there are several case reports of deaths associated with the use of flumazenil .…”