Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure

Abstract

Background and Aims: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥ 2 for efficacy and outcome.Patients and Methods: Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit.Results: Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P = 0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P = 0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P = 0.03], HESA score [HR, 6.01 (1.27 to 28.5); P = 0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P = 0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P = 0.010) and at 90 days was 68.9% versus 48.3% (P = 0.940), respectively, with fewer persons relapsing with HE in the PEG arm.Conclusions: PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.

Polyethylene glycol versus lactulose in the treatment of hepatic encephalopathy: a systematic review and meta-analysis

“…Naderian et al 21 found that patients treated with PEG and lactulose had a shorter mean hospital stay of 6.8 days compared with patients treated with lactulose alone (mean 8.9 days). These results were also validated by Ahmed et al 22 who found that patients treated with both PEG and lactulose had a mean hospital stay of 9 days compared with 13 days in patients treated with lactulose alone. However, despite the fact that the studies included in this analyses [8][9][10][11] commented on the shorter length of hospital stay in patient receiving PEG, our analysis failed to show statistical significance in terms of length of hospital stay even after omitting one study to create a more homogenous group.…”

“…Additionally, a significantly higher proportion of patients in the PEG group had a reduction of HESA Score by ≥1 grade at 24 hours post treatment compared with lactulose and a significantly higher proportion of patients in the PEG group had HESA Score of grade 0 at 24 hours. In fact, two studies by Naderian et al 21 and Ahmed et al 22 compared the concomitant use of PEG with lactulose versus lactulose and concluded that the combination had led to a higher 24 hours HESA Score change as well as a higher reduction in HESA Score by more than one grade at 24 hours post treatment. The mechanism by which PEG improved HESA Score remains debatable.…”

Comparative Effectiveness and Safety of Polyethylene Glycol Electrolyte Solution Versus Lactulose for Treatment of Hepatic Encephalopathy

“…Three studies with a total of 148 patients compared PEG (n=73) with lactulose (n=75) in the levels of serum ammonia concentration. 10 , 11 , 14 The results showed that the ammonia concentration of the baseline was consistent (WMD=6.851, 95% CI: −2.72 to 16.424; P =0.161; Supplementary File 5: Figs. S5A, S5B, Supplemental Digital Content 1, http://links.lww.com/JCG/A784 ) with insignificant heterogeneity (χ 2 =3.09, P =0.214, I 2 =35.2%).…”

“…Since PEG is a highly effective laxative, the potential clinical improvement of HE may be more clinically significant than the actual decline in ammonia levels. 10 Publication bias and sensitivity analysis were not conducted due to only 3 studies include in the analysis. As such, this conclusion should be explained with caution and require more high-quality, multicenter RCTs validation.…”

Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel

“…Two Indian randomized control trials reported significant improvement of HESA score in the PEG group when compared to lactulose. 86,87 Currently, two trials are under process to access the therapeutic use of PEG in HE. 88,89 Nitazoxanide Nitazoxanide (NTZ) is a broad-spectrum thiazolide antiparasitic agent which has action against many anaerobic bacteria, protozoa, and helminthic species.…”