Flumazenil causes short-term improvement of hepatic encephalopathy in patients with chronic liver disease

Als-Nielsen B, Gluud LL, Gluud C

Published Online:

January 21, 2009

Hepatic encephalopathy refers to changes in mental state, ranging from minor signs of altered brain function to deep coma occurring in patients with liver failure. Hepatic encephalopathy may be caused by an activation of a receptor-complex in the brain. Flumazenil, which inhibits this receptor-complex, might ameliorate the symptoms. This review found that flumazenil leads to a short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis.

Abstract (click to read)

Background:

Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.

Objectives:

To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy.

Search strategy:

Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies.

Selection criteria:

Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy.

Data collection and analysis:

Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I2. Potential sources of heterogeneity were explored through subgroup analyses.

Main results:

Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous.

Authors' conclusions:

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.

This record should be cited as:

Als-Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002798. DOI: 10.1002/14651858.CD002798.pub2

Assessed as up to date:

February 23, 2004

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Primary Review Group:

Hepato-Biliary Group

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Flumazenil causes short-term improvement of hepatic encephalopathy in patients with chronic liver disease

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