Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta‐analysis

Abstract

Background: Randomized controlled trials testing flumazenil in hepatic encephalopathy have shown conflicting results. Aim: To compare flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis. Methods: An overview of randomized controlled trials comparing flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis was performed. For each end‐point, heterogeneity and treatment efficacy were assessed by Peto and Der Simonian methods. As most trials were crossover in nature, a sensitivity analysis was performed including the two treatment periods. Results: Six double‐blind randomized controlled trials, including 641 patients (326 treated with flumazenil and 315 with placebo), were identified. The treatment duration ranged from 5 min to 3 days. Heterogeneity tests between control groups were not significant. The mean percentages of patients with clinical improvement (five trials) were 27% in treated groups and 3% in placebo groups. This difference was significant by both methods (Peto: odds ratio=6.15; 95% confidence interval, 4.0–9.5; P < 0.001; Der Simonian: mean rate difference, 29%; 95% confidence interval, 17–41; P < 0.001). The mean percentages of patients with electroencephalographic improvement were 19% in treated groups and 2% in placebo groups. This difference was significant only with the Peto method (odds ratio=5.8; 95% confidence interval, 3.4–9.7; P < 0.001). The sensitivity analysis showed similar results. Conclusions: This meta‐analysis shows that flumazenil induces clinical and electroencephalographic improvement of hepatic encephalopathy in patients with cirrhosis.

Late onset congenital central hypoventilation syndrome after exposure to general anesthesia

“…The initial but temporary response to flumazenil could be attributed to its central analeptic effect. 12 A number of investigations were undertaken to exclude any primary cardiac, pulmonary, hepatic, renal, or central nervous system pathology, diaphragmatic dysfunction or neuromuscular disease. The patient did not respond to central nervous system stimulants, and due to repeated failure of tracheal extubation, a tracheostomy was required.…”

Actualización en el tratamiento de la encefalopatía hepática

“…Se han realizado diversos estudios que muestran mejoría inmediata de la EH en algunos pacientes. Un metaanálisis que incluye 6 estudios y 641 pacientes demostró una mejoría en el grupo de tratamiento pero el efecto fue transitorio y en un subgrupo de pacientes con buen pronóstico (50). No se pudo demostrar beneficio en la mejoría global ni en la supervivencia.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…This state is also associated with increased levels, expression, and function of the DBI peptide and TSPO protein, which also leads to increased levels of neurosteroids THDOC and allopregnanolone (Rothstein et al, 1989;Itzhak et al, 1995;Ahboucha et al, 2006Ahboucha et al, , 2012. Flumazenil has a therapeutic effect in patients with hepatic encephalopathy and coma (Bansky et al, 1989;Goulenok et al, 2002), although it does not counteract the effects of neurosteroids. Although the setpoint of the GABA A receptors determining positive or negative BZ modulation might be different between different subjects or it might change because of illness or drug treatment, it is possible that at least a part of the intrinsic activity of flumazenil can be accounted for by antagonism of various endogenous ligands.…”

“…Interestingly, flumazenil has shown variable intrinsic activity in preclinical and clinical settings, varying from weak partial agonism (positive allosteric modulation) to partial inverse agonism (negative modulation) (e.g., File et al, 1982a,b;Nutt et al, 1990;Da Cunha et al, 1992;Smolnik et al, 1998;Izumi et al, 1999;Goulenok et al, 2002). Its intrinsic efficacy has been explained by antagonism of endogenous positive or negative modulators.…”