EFFECT OF FLUMAZENIL ON THE ELECTROENCEPHALOGRAM OF PATIENTS WITH PORTOSYSTEMIC ENCEPHALOPATHY - RESULTS OF A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED MULTICENTER TRIAL

The efficacy of the benzodiazepine antagonist flumazenil has been asse ssed clinically in a double blind, randomised, placebo-controlled mult icentre study in patients with grade I-III portosystemic encephalopath y. In an ancillary study reported here the effect of flumazenil on the electroencephalogram (EEG) was analysed in 32 patients who had EEG gr ading according to protocol. Following the baseline observation period , patients were randomised to receive (at 1 min interval) 3 sequential bolus injections of flumazenil (0.4, 0.8 and 1 mg) or placebo followe d by infusions of flumazenil (1 mg/h) or placebo for 3 h. Patients wer e monitored for 5 h after infusion. A positive response was defined as 1 point improvement in EEG grade. After independent analysis of the E EG gradings 5 out of 17 (29%) flumazenil treated patients showed an im provement in EEG grading (3 after bolus, 2 during follow-up) compared to 2 out of 15 (13%) placebo treated patients (1 after bolus, 1 during follow-up) (95% confidence interval of difference: -12% to +50%). Of the 5 EEG responders after flumazenil, 3 also had an improvement in cl inical PSE grading (none after bolus, 2 during infusion, 1 during foll ow-up), compared to neither of the 2 EEG responders after placebo. EEG responders did not differ from non-responders with respect to Child-P ugh score, basal EEG, PSE grade and positivity for benzodiazepines. In conclusion, treatment perspectives for flumazenil in portosystemic en cephalopathy appear to be present for only a minority of patients; how ever, this study yields no support for a major role of benzodiazepine antagonists in the treatment of hepatic encephalopathy.