Trial

Type of hepatic encephalopathy

Neuropsychiatric assessment

Definition of overall improvement

Amodio 1997

Minimal

Number Connection Test and Brainstem Auditory Evoked Response.

Investigators did not define or assess the number of participants with an overall improvement.

Barbaro 1998

Overt

Mental status assessed using a clinical scale (Table 2), Modified Glasgow Coma Scale (Table 2), and electroencephalography (Table 3).

Improvement in clinical scores or electroencephalography.

Cadranel 1995

Overt

Mental status assessed using a clinical scale (Table 2), and electroencephalography (Table 3).

Improvement in clinical score or electroencephalography.

Dursun 2003

Minimal or overt

Mental status assessed using a clinical scale (Table 2), Number Connection Test results, and electroencephalography (Table 3).

Improvement based on the clinical score and Number Connection Test results.

Giger‐Mateeva 1999

Minimal

Number Connection Test and brainstem auditory evoked response.

Not defined. The investigators included a post‐hoc subjective assessment of alertness.

Gooday 1995

Minimal

Simple and complex reaction time, verbal memory, psychomotor speed, short‐term and working memory.

Improvement in psychomotor speed evaluated using change in reaction time; Investigators did not define or assess the number of participants with overall improvement. .

Gyr 1996

Overt

Mental status (Table 2), and electroencephalography (Table 3).

Clinically relevant improvement defined as a 2‐point improvement in clinical score at any time during treatment compared with baseline. The investigators also reported improvement defined using the clinical scale score (mean for all individual observations).

Hermant 1991

Overt

Glasgow Coma Scale (Table 2), and electroencephalography.

A 2‐point improvement in the Glasgow Coma Score and electroencephalography.

Klotz 1989

Overt

Clinical assessment (score not described).

Improvement in clinical status

Lacetti 2000

Overt

Mental status (scale not specified) and Glasgow Coma Scale (Table 2).

Investigators originally classified participants as Grade III to IV coma. Method of assessment not stipulated. The trial report defined 'clinically relevant improvement' as primary outcome defined as a 3‐point improvement in Glasgow Coma Score.

Li 2009

Overt

Glasgow Coma Scale (Table 2), and electroencephalography

Improvement in the Glasgow Coma Score of ≥ 3 points.

Pomier‐Layrargues 1994

Overt

Modified Glasgow Coma Score (Table 2), and electroencephalography.

Improvement in ≥ 2 items on modified Glasgow Coma Score within 1 hour after the end of treatment.

Van der Rijt 1995

Overt

Clinical scale (Table 2).

A ≥ 1 point decrease in severity of hepatic encephalopathy.

Zhu 1998

Overt

Clinical scale (Table 2).

Overall improvement in hepatic encephalopathy based on clinical grade.

Scale (Grippon 1988) used in Cadranel 1995 ; Barbaro 1998 .

I

Euphoria or depression, mild confusion, slowness, disorder in sleep rhythm.

II

Drowsiness, inappropriate behaviour, accentuation of stage I.

III

Stupor; participant sleeps most of the time but is rousable; incoherent speech; marked confusion.

IVa

Coma, co‐ordinated response to painful stimuli.

IVb

Coma, hyperextension, and pronosupination after painful stimuli.

IVc

Coma, no response to painful stimuli.

V

Clinical decerebration.

Scale (Fitz 1998) used in Dursun 2003 .

Subclinical

Normal examination with subtle changes in psychometric or Number Connection Tests.

I

Impaired attention, irritability, depression, or personality changes.

II

Drowsiness, behavioural changes, sleep disorders, and poor memory.

III

Confusion, disorientation, somnolence, and amnesia.

Scale (Jones 1988) used in Gyr 1996 .

‐

Clinical assessment criteria consisted of the anamnestic criterion: disorders of sleep pattern (insomnia, hypersomnia, inversion of sleep rhythm) in combination with assessment of the level of consciousness (1 to 4 as described below). Score items weighted so major disturbances of consciousness (portal systemic encephalopathy stage III and IV) were associated with scores of ≥ 11. Portal systemic encephalopathy stage II defined as scores of 5 to 10 and stage I of 3 to 4.

