Flumazenil therapy for hepatic encephalopathy. A double-blind cross over study

Thirty-one patients with acute or chronic liver disease were included in the study to investigate the effect of flumazenil on hepatic encephalopathy. After screening for recent benzodiazepine use or non-hepatic causes of encephalopathy, 18 patients entered a double-blind cross-over study. The 13 remaining patients, most of them with renal failure or recent use of benzodiazepines, were given flumazenil in an open study. In the controlled study, flumazenil (1.0 mg) or placebo was given in a single injection on two separate days to study the immediate effect; half the patients received a continuous infusion of flumazenil (0.25 mg/h) or placebo for two 3-day periods to study a potential steady state effect. In the open study, a single bolus of flumazenil (1.0 mg) was given.

In the controlled study, fifteen minutes after bolus injection, the clinical grade of hepatic encephalopathy decreased in 6 patients after injection of flumazenil, whereas a decrease was found in 2 after the placebo (P = 0.06). However, the EEG grade did not change in any of the patients, and the changes in the mean dominant frequency as measured by spectral analysis did not differ between flumazenil and the placebo. Furthermore, patients on flumazenil did not differ significantly from those on placebo during the infusion period. Subgroup analysis of underlying liver disease and the causes of encephalopathy revealed a trend for clinical improvement only in the patients with chronic liver disease, but without significant changes in the mean dominant frequency. In the open study, the clinical grade of encephalopathy decreased in 3 patients and, in contrast to the controlled study, the EEG also improved in 2 patients and the mean dominant frequency increased significantly. Responders had previously used benzodiazepines.

Our study does not support a major therapeutic effect of flumazenil on hepatic encephalopathy.