Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. The efficacy of flumazenil in subclinical to mild hepatic encephalopathic ambulatory patients. A prospective, randomised, double-blind, placebo-controlled study. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Flumazenil therapy for hepatic encephalopathy. A double-blind cross over study. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study. Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy. Differential effects of flumazenil in alcoholic and nonalcoholic cirrhotic patients. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial.
The aim of this study was to evaluate the effects of flumazenil on hepatic encephalopathy in patients with liver cirrhosis.
                . In the double blind randomized, placebo controlled study, 54 patients with hepatic encephalopathy grade III-IV were randomly assigned to receive either flumazenil 2 mg iv (group A) or placebo (group B); conventional treatment with branched-chain amino acid, saline, glucose, and lactulose was administered in both groups. A 24-hour observation period was established. Clinical improvement was defined as a 3 point decrease in the Glasgow coma score at any time within 24 hours.
                Clinical improvement was obtained in 22/28 patients in group A and in 14/26 in group B (p<0.05); improvement was observed within the first six hours in 21/22 patients in group A and only in 3/14 in group B. Mortality rate was not different between group A and B; however, all 6 non-responders in group A and only 5 out of 12 in group B died within 24 hours. Among patients with post-bleeding encephalopathy, 11 out of 17 in group A and only 2 out of 14 in group B improved (p<0.001).
                Flumazenil may exert a beneficial effect in a subset of patients with acute hepatic encephalopathy; encephalopathy associated with bleeding is more likely to respond to flumazenil; responders to the treatment usually improve within the first 6 hours while lack of response usually represents a bad prognostic sign. Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with fulminant hepatic failure and chronic liver disease. Its pathogenesis is unclear. One of the factors implicated is enhanced GABA-ergic tone, which is probably related to increased concentrations of cerebral benzodiazepine (BNZ). In the present study, we tested flumazenil, a cerebral BNZ antagonist, in cirrhosis patients with hepatic encephalopathy.
                Out of 47 patients, 7 were excluded prior to randomization for various reasons. Twenty patients were included in the flumazenil group and 20 in the placebo group in a prospective, randomized, double-blind, placebo-controlled study. Patients were given flumazenil (1 mg/h, continuous IV infusion) or an equal volume of saline solution for 5 hours. Before and after treatment, portosystemic encephalopathy (PSE) stage and number connection test (NCT) scores were checked every half hour for 5 hours. EEG was recorded 15 minutes before and 1 hour after treatment.
                While significant improvements were determined in PSE stage and NCT score in the flumazenil group, there were no such improvements in the placebo group. There was no statistically significant difference between pre- and post-treatment EEGs in either group.
                It was concluded that continuous IV infusion of flumazenil had beneficial and safe effects in the treatment of hepatic encephalopathy patients. To evaluate the effects of flumazenil on hepatic encephalopathy in patients with cirrhosis.
                Double-blind randomized study.
                Liver intensive care unit over a 2-year period.
                Fourteen patients with cirrhosis (median age 54 years, range 41-73 years), comprising 10 men and four women enrolled during 18 episodes of hepatic encephalopathy.
                Placebo or flumazenil (1 mg at 0.1 mg/min infusion rate) was infused in coded vials. The patients' hepatic encephalopathy was graded clinically and by electroencephalography (EEG).
                In eight episodes of hepatic encephalopathy the placebo was infused first and no improvement occurred (0%). During 12 episodes of hepatic encephalopathy, flumazenil was administered and the EEG recording improved within 7 min (range 4-47 min; 12 out of 18 cases; 66 versus 0% for flumazenil versus placebo, respectively; P < 0.01); a modest clinical improvement in hepatic encephalopathy was observed within 83 min (range 30-340 min). The amount of flumazenil infused averaged 0.7 mg (range 0.4-1 mg).
