Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial

Abstract

Background: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24 h, day 3, and day 7. The primary outcome was an improvement in encephalopathy by ≥ 1 grade at 72 h.

Patients and methods: European association for study of liver (EASL) defined ACLF patients with overt HE were assessed and randomized into the experimental arm (IV-BCAA - 500 mL/day for 3 days + Lactulose; n = 39) and the comparator arm (Lactulose alone; n = 37). Six patients developed COVID-19 after randomization and were excluded (4-experimental arm and 2-comparator arm).

Results: Of 222 screened patients, 70 (35 in each arm) were included in the analysis. Baseline characteristics, including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7; P = 0.86) and (chronic liver failure) CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7; P = 0.65), were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%; P = 0.14). Improvement in hepatic encephalopathy scoring algorithm (HESA) by ≥ 1 grade at 24 h occurred in 14 patients (40%) in the BCAA arm and 6 patients (17.1%) in the control group (P = 0.03) which translated to a shorter intensive care unit (ICU) stay. The median change in HESA at 24 h was greater in the BCAA arm than the control arm (P = 0.006), which was not sustained at days 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient (ρ) = - 0.0843; P = 0.29).

Conclusion: Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF.

Trial registration no: NCT04238416 (clinicaltrials.gov).

Keywords: acute-on-chronic liver failure; branched chain amino acids; hepatic encephalopathy; lactulose.

Figure 1

CONSORT enrollment diagram. ACLF – Acute-on-chronic liver failure, BCAA – branched chain amino acid, COVID-19 – coronavirus disease of 2019, EASL-CLIF – European association for study of liver - chronic liver failure, GCS – Glasgow coma scale, HCC – hepatocellular carcinoma, HE – hepatic encephalopathy, HESA – hepatic encephalopathy scoring algorithm, HIV – human immunodeficiency virus, IV – intravenous, ONSD – optic nerve sheath diameter, WHC – west haven classification.

Figure 2

Ammonia levels in both arms at different time points.

Figure 3

Kaplan Meier survival analysis demonstrating 28-day mortality stratified by treatment group (panel A) and CLIF-C ACLF score at admission (panel 2).