Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial

Abstract

Importance: Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades.

Objective: To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose.

Design, setting, and participants: The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE.

Interventions: Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization.

Main outcomes and measures: The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay.

Results: A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.

Conclusions and relevance: PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.

Trial registration: clinicaltrials.gov Identifier: NCT01283152.

Figure 1

Flow Diagram of Patient Recruitment, Randomization, and Follow-up ED indicates emergency department; HE, hepatic encephalopathy; HESA, HE scoring algorithm; ITT, intention to treat; LAR, legally authorized representative; and PEG, polyethylene glycol 3350–electrolyte solution.

Figure 2

Change in HESA Grade With Treatment The initial (hour 0) and follow-up (hour 24) HESA scores are depicted for the lactulose control (A) and PEG experimental (B) groups. Each transparent symbol represents a patient whose HESA score had changed from 0 to 24 hours; solid symbols represent patients whose HESA score showed no change at 24 hours. HESA indicates hepatic encephalopathy scoring algorithm; PEG, polyethylene glycol 3350–electrolyte solution.

Figure 3

Time to Hepatic Encephalopathy (HE) Resolution Shown is a Kaplan-Meier graph depicting the proportion of patients at risk for HE who received either standard-of-care lactulose therapy or polyethylene glycol 3350–electrolyte solution (PEG). Patients receiving PEG had more rapid resolution of HE than those receiving lactulose (P = .01).