Study	Reason for exclusion
Bansky 1989	Prospective study including 14 participants with cirrhosis and overt hepatic encephalopathy. The investigators reported an improvement in mental status in 71% of participants within minutes of receiving intravenous flumazenil lasting for 1 to 2 hours. Participants also received lactulose . Six participants died. The study was excluded as it did not include a control group.
Devictor 1995	Prospective study evaluating 7 children with fulminant hepatic failure awaiting emergency liver transplantation. The investigators reported that flumazenil injection led to a transient improvement in mental status in 1 child but had no effect on mental status in the remaining six. The study was excluded as none of the participants had hepatic encephalopathy associated with cirrhosis and it did not include a control group.
Golubovic 1999	Prospective study including 10 participants with alcohol‐related cirrhosis and overt hepatic encephalopathy classified as grade IV based on an assessment of mental status, electroencephalography, and visual evoked responses. The investigators reported an improvement in mental status in 8/10 participants. Six participants died within 1 year. The study was excluded as it did not include a control group.
Grimm 1988	Prospective study including 17 participants (2 children) with hepatic encephalopathy associated with acute liver failure (9 participants) or cirrhosis (8 participants). Cointerventions included lactulose, branched‐chain amino acids, antibiotics, diuretics, histamine‐receptor antagonists, human albumin, and fresh frozen plasma. Transient improvement in the manifestations of hepatic encephalopathy was seen following flumazenil in 4 (44%) participants with fulminant hepatic failure and 5 (63%) with cirrhosis. Mortality was not reported. This study was excluded as it did not include a control group.
Jia 1999	Open, single‐centre, non‐randomised study which is included in the sensitivity analyses of serious adverse events. The study involved 22 participants with cirrhosis and overt hepatic encephalopathy (Grades I‐III using West Haven criteria) recruited between April 1996 and September 1997. Intervention comparison: 12 participants received an intravenous bolus of flumazenil 0.5 mg followed by an intravenous infusion of flumazenil in a dose of 1.0 mg over 4 hours for an unspecified period of time. The remaining 10 participants received Xing‐Nao‐Jing, a traditional Chinese medicine also given as an intravenous infusion. Total dose of flumazenil: 1.5 mg. Outcomes: The study report stated that 2 participants in the flumazenil group died of liver failure but the time of death in relation to the intervention was not specified and study did not specifically state if there were any deaths in control group. The article was published in Chinese but a translation was available. The study was excluded as it did not contain a control group.
Kapczinski 1995	Double‐blind, cross‐over, placebo‐controlled, single‐centre randomised clinical trial including 20 liver transplant candidates with cirrhosis. The trial is included in the sensitivity analyses of serious adverse events. The main objective of trial was to evaluate the differential effects of flumazenil on cognitive function and anxiety in people with alcohol‐related (10 participants) or non‐alcohol‐related (10 participants) cirrhosis. None of the included participants had evidence of overt hepatic encephalopathy. The investigators evaluated a range of psychometric tests and reported the results as group mean values. No information was provided about the number of participants with abnormal test results. Proportion of men: 60%. Mean ± SD age: alcohol‐related cirrhosis: 47.7 ± 10.5 years; non‐alcoholic cirrhosis: 48.4 ± 11.7 years. Proportion testing positive for benzodiazepines at baseline: not tested Intervention: intravenous infusion flumazenil 0.1 mg/minute for 10 minutes then 0.05 mg/minute for 20 minutes versus placebo (saline). Total dose of flumazenil: 2 mg. Washout period: 60 minutes. Outcomes: The investigators reported changes in psychometric tests for participants with alcohol‐related or non‐alcohol‐related cirrhosis without providing an overall estimate of numbers with (or without) improved manifestations. The trial did not report any deaths or serious adverse events. The study was excluded because none of the participants had hepatic encephalopathy.
Marsepoil 1990	Open, single‐centre, prospective, non‐randomised study included in the sensitivity analyses of serious adverse events at 48 hours. The study involved 25 participants with alcohol‐related cirrhosis and acute hepatic encephalopathy, 13 of whom received flumazenil. The proportion of men and the mean age of participants was not reported. Proportion testing positive for benzodiazepines at baseline: not mentioned Intervention: intravenous bolus of flumazenil 0.2 mg every ten minutes until improvement in clinical status up to a maximum total dose of 2 mg followed by a continuous maintenance infusion of 0.3 mg. per hour for 48 hours. Total dose of flumazenil: maximum 16.4 mg. Outcomes: .The Investigators reported that the mortality rates were similar in the flumazenil and control groups, but did not provide information on the number of participants who died. Published in French but a translation was available.The study was excluded as it was not randomised.
Ozyilkan 1997	Prospective study evaluating the effect of 30‐minute, incremental intravenous boluses of flumazenil in 11 participants with cirrhosis (6 stage 0,4 stage one, one stage 2 hepatic encephalopathy) in whom baseline somatosensory evoked potentials were abnormal. Four patients (36%) showed a clear improvement in evoked potentials with flumazenil. Mortality was not described. The study was excluded as it did not include a control group.
Wu 2001	Randomised clinical trial comparing intravenous flumazenil plus lactulose enemas versus flumazenil alone. A total of 20 participants (18 men) with cirrhosis and hepatic encephalopathy were included. The maximum dose of flumazenil was 9 mg. The dose was adjusted based on the clinical effect. Investigators assessed hepatic encephalopathy based on Conn Criteria and defined an improvement from Grade IV to I within 6 hours as clinically significant. None of the included participants died and all 12 in the flumazenil plus lactulose group and all 8 in the flumazenil group showed improved manifestations of hepatic encephalopathy. The study was excluded as there was no placebo arm.

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