Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis: An Open-Label, Randomized Controlled Trial of Lactulose, Probiotics, and No Therapy

OBJECTIVES: Lactulose is effective in secondary prophylaxis of hepatic encephalopathy (HE). Probiotics improves minimal hepatic encephalopathy (MHE), which predisposes to HE. No study has been conducted on the secondary prophylaxis of HE using probiotics. Our objective was to study the effects of lactulose and probiotics for secondary prophylaxis of HE. METHODS: Consecutive cirrhotic patients who had recovered from HE were randomized to receive lactulose (Gp-L, 30 ml three times per day), three capsules of probiotics (Gp-P) per day containing 112.5 billion viable lyophilized bacteria per capsule, or no therapy (Gp-N). All patients were assessed by psychometry (number connection test (NCT-A, B), figure connection test if illiterate (FCT-A, B), digit symbol test (DST), and block design test (BDT)), critical flicker frequency (CFF) test, and arterial ammonia at inclusion. The patients were followed up monthly. The primary end point was development of overt HE according to West Haven criteria or a follow-up of 12 months. RESULTS: Of 360 patients who recovered, 235 (65.2%) met the inclusion criteria (Gp-L, n=80; Gp-P, n=77; and Gp-N, n=78). In all, 38 patients (16.1%) were lost to follow-up and 77 patients developed HE (Gp-L, n=18; Gp-P, n=22; and Gp-N, n=37). There was a significant difference between Gp-L and Gp-N (P=0.001) and between Gp-P and Gp-N (P=0.02) but no difference between the Gp-L and Gp-P groups (P=0.349). The rate of readmission for causes other than HE (Gp-L, Gp-P, and Gp-N, 19: 21: 28; P=0.134) and deaths (Gp-L:Gp-P: Gp-N=13:11:16; P=0.56) in all three groups were similar. There was a high prevalence of abnormal psychometry test results (NCT-A, 71.5%; NCT-B, 69.2%; DST, 76.9%; and BDT, 85.2%), and FCT-A and -B were abnormal in 35 of 48 patients (72.7%). CFF was <38 Hz in 118 patients (50.2%). Upon multivariate analysis, recurrence of overt HE was significantly associated with two or more abnormal psychometric tests and arterial ammonia after the recovery of an episode of HE. CONCLUSIONS: Lactulose and probiotics are effective for secondary prophylaxis of HE in patients with cirrhosis.