Evaluation of mental state in a clinical trial of MARS for patients with acute hepatic encephalopathy: comparison of two scales

It is important to assess the severity of hepatic encephalopathy (HE) and to quantitate improvement in HE after therapeutic interventions in a reliable and reproducible manner. The lack of a well standardized method of measurement has led to the use of different techniques by different clinical investigators, making a comparison between studies problematic. Although this issue had been noted more than 2 decades ago,1, 2 it is still unresolved and is reflected in the diversity of end-points and methods used in the assessment of acute HE in clinical trials over the last 15 years, e.g. West Haven criteria, Glasgow coma scale, PSE index with arterial or venous ammonia, and the EEG) (Table 1). Also different conditions have been classified as chronic HE (not reviewed here). The problem of how HE should be assessed, together with the considerable diversity of terms used to define different clinical settings, prompted a gathering of a panel of international experts to reach a consensus. Table 1. Clinical treatment trials of episodic hepatic encephalopathy (precipitated or spontaneous) in the last 15 years. SMT: standard medical treatment Author and Year Type of patients Therapy studied Primary End-point Measurement of HE Kramer, 200115 Stage II and III HE Cirrhosis Sorbent dialysis + SMT vs SMT only Sensory evoked potentials Clinical staging (West Haven), sensory evoked potentials automated EEG Laccetti, 200016 Stage III-IV HE Cirrhosis Flumazenil + SMT vs placebo + SMT Clin ical improvement Glasgow coma scale Barbaro, 199816 Stage IVa HE Cirrho sis Flumazenil + lactulose vs placebo + lactulose Clinical improvement and EEG. EEG and modified Glasgow coma scale (Pappas and Jones), including: verbal ability, eye-opening, pupillary light reflex, corneal reflex, spontaneous eye movements, oculocephalic reflex, motor response, respiration pattern Barbaro, 199818 Stage III-IVa HE Cirrhosis Flumazenil + lactulose vs placebo + lactulose Clinical improvement and EEG EEG and modified Glasgow coma scale (Pappas and Jones), including: verbal abilitiy, eye-opening, pupillary light reflex, corneal reflex, spontaneous eye movements, oculocephalic reflex, motor response, respiration pattern Gyr, 199614 Stage I-III HE Cirrhosis Flumazenil vs placebo (Lactulose permitted in both groups) Clinical improvement Own adapted clinical PSE score, EEG Van der Rijt, 199519 HE staged by EEG (clinical stage varied from 0 to IV) Acute or chronic liver disease Flumazenil vs placebo Clinical improvement and EEG Clinical staging asses sed by own classi ficatio n: stage I: > 2 of inverted sleep pattern, disturbed memory, impaired serial 7’s, slowness of speech, flapping tremor; stage II: > 2 of lethargy, time disorientation, asterixi s; stage III: > 2 of state that subject had to be stimulated repetitively to open eyes or execute commands, place and person disorientation; stage IV: coma. EEG Cadranel, 199520 Stage II-IV HE Cirrhosis Flumazenil vs placebo Clinical improvement and EEG Clinical grading with own classification: I: euphoria/depression, mild confusion, slowness, disordered sleep rhythm; II: drowsiness, inappropriate behaviour, accentuation of grade I; III: stupor, patient sleeps most of time but rousable, incoherent speech, marked confu sion; IVa: coma, coordinated response to pain; IVb: hyperextension and pronosupination to pain stimuli; IVc: no response to pain; V: clinica l decerebration. EEG Pomier-Layrargues, 199421 Stage IV HE Cirrhosis Flumazenil + lactulose vs placebo + lactulose Clinical improvement Modified Glasgow coma score, including: verbal ability, eyeopening, pupillary light, corneal and oculocephalic reflexes, spontaneous eye movements, motor response, respiration pattern. EEG Blanc, 199422 Acute HE Cirrhosis Lactulose + neomycin vs placebo PSE index PSE Index (mental state (West Haven), number conection test, EEG, asterixis and arterial ammonia) Strauss, 199223 Acute HE stages I-IV Cirrhosis Neomycin vs placebo Clinical improvement Clinical criteria (I to IV) but no reference or explanation. Sushma, 199224 Acute HE stages II-IV Cirrhosis Lactulose vs sodium benzoate Clinical improvement Mental state (WH), asterixis, psychometric tests, arterial ammonia, EEG, evoked potentials Vilstrup, 199025 Acute HE stages II-IV Cirrhosis BCAA iv + lactulose vs glucose iv + lactulose Clinical improvement Glasgow coma scale Klotz, 198926 Stage III HE Cirrhosis Flumazenil vs placebo Clinical improvement Coma status evaluated by reactions and reflexes to stimuli (no further explanation or reference) Uribe, 198727 Acute HE (stage II Cirrhosis Lactitol and lactose enemas vs nonacidifying enemas PSE index PSE index: mental state (WH), NCT, asterixis, EEG, fasting arterial ammonia. Morgan, 198713 Acute HE Cirrhosis Lactitol vs lactulose PSE index PSE index: mental state (WH), NCT-A, asterixis, EEG, venous ammonia