Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy.
BACKGROUND
The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor antagonists for hepatic encephalopathy, but the results are conflicting.


OBJECTIVE
To evaluate the efficacy and safety of benzodiazepine receptor antagonists for patients with acute or chronic hepatic encephalopathy.


METHODS
Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of relevant articles, authors of trials, and the pharmaceutical company known to produce benzodiazepine receptor antagonists.


METHODS
Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy were included, regardless of language or publication status.


METHODS
Trial inclusion and data extraction were made independently by two contributors. Depending on the presence or absence of significant heterogeneity (P<0.1) a random or fixed effect model was used. Potential causes for heterogeneity were explored by sensitivity analyses.


RESULTS
Twelve randomised trials with 765 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 (341/370 (92%) survived in the flumazenil group versus 325/356 (91%) in the placebo group). Flumazenil had no significant effect on full recovery (two trials), survival (nine trials), or on the occurrence of adverse events (five trials). However, flumazenil was associated with a significant effect on improvement of hepatic encephalopathy compared to placebo at the end of treatment (103/346 (30%) versus 23/332 (7 %), risk difference 0.23, 95% confidence interval 0.18 to 0.28, five trials).


CONCLUSIONS
Flumazenil had no significant effect on recovery or survival from hepatic encephalopathy. However, flumazenil had a significant effect on short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis. 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.
Als-Nielsen
B
B
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshospitalet, Dep. 7701, Blegdamsvej 9, Copenhagen, Denmark, DK-2100. Bodil.a@ctu.rh.dk
Kjaergard
L L
LL
Gluud
C
C
D000208:Acute Disease; D000931:Antidotes / Q000627:therapeutic use*; D002908:Chronic Disease; D005442:Flumazenil / Q000627:therapeutic use*; D018757:GABA Modulators / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
D000931:Antidotes; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D005442:Flumazenil