1

Light disturbance of consciousness if ≥ 1 of following symptoms were present: drowsiness (tendency to fall asleep but wake up spontaneously or in response to normal voice or light), intermittent or permanent disorientation, retardation of ability to perform mental tasks (serial subtractions of sevens), mood disorder, inappropriate behaviour.

2

Somnolence (arousable to physical stimuli such as mild prodding or shaking only).

3

Stupor (localised motor response to pain).

4

Coma (unarousability, no or unlocalised motor reactions to painful stimuli).

Scale (no reference provided in paper) used in Van der Rijt 1995 .

1

Presence of ≥ 2 of following abnormalities: inverted sleep pattern, disturbed memory, impaired calculation (serial sevens), slowness of speech, or flapping tremor.

2

Presence of ≥ 2 of following: lethargy, time disorientation, or flapping tremor.

3

Presence of ≥ 2 of following: a state in which person had to be stimulated repetitively to open his/her eyes or execute commands, disorientation in terms of place and disorientation with respect to person.

4

Coma.

Scale (Conn 1977) used in Zhu 1998 .

1

Trivial lack of awareness, euphoria or anxiety, shortened attention span, impaired performance of addition or subtraction.

2

Lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behaviour.

3

Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation.

4

Coma.

Glasgow Coma Scale (CGS) (Teasdale 1974) used in Hermant 1991 ; Lacetti 2000 ; Dursun 2003 ; Li 2009 .

Scores

Eye opening (E):

• 4 = spontaneous;

• 3 = to voice;

• 2 = to pain;

• 1 = none.

Verbal response (V):

• 5 = normal conversation;

• 4 = disoriented conversation;

• 3 = words, but not coherent;

• 2 = no words, only sounds;

• 1 = none.

Motor response (M):

• 6 = normal;

• 5 = localised to pain;

• 4 = withdraws to pain;

• 3 = decorticate posture (an abnormal posture that can include rigidity, clenched fists, legs held straight out, and arms bent inwards towards the body with wrists and fingers bend and held on chest);

• 2 = decerebrate (an abnormal posture that can include rigidity, arms and legs held straight out, toes pointed downwards, head and neck arched backwards);

• 1 = none.

Grading

• Severe: GCS 3‐8 (minimum score 3).

• Moderate: GCS 9‐12.

• Mild: GCS 13‐15.

Modified Glasgow Coma Scale (Pappas 1983) used in Pomier‐Layrargues 1994 ; Barbaro 1998 .

Scores

1. Verbal ability;

2. Eye‐opening;

3. Pupillary light reflex;

4. Corneal reflex;

5. Spontaneous eye movements;

6. Oculocephalic reflex;

7. Motor response; and

8. Pattern of respiration.

Electroencephalography grading/Fischer classification (Nusinovici 1977 and Spehlman 1991) used in Hermant 1991 ; Pomier‐Layrargues 1994 ; Cadranel 1995 ; Barbaro 1998 .

I

Irregular background activity (theta and alpha).

II

Continuous theta activity, bursts of delta waves.

III

Prevalent delta activity; polyphasic transients sharp and slow wave complexes.

IVa

Continuous delta activity; abundant sharp and slow wave complexes; electroencephalography reactivity present.

IVb

Slower activity (delta and some polyphasic transients); electroencephalography reactivity = 0.

IVc

Discontinuous activity with silent periods.

V

Flat.

Electroencephalography grading (Parsons‐Smith 1957) used in Dursun 2003 .

A

Generalised suppression of alpha rhythm and its frequent replacement by faster potentials in all leads. The tracings in this grade are generally flat and featureless.

B

Alpha rhythm very unstable and disturbed by random waves at 5‐7 per second over both hemispheres. Rhythms most often seen over temporal lobes. In many cases with underlying fast activity.

C

Alpha rhythm still seen, but disturbed over both hemispheres by medium‐voltage 5‐6 per second waves. These occur in runs, are not paroxysmal, and do not usually block to eye opening although blocking may occur. Rhythms are particularly well seen over temporal and frontal lobes.

D

5‐6 per second rhythms seen in grade C are now constant in all areas and replace all other cortical activity recorded on electroencephalogram. Appearance of this abnormality in a patient presenting with only slight neuropsychiatric symptoms is very striking.

