FLUMAZENIL IN CIRRHOTIC-PATIENTS IN HEPATIC-COMA - A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED CROSSOVER TRIAL

Previous reports have suggested that ''endogenous'' benzodiazepines co uld contribute to neural inhibition in hepatic encephalopathy. RO 15-1 788 (flumazenil), a specific antagonist of brain benzodiazepine recept ors, could thus reverse the neurological symptoms of hepatic encephalo pathy. To test this possibility, we conducted a double-blind, placebo- controlled crossover trial of the efficacy of flumazenil in cirrhotic patients in hepatic coma. Seventy-seven cirrhotic patients in hepatic coma were evaluated. Fifty-six were excluded from the trial because of multiorgan failure or because coma was precipitated by prior use of b enzodiazepines, and 21 patients were randomly assigned to the flumazen il group (11 patients) or the placebo group (10 patients). Treatment w as administered intravenously as a 20-ml solution (placebo or 2 mg flu mazenil); seven patients were crossed over. Clinical status was assess ed blindly by two observers, using a modified Glasgow scale, every 15 min for 6 hr. Electroencephalogram tracings obtained before and after drug administration were evaluated blindly by two independent observer s. Serum concentrations of benzodiazepines before treatment were measu red by means of a fluorescence polarization immunoassay. Improvement i n neurological symptoms was observed in six patients treated with flum azenil, whereas none in the placebo group showed improvement (p < 0.05 ; Fisher's exact test). Improvements in electroencephalogram tracings were demonstrated in four patients treated with flumazenil, compared w ith two patients in the placebo group (p = NS). Benzodiazepines were f ound in the serum of four patients treated with flumazenil (two respon ders and two nonresponders); all of these patients had received pharma ceutical benzodiazepines 4 to 6 days before the trial. We conclude tha t flumazenil is effective in a subset of highly selected cirrhotic pat ients with severe hepatic encephalopathy and that this beneficial effe ct is not related to the presence of benzodiazepines in the blood.