Lacetti 2000

Methods	Double‐blind, single‐centre, parallel‐arm placebo‐controlled RCT.
Participants	54 participants with cirrhosis and acute hepatic encephalopathy (Grade III or IV). Precipitating factors are described (Table 6). Mean age ± SD: flumazenil: 59.6 ± 6.0 years; placebo: 57.7 ± 5.4 years. Proportion of men: 54%. Aetiology of cirrhosis: hepatitis B/C 100%. Proportion testing positive for benzodiazepines at baseline (Table 7): 0%.
Interventions	Intervention comparison: intravenous infusion flumazenil 0.4 mg/mL at 10 mL/minute for 5 minutes versus placebo (saline). Total dose of flumazenil: 2 mg. Cointerventions: lactulose enemas; branch‐chain amino acids.
Outcomes	Outcomes included in meta‐analyses: mortality, hepatic encephalopathy (Table 3), and serious adverse events (Table 8) assessed for maximum of 24 hours after intervention.
Neuropsychiatric assessment	Baseline and post infusion: Clinical assessment of mental status (score not specified) assessed at baseline; Glasgow Coma Score (Table 4) assessed at baseline and every 30 minutes for the first 6 hours and then every 6 hours for 24 hours post infusion.
Inclusion period (date)	January 1997 to December 1997.
Country	Italy.
Notes	Included data: we included data on all participants in our analyses. Notes about the design: investigators repeated the intervention once after 3 hours in non‐responders (no improvement in neurological status) or immediately if they detected an improvement followed by a relapse. The report did not include information about the number of participants who received a second infusion. In the results section of the report the investigators stipulate that the second infusion was the same as the one first received.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported.
Allocation concealment (selection bias)	Low risk	Double‐blind administration of flumazenil and placebo.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and personnel using placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment using placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data and all participants were included in the analyses.
Selective reporting (reporting bias)	Low risk	Trial described clinically relevant outcomes. We had no access to information about outcomes described in the original protocol or information in trial registries.
For‐profit funding	Unclear risk	No information provided.
Other bias	Low risk	No other biases.
Overall assessment	High risk	High risk of bias.