EVALUATION OF THE EFFICACY AND SAFETY OF FLUMAZENIL IN THE TREATMENT OF PORTAL-SYSTEMIC ENCEPHALOPATHY - A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED MULTICENTER STUDY

Background-Portal systemic encephalopathy (PSE) is a complex neuropsyc hiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be eff ective in ameliorating PSE. Aims-To determine the efficacy of flumazen il in patients with non-comatous mild to moderate PSE (stages I to III ) due to severe chronic liver disease. Patients-49 male and female adu lts without symptoms of severe bleeding and sepsis and who screened ne gative for benzodiazepine in both blood and urine, were included in th e study. Methods-Patients were randomised to receive either three sequ ential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either f lumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading an d vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures we re improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement). Results-The mean average improvement in the PSE score in the subjects treated wit h flumazenil was not statistically significantly different from placeb o. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significan t (seven of 28 v none of 21; p=0.015). Flumazenil was well tolerated. Conclusions-A subgroup of patients with PSE resulting from chronic liv er disease may benefit from the administration of flumazenil.