Primary Prophylaxis to Prevent the Development of Hepatic Encephalopathy in Cirrhotic Patients with Acute Variceal Bleeding

Abstract

Background and aim: Variceal bleeding is the second most important precipitating factor related to the development of episodic hepatic encephalopathy; but to date there are no recommendations to prevent this complication. The aim of this study was to compare if primary prophylaxis with lactulose or L-ornithine L-aspartate or rifaximin, in cirrhotic patients with variceal bleeding, is better than placebo for avoiding the development of hepatic encephalopathy.

Methods: A randomized, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT02158182) which included cirrhotic patients with variceal bleeding, without minimal or clinical hepatic encephalopathy at admission.

Findings: 87 patients were randomized to one of four groups. The basal characteristics were similar between groups. Comparatively with placebo, the frequency with regard to the development of hepatic encephalopathy was as follows: lactulose (54.5% versus 27.3%; OR = 0.3, 95% CI 0.09-1.0; P = 0.06); L-ornithine L-aspartate (54.5% versus 22.7%, OR = 0.2, 95% CI 0.06-0.88; P = 0.03); rifaximin (54.5% versus 23.8%; OR = 0.3, 95% CI 0.07-0.9; P = 0.04). There was no significant difference between the three groups receiving any antiammonium drug (P = 0.94). In the group receiving lactulose, 59.1% had diarrhea, and 45.5% had abdominal discomfort, bloating, and flatulence. Two patients (10%) treated with lactulose and a patient (4.5%) in the placebo group developed spontaneous bacterial peritonitis due to E. coli; one of them died due to recurrent variceal bleeding. There were no other adverse effects.

Conclusions: Antiammonium drugs, particularly L-ornithine L-aspartate and rifaximin, proved to be effective in preventing the development of hepatic encephalopathy in those cirrhotic patients with variceal bleeding.

Figure 1

Group A was treated with lactulose orally, 30 mL every 8 hours; meanwhile it was adjusted according to the dose response to achieve two to three daily soft stools. Group B was treated with LOLA administered at a standard dose of 10 grams intravenously diluted with saline solution of 500 ml with a continuous infusion for 24 hours. Group C was treated with rifaximin administered at a standard dose of 400 mg orally every 8 hours. Group D was the control group that received all the corresponding placebos to achieve blinding of the study; patients in this group received an intravenous glucose solution of 5% for 24 hours, dextrose solution of 30 ml orally every 8 hours, and 2 dextrose tablets orally every 8 hours in similar size, color, and shape to the tablets of rifaximin. Groups A, B, and C received also the other corresponding placebos in other double-blind study. The duration of therapy was 7 days in all groups. ^∗Withdrawn his informed consent.