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Rahimi 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(11):1727-1733.
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Clinical Question

In patients that present to Emerg with Hepatic Encephalopathy (HE), will a single dose polyethylene glycol (PEG) 3350 compared to standard of care (multiple doses of lactulose) decrease signs and symptoms at 24 hours.

Bottom Line

Patients with HE that received PEG had a more rapid resolution of symptoms and sorter overall hospital length of stay and preferred it over the standard of care with lactulose. More study is required.

Major Points

Lactulose has been the standard of care for acute and chronic hepatic encephalopathy for decades. [1] Treatment of HE still presents a problem and a burden for the healthcare system. Several new treatments have been developed in recent years such as rifaximin. [2][3] This trial demonstrates that bowel-purging techniques may be of benefit. Over half of the participants in the PEG arm preferred the PEG over the standard lactulose and requested that their maintenance lactulose be switched, however, tolerability and safety of PEG used chronically for this indication still requires study.


As of 1 Aug 2015, guidelines from the American Association for the Study of Liver Diseases and European Association for the Study of the Liver [4] do not reflect the findings of this study.


  • Single-centre, Single-blind, randomized, controlled trial
  • N=50
    • Polyethylene Glycol (PEG) 3350 (n=25)
    • Lactulose (n=25)
  • Setting: Single university affiliated centre in USA
  • Enrollment: January 2011 - June 2012
  • Analysis: Intention-to-treat
  • Primary Outcome:
    • Improvement of ≥1 in the hepatic encephalopathy scoring algorithm (HESA) score at 24 hours
  • Secondary Outcomes:
    • Time to HE resolution
    • Length of Stay
    • Change in serum ammonia


Inclusion Criteria

  • All comers presenting to Emerg
  • age 18 to 80 years
  • diagnosis of cirrhosis from any cause
  • altered mental status (AMS)
  • presence of any grade of HE
  • availability of Legally Authorized Representation (LAR) for interview and consent

Exclusion Criteria

  • acute liver failure
    • coagulopathy (international normalized ratio >1.5)
    • any degree of AMS in the absence of underlying chronic liver disease (CLD)
  • AMS from a cause other than HE
  • treatment with rifaximin or neomycin within previous 7 days
  • receipt >1 dose of lactulose prior to consent
  • lack of an LAR to provide consent
  • refusal of consent by LAR
  • previous participation in present study
  • hemodynamic instability treated with vasopressors
  • pregnancy
  • being a prisoner

Baseline Characteristics

  • Age, mean (SD), y 56(9)
  • Women, No.(%) 19(38)
  • Race/ethnicity, No.(%): African American 4(8); Asian 1(2); White Hispanic 35(70); White, non-Hispanic 10(20)
  • Cirrhosis cause, No. (%): Alcoholic liver disease 19(38); Cryptogenic 12(24); Hepatitis C 17(34) Hepatitis B 2(4)
  • WBC count, mean (SD), ×109/L: 6.2(2.6)
  • BUN, mean (SD), mmol/L [mg/dL]: 9.3(5.4) [26(15)]
    • Lactulose vs. PEG: 7.5(3.9) [21(11)] vs. 10.7(6.1) [30(17)]; P=0.03
  • Creatinine, mean (SD), mcmol/L [mg/dL]: 124(90) [1.41(1.02)]
  • Total bilirubin, mean (SD),mcmol/L [mg/dL]: 56(39) [3.3(2.3)]
  • INR, mean (SD): 1.5(0.4)
  • Albumin, mean (SD), g/L [g/dL]: 27(6) [2.7(0.6)]
  • Model of End-Stage Liver Disease (MELD) score, mean (SD): 17(5)
  • Child-Turcotte-Pugh (CTP) score, mean (SD): 10(2)


  • Lactulose
    • 20-30g PO or NG (as per treating physician digression) ≥3 doses in 24 hrs
    • 200g PR if PO intake not possible/inadequate
  • PEG 3350
    • 4L PO or NG, single dose over 4hrs


Comparisons are Lactulose (n=25) vs. PEG (n=25); P-value

Primary Outcomes

HESA Score change after 24hrs, mean(SD)
0.7(0.8) vs. 1.5(0.8); 0.002

Secondary Outcomes

Length of Stay, days
8 vs. 4; 0.07
Time to HE Resolution, median, days
2 vs. 1; 0.01
Patients with decreased HESA score at 24 hours, No.(%)
One grade: 9(36) vs. 10(43)
Two grades: 3(12) vs. 9(39)
Three grade: 1(4) vs. 1(4)
No improvement: 12(48) vs. 2(9)
Complete resolution of Symptoms (Grade Zero): 2(8) vs. 10(43)
Patients requiring placement of NG, No.(%)
3(12) vs. 4(16%); NS
Change in serum ammonia levels, mean(SD), mcmol/L
56 vs. 93; 0.03

Presented as before vs. after treatment, see Supplement

Change in serum BUN, median(range), mmol/L [mg/dL]
All (n=43): 7.9(0.7-24) [22(2-69)] vs. 7.5(1.1-20.7) [21(3-58)]; NS
Lactulose(n=21): 7.1(0.7-12.5) [20(2–35)] vs. 6.8(1.1-13.6) [19(3–38)]; NS
PEG(n=22): 10.4(1.8-24.6) [29(5–69)] vs. 10(2.5-20.7)[28(7–58)]; NS
Change in Anion Gap (surrogate for Acid-Base status), mean(SD)
Lactulose(n=21): 12(3) vs. 13(3); NS
PEG(n=22): 14(3) vs. 14(3); NS

Adverse Events

Change in serum Potassium from baseline to 6-24hrs after treatment, median(range) mmol/L
Lactulose: 4.2(2.1-4.9) vs. 3.9(2.7-4.9); 0.19
PEG: 4.4(2.7-5.7) vs. 3.8(3.0-4.7); 0.007

“More" bloating in Lactulose group

“More” diarrhea in PEG group


  • Clinicians must be certified to complete the hepatic encephalopathy scoring algorithm (HESA), hurting the
  • HESA is propriety to the University of California, San Diego
  • PEG Group had higher BUN levels, unclear how this might have altered results if other factors were balanced between groups
  • Did not outline the number of doses of Lactulose the standard of care arm received, if more aggressive, would there have been less of a difference?
  • Excluded those receiving rifaximine, arm including those patients would have been beneficial
  • Increased diarrhea in treatment arm, this could lead to more adverse events associated with dehydration


  • National Institutes of Health (NIH) grant 5-T32- DK007745-15 (Rahimi)
  • NIH National Center for Advancing Translational Sciences grant KL2TR000453 (Singal)

Further Reading

  1. Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of chronic portal-systemic encephalopathy: a double-blind clinical trial. N Engl J Med. 1969;281(8):408-412.
  2. Lawrence KR, Klee JA. Rifaximin for the treatment of hepatic encephalopathy. Pharmacotherapy. 2008;28(8):1019-1032
  3. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. 2003 Jan;38(1):51-8.
  4. Vilstrup H, et al. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol 2014;61(3):642-659 [1]