E

5 to 6 per second rhythms replaced by frontally preponderant bi‐lateral synchronous 2 per second rhythms, which spread backwards over hemispheres. At times, 6 per second rhythms might reappear, but special features of records are occurrence of these diencephalic discharges.

Electroencephalography grading (Kennedy 1973) used in Gyr 1996 .

0

8 to 12 per second basic rhythm, mean dominant frequency > 8 per second, % theta < 20.

1

Sudden shifts between normal alpha frequency (around 9 or 10 per second) and slow substitutes (6‐8 per second); mean dominant frequency > 7 per second, % theta > 35.

2

Diffuse slow activity posterior alpha rhythm seen occasionally, mean dominant frequency 5 to 7 per second, % theta > 60.

3

Dominant slow activity in all areas, mean dominant frequency 3 to 5 per second, % delta 70.

4

Bilaterally synchronous, 2‐3 per second waves, predominating over frontal lobes and spreading backwards to occipital lobes; occasional short‐lived appearance of faster rhythms (5 or 6 per second) or voltage depression, mean dominant frequency < 3 per second, % delta 70.

Electroencephalography grading (Markand 1984) used in Van der Rijt 1995 .

0

Background activity consisting of alpha rhythm.

1

Alpha rhythm with some scattered theta waves.

2

Background activity of theta activity intermixed with some delta and alpha frequencies.

3

Background of delta polymorphic activity of high amplitude with spontaneous variability.

4

Delta activity of relatively small amplitude.

Trial

Participants

(n)

Precipitating factors (n)

Barbaro 1998

527

Gastrointestinal bleeding (352), surgery (95), sepsis (45), dehydration (6), unknown (29).

Cadranel 1995

14

Gastrointestinal bleeding (4), sepsis (7), alcoholic hepatitis (3), portal vein thrombosis (1), viral hepatitis (1), unknown (2).

Lacetti 2000

54

Gastrointestinal bleeding (31), sepsis (7), drugs (11), surgery (1).

Pomier‐Layrargues 1994

21

Gastrointestinal bleeding (7), sepsis (2), dehydration (1), surgery (2), none (9), portacaval shunting (4).

Van der Rijt 1995

18

Hepatitis (5), acute exacerbation in cirrhosis (2), partial hepatectomy (1).

Zhu 1998

25

Gastrointestinal bleeding (13), protein overload (6), infection (2), wounds (1), unknown (3).

Trial

Required period free of benzodiazepines before inclusion

Baseline screening for benzodiazepines

Screening method and detection level

Negative testing at baseline an inclusion criterion

Proportion testing positive for benzodiazepines at baseline

Amodio 1997

2 weeks

Yes

• Blood

• Emit‐dau technique, Dupont

• Detection limit 0.3 μg/mL diazepam

No

0%

Barbaro 1998

4 days

Yes

• Blood

• Thin‐layer chromatography:

• Detection limit > 11 mg/L

No

1.9%

Cadranel 1995

Not reported

Yes

• Blood and urine

• Thin‐layer chromatography:

