Effects Of The Benzodiazepine Antagonist Flumazenil In Hepatic Encephalopathy in Man

Abstract

We tested the proposed role of increased γ-aminobu-tyric acid (GABA) neurotransmission in the pathogenesis of hepatic encephalopathy by acute intravenous administration of the benzodiazepine antagonist flumazenil to 14 patients with hepatic encephalopathy due to cirrhotic liver disease. Flumazenil administration induced variable and transient, but distinct improvements of the mental status in 71% of patients. Grade IV hepatic encephalopathy converted to grade II in 4 patients and to grade III in 2 patients. Although all patients with less advanced encephalopathy (3 grade III, 1 grade II) did also improve, their responses were clinically less impressive. The arousal effect occurred in less than 1 minute and lasted for 1 to 2 hours. Furthermore, it was accompanied by a significant increase of the mean EEG frequency from 4.2 to 5.2 cycles per second. Among 8 patients who could ultimately be discharged from the hospital 7 responded to flumazenil, whereas no patient dying within 48 hours after flumazenil testing showed any arousal effect. These results strongly favour a prominent pathogenetic role of increased GABAergic tone in hepatic encephalopathy in man and suggest that positive flumazenil response might be of prognostic value in predicting short-term survival in severe hepatic encephalopathy.