Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: An italian multicenter double-blind, placebo-controlled, cross-over study

Abstract

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. (HEPATOLOGY 1998;28:374-378.)Several factors suggest that endogenous benzodiazepines and ␥-aminobutyric acid may be involved in the pathophysiology of hepatic encephalopathy (HE). 1,2 Flumazenil, a specific benzodiazepine antagonist, has been used in the treatment of intoxication patients with coma 3 and has shown diagnostic utility in coma patients with suspected poisoning. 4 Contrasting opinions exist on the therapeutic efficacy of flumazenil in the treatment of HE and on the applicability of this treatment to unselected patients with a different HE grade. [5][6][7][8][9][10] Our study was planned to assess the efficacy of flumazenil in cirrhotic patients with severe HE admitted to Intensive Care Units over a 5-year period. This is the first large-scale trial that provides quantitative data on the clinical response to flumazenil in a selected population of cirrhotic patients with severe HE by a double-blind, placebo-controlled, cross-over design. PATIENTS AND METHODSPatient Selection. Patients with biopsy-proven cirrhosis and with HE grade III or IVa were eligible for the study. According to Grippon and Opolon, 11 HE grade III patients were considered those ''in stupor, sleeping most of the time, but rousable, with incoherent speech and marked confusion,'' whereas HE grade IVa patients were considered those ''in coma with coordinated response to painful stimuli.'' The study did not consider the following: patients under 18 years of age; those who received synthetic benzodiazepines ...

Hepatic encephalopathy

“…In a large clinical trial of 560 patients, an i.v. bolus of flumazenil improved mental state in approximately 15% of patients, as compared to 3% of placebo-treated controls (52). Although these results are not striking, flumazenil may be administered to patients with HE and suspected benzodiazepine ingestion.…”

Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines

“…Indeed, benzodiazepine (BZD) administration is known to give rise to the initial appearance of anterior fast (b range) activities, which eventually slows down (and transiently cross the a range) with increasing dosages. Of note, stuporous HE patients may transiently recover following the administration of flumazenil, a BZD antagonist (13). At any rate, research on this issue is still needed to confirm changes in the spatial distribution of rhythms in the first stages of HE, their frequency, pathophysiology and meaning.…”

Drug therapies in liver disease

“…60 Clearly, it is likely to be of most benefit in patients in whom benzodiazepine use is suspected of precipitating HE.…”