Previous reports have suggested that "endogenous"
benzodiazepines could contribute to neural inhibition in
hepatic encephalopathy.
RO 15-1788 (
flumazenil), a specific antagonist of brain
benzodiazepine receptors, could thus reverse the neurological symptoms of
hepatic encephalopathy. 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
benzodiazepines, and 21 patients were randomly assigned to the
flumazenil group (11 patients) or the placebo group (10 patients). Treatment was administered intravenously as a 20-ml
solution (placebo or 2 mg
flumazenil); seven patients were crossed over. Clinical status was assessed 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 observers. Serum concentrations of
benzodiazepines before treatment were measured by means of a fluorescence polarization immunoassay. Improvement in neurological symptoms was observed in six patients treated with
flumazenil, 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 with two patients in the placebo group (p = NS).
Benzodiazepines were found in the serum of four patients treated with
flumazenil (two responders and two nonresponders); all of these patients had received
pharmaceutical benzodiazepines 4 to 6 days before the trial.(ABSTRACT TRUNCATED AT 250 WORDS)