Abstract & Commentary
Is It Time to Rethink Lactulose for the Treatment of Acute Hepatic Encephalopathy?
Jennifer Best, MD, FACP, FHM
Associate Professor, University of Washington School of Medicine, Seattle, WA
Dr. Best reports no financial relationships in this field of study
SOURCE: Rahimi RS, et al. Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: The HELP randomized clinical trial. JAMA Intern Med. 2014; 174:1727-33.
For decades, lactulose, a non-absorbable disaccharide, has been considered to be the standard-of-care, first-line therapy for acute (overt) hepatic encephalopathy. Hepatic encephalopathy (HE), a complication of decompensated liver cirrhosis, represents a spectrum of clinical manifestations ranging from mild neuropsychiatric changes to coma and is a common indication for hospital admission. The pathogenesis of this condition is not entirely well understood, though certain entities, such as ammonia and its interaction with the bacterial flora of the gut, are known to be important. Prior to the use of non-absorbable disaccharides, laxatives represented a primary mode of therapy with the goal of gut lavage and more rapid transit, preventing bacterial metabolism of ammonia. Though evidence now supports the use of rifaximin for recurrent HE, this agent does not represent an advance in first-line therapy. Furthermore, the effectiveness of bowel catharsis with laxatives, such as polyethylene glycol (PEG, commonly utilized for bowel preparation) has not been evaluated in comparison with non-absorbable disaccharides.
In this randomized trial performed at a single academic medical center (HELP: Hepatic Encephalopathy: Lactulose vs. Polyethylene Glycol 3350-Electrolyte Solution), Rahimi and colleagues at UT Southwestern enrolled adult patients presenting to the ED with documented cirrhosis and altered mental status suggestive of HE. Patients with acute liver failure, an alternative, identified cause of altered mental status, rifaximin or neomycin use within 7 days, receipt of >1 dose of lactulose prior to randomization, hemodynamic instability or pregnancy were excluded. For each patient, a baseline severity of HE was established utilizing the hepatic encephalopathy scoring algorithm (HESA), which grades HE on a 0-4 scale. 50 patients were then randomized to each group — usual care, consisting of lactulose administered orally or via NG (20-30 g per dose with ≤3 doses in 24h) or rectally (200 g) or to 4 L of PEG administered orally or via NG tube. Over the ensuing 24 hours post PEG administration, no lactulose or other treatment for HE was allowed. At the 24-hour point and then daily, HESA grade was again established. Resolution of HE was defined as an improvement in HESA grade to 0, patient death or discharge or identification of 2 days over which time HESA grade improved by at least 1 grade and then remained stable at 1. The primary clinical outcome of this trial was improvement of 1 or more in HESA grade at 24 hours. Adverse events were also tracked for both cohorts.
The two groups were similar in baseline characteristics, including demographics, clinical features, laboratory data and HESA grade. They received the same amount of lactulose prior to randomization. The number of patients in the PEG group with improvement in 1 HESA grade was 43% (v. 36% with lactulose), 2 grades 39% (v. 12%) and 3 grades 4% (v. 4%). Overall, 91% of PEG patients achieved the primary clinical outcome, as compared with 52% of lactulose-treated patients (P<0.01). Only 9% of patients taking PEG had no improvement, as compared with 48% in the lactulose cohort. 43% of patients taking PEG had a HESA score of 0 at 24 hours, as compared with 8% for lactulose. Overall, PEG patients had a lower mean HESA score at 24 hours than patients receiving lactulose (1.0 vs. 1.6; p=0.002) and the time to resolution of HE was 1 day for PEG, as compared with 2 days with lactulose (P=0.01). During the study period, none of the 8 serious adverse events were directly attributable to either study medication. Three adverse events were deemed to be “possibly related,” consisting of recurrent HE and lactulose refusal >24 hours after administration of study medication. Subjectively, patients on lactulose experienced more bloating, whereas patients receiving PEG reported more diarrhea. The taste of PEG, which is salty rather than sweet, was preferred by patients to that of lactulose, and patients requested that it replace lactulose at hospital discharge. Neither therapy materially altered blood chemistry or electrolyte values. Interestingly, ammonia levels, which are not believed to correlate with the severity of HE, were lowered more by lactulose than by PEG, though clinical improvement with PEG was more common.
In conclusion, these authors suggest that PEG offers a safe and more rapidly effective therapy for acute HE, when compared with the current standard of care, lactulose. This is a small study at a single center, but the findings are compelling and may hold much significance for inpatient management. Because of the nature of the therapies, it was not possible to blind patients to their study arm; however, lengths were undertaken to ensure that investigators were blinded as much as possible through the division of labor involved in randomization, drug allocation and HESA administration. This study does not address whether PEG is a more appropriate choice for HE prophylaxis in the ambulatory setting or how it compares with lactulose or rifaximin for recurrent HE, but this study does suggest that it may have promise for shortening hospital stays and decreasing hospital costs. Further study is warranted.