Abstract

Background: Critically ill cirrhosis (CIC) patients admitted to the intensive care unit (ICU) are usually on broad-spectrum intravenous antibiotics due to suspected infection or as a protocol. Few reports have suggested rifaximin to be beneficial in acute overt hepatic encephalopathy (OHE). However, the role of rifaximin in patients on broad-spectrum antibiotics admitted to ICU is still unclear. Therefore, we aimed to assess the efficacy of addition of rifaximin to broad-spectrum antibiotics for CIC patients admitted to ICU for OHE.

Methods: In this double-blind trial, patients with OHE admitted to ICU were randomized to receive antibiotics alone (Gr. A) or antibiotics with rifaximin (Gr. B). All patients received lactulose. The primary objective was to compare the resolution of HE (defined as 2-grade reduction and/or complete resolution of HE by West-Haven criteria) among the two groups. The secondary objective was to compare the time taken for the resolution of HE, in-hospital mortality, nosocomial infection, endotoxin levels, and predictors of HE resolution.

Results: 184 patients (age-47.8±11.7 years; females-11.4%; alcohol-66.3%; MELD-29.4±9.4; 92 patients in each group) were included. Baseline characteristics, including age, sex distribution, and severity scores, were similar among both groups. The most common precipitant of OHE was constipation with dyselectrolytemia in both groups (41%). The median number of stools passed per day in both groups was similar (4 [0-6] vs. 4 [2-6] in Gr.B; P=0.86). Forty-one percent in Gr. A and 50% in Gr. B received L-ornithine L-aspartate infusion concomitantly (P=0.3). The most common antibiotic used was carbapenems, followed by cephalosporin with beta-lactamase inhibitor in both groups. The proportion of patients achieving HE resolution was similar in both groups (44.6% [95%CI, 32-70.5] in Gr. A vs. 46.7% [95%CI, 33.8-63] in Gr. B; P=0.88) (Fig. a). Time to achieve the primary objective was 3.65±1.82 days and 4.11±2.01 days in Gr. A and B, respectively (P=0.27). In-hospital mortality was similar among both groups (62% vs. 50% in Gr. B; P=0.13). Seven percent and 13% in Gr. A and B developed nosocomial infections (P=0.21). 12% and 14.1% in Gr. A and B (P=0.82) needed the addition of another antibiotic or upgradation to carbapenems. Baseline endotoxin levels (1.22±0.72 vs. 1.3±0.86 EU/ml; P=0.8) and the delta change in levels of endotoxin at the resolution of HE were similar among both groups (Fig. b). On multivariate Cox regression analysis, a higher SOFA score predicted a lesser chance of OHE resolution (hazard ratio [HR], 0.85 [0.79-0.92];P<0.001), while higher albumin levels increased the chance of OHE resolution (HR, 1.6 [1.06-2.4]; P=0.02).

Conclusion: The addition of rifaximin to broad-spectrum antibiotics has no beneficial role in critically ill cirrhosis patients with acute OHE admitted to ICU.