Drug Administration Using a computer-generated sequential 3:2 block randomization list, Pazopanib patients were assigned to receive rifaximin (Normix?, Alfa Farmaceutici SpA, Bologna, Italy) at 1200 mg per day in three divided doses (n=32) or lactulose (Duphalac syrup?, Choongwae Pharmaceutical, Seoul, Korea) at 90 mL a day (n=22). The treatment duration was 7 days unless symptoms worsened or serious side effects occurred. All patients were given a nutritious diet containing a maximum of 40g of protein per day. At the beginning of the trial, patients underwent a full assessment, including a detailed history taking, and physical and neurological examinations. The following parameters were evaluated before and at the end of the treatment period: complete blood count, blood chemistry, serum electrolytes, renal function, blood sugar, and urinalysis.

Adverse events were assessed by the investigators. Any abnormal clinical or laboratory findings observed during the trial were monitored and documented. Drug administration was discontinued in the event of 1) severe side effect, 2) taking any medication that could potentially interfere with the course of HE, 3) a serious cirrhotic complication such as acute variceal bleeding, or spontaneous bacterial peritonitis, and 4) a patient’s refusal to participate in the trial. Grade of mental state This was examined semi-quantitatively using Conn’s modification of the Parsons-Smith classification.

21 Grade 0: no abnormality; Grade 1: trivial loss of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction performance; Grade 2: lethargy, disorientation with respect to time, obvious personality change, inappropriate behavior; Grade 3: somnolence to semi-stupor, responsive to stimuli, confusion, gross disorientation, bizarre behavior; and Grade 4: coma, unable to test mental function. The severity of flapping tremor Severity was determined by extending the patients’ arms and forearms with the wrists dorsiflexed for at least 30 seconds. We adopted a simplified grading system to minimize inter-observer variance. Grade 0: no flapping motion; Grade 1: infrequent flapping motion; Grade 2: continual flapping motion; and Grade 3: unable to test. Number connection test (NCT) The time taken to connect 25 progressive numbers, i.e. part A of the number connection test.22,23 Grade 0: < 30 sec (normal); Grade 1: 31-50 sec; Grade 2: 51-80 sec; Grade 3: 81-120 sec; and Cilengitide Grade 4: > 120 sec. Blood ammonia levels Blood ammonia was measured before and after the treatment using Cobas Integra 800 (Roche, Basel, Switzerland). Grade 0: < 75 ��M/L; Grade 1: 76-150 ��M/L; Grade 2: 151-200 ��M/L; Grade 3: 201-250 ��M/L; and Grade 4: > 251 ��M/L.