                The infusion of 0.4-1 mg flumazenil results in a modest but rapid improvement in the EEG grading of hepatic encephalopathy and to a moderate but delayed improvement in the clinical grade of hepatic encephalopathy. 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. 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) The rationale for use of benzodiazepine receptor antagonists is based on the so-called benzodiazepine pathogenetic hypothesis of hepatic encephalopathy (HE). To assess the efficacy of flumazenil, a specific benzodiazepine receptor antagonist, in a large and selected population of cirrhotic patients with severe HE, we conducted a double-blind, placebo-controlled, cross-over trial on 527 cirrhotic patients with HE grade III and IVa admitted to Intensive Care Units over a 5-year period; among them, 265 (132 of grade III and 133 of grade IVa) received flumazenil, whereas 262 (130 of grade III and 132 of grade IVa) received placebo. Treatment was begun within 15 minutes of randomization; the response to treatment was assessed by neurological score and by continuous electroencephalographic (EEG) recordings. Improvement of the neurological score was documented in 17.5% of grade III patients treated with flumazenil and in 14.7% of grade IVa patients, compared, respectively, with 3.8% and 2.7% of the patients of both groups treated with placebo. Improvements in EEG tracings were observed in 27.8% of grade III patients and in 21.5% of grade IVa patients, compared, respectively, with 5% and 3.3% of the patients of both groups treated with placebo. Benzodiazepines were detected in the serum of 10 patients (4 in grade III group and 6 in grade IVa group). Flumazenil is beneficial only in a selected subset of cirrhotic patients with severe HE; the applicability of this treatment to unselected patients with severe HE still remains to be determined. Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE.
                To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease.
                49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study.
                Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement).
                The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated.
                A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil. Endogenous benzodiazepine-like substances are thought to play a role in the development of hepatic encephalopathy (HE). Ten patients with sub-clinical or latent hepatic encephalopathy (LHE) and ten normal controls were cognitively assessed pre- and post-infusion of 0.2 mg of the benzodiazepine (BZ) antagonist flumazenil in a placebo-controlled, cross-over, double-blind design. Flumazenil infusion resulted in a significant improvement in simple reaction time in patients, but not in controls. Saline infusion had no effect on any of the cognitive measures in either group. Flumazenil appeared to have a particular enhancing effect on the cognitive, as opposed to the motor, component of the reaction time task. This finding supports the view that the benzodiazepine/GABA system is implicated in the bradyphrenia that is characteristic of chronic liver disease, even before hepatic encephalopathy is apparent. We conclude that benzodiazepine receptor antagonism may improve cognitive function, particularly speed of information processing, in patients with latent hepatic encephalopathy. Ligands to the benzodiazepine receptor (BZR) accumulate in hepatic encephalopathy; the benzodiazepine antagonist flumazenil can reverse some manifestations of this condition. This study was designed to explore the effects of flumazenil on cognitive function and anxiety levels in cirrhotic patients without hepatic encephalopathy. Twenty such patients--ten alcoholic, ten nonalcoholics--and ten normal volunteers matched for age and sex were randomly allocated to treatment order (flumazenil or placebo first) in a double-blind cross-over trial. Cognitive function was evaluated with a battery of psychological tests shown previously to be sensitive to the impairment induced by liver disease. Cirrhotic patients performed worse than controls on several tests: digit cancellation, digit symbol substitution, key tapping and Reitan's trail B test. Flumazenil did not reverse these cognitive impairments but it did induce anxiety in nonalcoholic cirrhotics. On one index of memory--delayed word recall--alcoholics performed worse than nonalcoholic cirrhotics. Flumazenil reversed this memory impairment in the alcoholic cirrhotic group. These results suggest that alcohol consumption induces changes at the BZR that are different from changes induced solely by liver impairment. Seventy-five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic encephalopathy. The control group received 4 g of enteral neomycin daily along with 25% dextrose by a central venous catheter. The experimental group received a placebo resembling neomycin and isocaloric dextrose plus a modified amino acid mixture enriched with branched-chain amino acids to 36% and deficient in aromatic amino acids and methionine. Thirty patients in the F080 group and 29 in the control group completed the trial. The group receiving the modified amino acid mixture demonstrated a statistically significant improvement in encephalopathy as compared to the neomycin group, while maintaining nitrogen equilibrium. Survival and discharge from the hospital were statistically greater in the group treated with the modified amino acid solution and hypertonic dextrose. Treatment of hepatic encephalopathy in the presence of hepatic decompensation with an amino acid solution formulated for its treatment seems to produce faster, more complete recovery with improved capacity for nutritional support.
Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.