Treatment of Hepatic Encephalopathy With Flumazenil and Change in Cortical GABA Levels in MRS

Subjects will be referred to the PI by the Yale Liver Center. If interested in participating,
they will be contacted by a research assistant for an initial phone screening. If the subject
passes the screening, an appointment will be made for a MRS and fMRI at the Yale Magnetic
Resonance Research Center (MRRC). Subjects will be asked to abstain from their HE medication
(e.g. lactulose and/or rifaximin) for 12 hours prior to their appointment. At their
appointment for MRS/fMRI, they will receive two IVs, one for medication infusion and another
for periodic blood draws during the MRS. Subjects will be blindly randomized to one of two
groups: A or B. Group A will receive flumazenil (Romazicon) and Group B will receive placebo
(saline). One week post-infusion, patients will crossover groups; those originally in Group A
will crossover to Group B and those originally in Group B will crossover to Group A. Once
ready, a priming dose bolus of 0.4 mg of either flumazenil or placebo will be administered
intravenously (Minute 0). At this time the 1H-MRS scan will begin. Over the next 6 minutes, a
drip infusion of flumazenil or placebo mixed with saline will be administered to the patient
at a rate of 0.1 mg flumazenil or placebo per minute for a total of 7 doses during the scan.
A baseline pharmacokinetics (PK) sample will be drawn, processed and frozen and the
intravenous line used to draw the sample will remain in patient until all samples have been
drawn. Seven additional PK samples (2-4 mL each) collected during and after the scan will be
used to evaluate the level of flumazenil circulating throughout the bloodstream during the
course of the infusion and during the washout period.

Following the MRS and fMRI, subjects will undergo a 40-minute neuropsychologic battery. Other
testing procedures include liver function and drug testing. All procedures will repeat one
week later with placebo or flumazenil infusion (based on the group to which he/she has been
randomized). A follow-up phone call to assess for adverse events will take place in week 3.

Inclusion Criteria:

1. Age: 18 and older

2. ICD-9 diagnosis of hepatic encephalopathy

3. Ability to feel comfortable in confined areas (like MRI)

4. Ability to provide informed consent

5. Speaks fluent English without any communication barriers

6. Reliable family member or friend able to stay with participant during abstinence from
HE medication prior to visit.

Exclusion Criteria:

1. Current DSM-IV-R diagnosis of Alcohol or Other Drug Abuse or Dependence

2. Positive screen for alcohol abuse as determined by the CAGE questionnaire

3. Positive urine toxicity screen for benzodiazepine medications or illicit drugs

4. History of long-term use of benzodiazepine medications

5. Current use of non-benzodiazepine agonist medications

6. History of Panic Disorder

7. History of any Psychotic Disorder

8. History of seizures and/or Seizure Disorder

9. History of dysrhythmia, cardiovascular collapse, or recent head trauma

10. History of side effects from anticholinergic medications

11. History of cyclic antidepressant overdose or poisoning

12. Pregnant or nursing

13. Resides in nursing home or other long-term care facility