• Detection limit > 11 mg/L

No

21.4%

Dursun 2003

3 days

No

Not reported

Not reported

Not reported

Giger‐Mateeva 1999

3 months

Yes

• Urine

• Abbott TDx/TDxFLx immunoassay

• Detection limit < 200 ng/mL

No

0%

Gooday 1995

1 month

No

Not reported

Not reported

Not reported

Gyr 1996

Yes, but length not specified

Yes

• Blood and urine

• Abbott TDx immunoassay

• Detection limits: blood 10 ng/mL 100 ng/mL, urine < 200 ng/mL

Post‐hoc analysis

• High‐pressure liquid chromatography

• Detection limits: blood < 50 ng/mL, urine 10 ng/mL to 100 ng/mL

No

8.2% on screening tests

Flumazenil 11%; placebo 5%

12/49 samples for more sensitive testing lost

Hermant 1991

Not reported

Yes

Not reported

Yes

0%

Klotz 1989

Not reported

No

Not reported

Not reported

Not reported

Lacetti 2000

2 weeks

Yes

• Urine

• Roche KIMS immuno‐enzymatic assay

• Detection limit: not specified

Post‐hoc analysis

• High‐pressure liquid chromatography

• Detection limit: not specified

Yes

0%

Li 2009

Not reported

No

Not reported

N/A

N/A

Pomier‐Layrargues 1994

3 days

Yes

• Blood

• Abbott TDx immunoassay

• Detection limit 12 ng/mL

Post‐hoc analysis

• Gas chromatography‐mass spectroscopy

• Detection limit: 1 ng/mL

No

19%

Van der Rijt 1995

Recent

Yes

• Blood

• High‐pressure liquid chromatography

• Detection limit: not specified

Yes

0%

Zhu 1998

7 days

No

Not reported

Not reported

Not reported

Trial

Number of participants

Included in analyses of serious adverse events

Data included in primary analysis

Serious adverse events

Amodio 1997

13

No

Cross‐over RCT. Data from the first treatment period not described.

Publication does not describe any deaths or other serious adverse events.

Barbaro 1998

527

Yes

Cross‐over RCT. Data from the first treatment period included.

Thirteen non‐responders in the flumazenil group and 17 non responders in the placebo group died 3 to 4 days (range 2‐6) after randomisation. The causes of dead were septic shock (20 participants); hypovolaemic shock (8 participants) and lactic acidosis (2 participants) but information was not provided on the number of deaths by cause in each group.

Cadranel 1995

14

Yes

Cross‐over RCT. Data from the first treatment period included.

One of 12 responders died from septic shock on day 4 and 2 of 6 non‐responders died from septic shock (day 2) and lactic acidosis (day 4) but information is not provided on the groups to which they a were allocated.

Dursun 2003

40

Yes

Parallel‐arm RCT. We included all participants in the analyses.

Publication did not describe any deaths or other serious adverse events.

Giger‐Mateeva 1999

10

No

Cross‐over RCT. Data from the first treatment period not described.

Publication did not describe any deaths or other serious adverse events.

Gooday 1995

10

Yes

Cross‐over RCT. Data from the first treatment period included.

Publication did not describe any deaths or other serious adverse events.

Gyr 1996

49

Yes

Parallel‐arm RCT. We included all participants in the analyses.

Four of 28 participants allocated to flumazenil and 5 of 21 allocated to placebo died within 4 weeks of the trial. One participant in the placebo group died with respiratory failure during the course of the study. The authors described participants as having severe liver disease suggesting that the cause of death in the remaining 8 participants may have been cirrhosis‐related although this is not specifically stated. The investigators classified the remaining adverse events viz flushing, nausea, vomiting, and irritability, which were experienced by 4 participants, as non‐serious.

Hermant 1991

12

Yes

Parallel‐arm RCT. We included all participants in the analyses.

Publication did not describe any deaths or other serious adverse events.

Klotz 1989

2

No

Cross‐over RCT. Data from the first treatment period were not described.

Publication does not describe any deaths or other serious adverse events.

Lacetti 2000

54

Yes

Parallel‐arm RCT. We include all participants in the analyses.

Six of 28 participants in the flumazenil group and 5 of 26 in the control group died. The causes of death were not provided.

Li 2009

72

Yes

Parallel‐arm RCT. The included participants had hepatic encephalopathy associated with cirrhosis or acute liver failure. Data were not provide separately for the 2 groups.

Five of 39 participants in the flumazenil group and 4 of 33 participants in the control group died. The causes of death were not provided.

Pomier‐Layrargues 1994

21

Yes

Cross‐over RCT. Data from the first treatment period were included.

Publication did not describe any deaths or other serious adverse events.

Van der Rijt 1995

18

Yes

Cross‐over RCT. The included participants had hepatic encephalopathy associated with cirrhosis or acute liver failure. Data were not provide separately for the 2 groups. Data from the first treatment period were included.

Publication did not describe any deaths or other serious adverse events. Two participants with fulminant hepatic failure underwent orthotopic liver transplantation on day 1 of the study.

Zhu 1998

25

Yes

Parallel‐arm RCT. We included all participants in the analyses.

Three of 13 participants in the flumazenil group and 5 of 12 participants in the control group died. The causes of death were not provided.