Hepatic encephalopathy is considered a reversible metabolic encephalopathy characterized by a spectrum of CNS effects. Symptoms may progress from confusion and somnolence to coma. One current hypothesis implicates an increase in GABAergic tone in the development of encephalopathy.7,63
Animal studies of hepatic encephalopathy secondary to galactosamine or thioacetamide (hepatotoxins) demonstrate an increase in GABA effect, which is antagonized by flumazenil, bicuculline (a GABA receptor antagonist), and isopropylbiclophosphate chloride (a calcium channel blocker).7 Cerebrospinal fluid (CSF) from these animals contained a benzodiazepine receptor ligand with agonist activity. Rat studies involving hepatic encephalopathy resulting from acute liver ischemia showed only a slight response to flumazenil, but significant improvement after administration of a partial inverse agonist.12,69
Human studies have detected benzodiazepine binding activity in the CSF (but not in serum) of patients with hepatic encephalopathy. One group identified four to 19 peaks representing benzodiazepine binding ligands from the frontal cortex of 11 patients who died of hepatic encephalopathy.10 Two of the peaks were further characterized as diazepam and N-desmethyldiazepam. Brain concentrations of these substances were 2 to 10 times higher than normal in six of the patients and were normal in five patients. Patients with idiopathic recurring stupor who have measurable “endozepines” (endogenous benzodiazepine ligands) in serum and CSF are reported.58,66
Flumazenil improves the clinical and electrophysiologic responses of patients with hepatic encephalopathy and idiopathic recurring stupor.4,8,19,58,66 Some patients with encephalopathy have improved from stage IV to stage II encephalopathy following IV flumazenil. Maximal improvement after flumazenil lasts approximately 1 to 2 hours and gradually dissipates within 6 hours. The response rate in a meta-analysis averaged approximately 30%.29 The proposed explanations for the unresponsiveness include cerebral edema, hypoxia, other systemic diseases or complications, and irreversible CNS damage.
Animal and human data convincingly support the concept that increased GABAergic tone is responsible for hepatic encephalopathy. Evidence for endogenous benzodiazepine ligands that enhance GABA action also are demonstrated but controversial.1,3 The source of these benzodiazepine receptor agonists is unclear, but diet and/or production by gut bacteria is postulated.7 Most authorities believe endogenous de novo synthesis is unlikely and propose prior benzodiazepine exposure and persistence of clinical effects as an explanation. Hyperammonemia, neurosteroids, and hemoglobin metabolites are also implicated in the pathophysiology of hepatic encephalopathy.3,11,59
Flumazenil can lead to short term improvement of the clinical condition of a subgroup of patients with hepatic encephalopathy and may prove useful as an addition to conventional therapy.2,4,9 Existing guidelines recommend use be reserved for patients with acute hepatic encephalopathy and a history of benzodiazepine use.11,22 Additional research is necessary to prospectively identify responders, provide dosing considerations, and evaluate adverse events. There is no known survival benefit.
Animal studies indicate that many of the actions of ethanol are mediated through GABA neurotransmission.65 Acute ethanol administration appears to enhance GABA transmission and inhibit N-methyl-d-aspartate excitation. Chronic ethanol administration leads to downregulation of the GABA system. Ethanol enhances GABAA induced chloride influx in a dose-dependent fashion without a direct effect on chloride. Flumazenil does not influence this action of GABA. Chronic ethanol use selectively increases the sensitivity to inverse benzodiazepine agonists, invoking a change in coupling or conformation of the receptor. These changes may explain the development of tolerance and the kindling and production of seizures that occur on ethanol withdrawal.
A randomized, double-blind, crossover study of eight male volunteers given IV ethanol to achieve a constant serum ethanol concentration of 160 mg/dL was conducted.16 Once stabilized, the volunteers were given either placebo or 5 mg flumazenil. Subjective and objective psychomotor tests were conducted, with no differences noted between volunteers given flumazenil and volunteers given placebo. Thus the probability of ethanol reversal at the doses achieved appears unlikely.
Based on this information, flumazenil likely does not have a significant effect on ethanol intoxication, and low doses of flumazenil (< 1 mg) have no effect.44,47 The 5 mg doses reportedly produce favorable changes in sensorium, but these findings may be the result of confounding factors. Because we would not administer 5 mg flumazenil in the overdose setting to avoid the increased risk of adverse effects at this dose, flumazenil cannot be recommended for reversal of ethanol intoxication.