Background and Aims: Data on the use of intravenous L-ornithine Laspartate (LOLA) in the treatment of overt HE (OHE) is limited. We evaluated the role of intravenous LOLA in patients of cirrhosis with OHE grade III-IV. Approach and Results:In a double-blind randomized placebo-controlled trial, 140 patients were randomized to a combination of LOLA, lactulose, and rifaximin (n = 70) or placebo, lactulose, and rifaximin (n = 70). LOLA was given as continuous intravenous infusion at a dose of 30 g over 24 h for 5 days. Ammonia levels, TNFα, ILs, and endotoxins were measured on days 0 and 5. The primary outcome was the improvement in the grade of HE at day 5. Higher rates of improvement in grade of HE (92.5% vs. 66%, p < 0.001), lower time to recovery (2.70 ± 0.46 vs. 3.00 ± 0.87 days, p = 0.03), and lower 28-day mortality (16.4% vs. 41.8%, p = 0.001) were seen in the LOLA group as compared with placebo. Levels of inflammatory markers were reduced in both groups. Significantly higher reductions in levels of blood ammonia, IL-6, and TNFα were seen in the LOLA group.Conclusions: Combination of LOLA with lactulose and rifaximin was more effective than only lactulose and rifaximin in improving grades of HE, recovery time from encephalopathy, with lower 28-day mortality.

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