Sunday, October 19, 2014

Role for polyethylene glycol in treating hepatic encephalopathy?

Hepatic encephalopathy is a frequent and debilitating complication of liver disease.  The mainstay of treatment, lactulose, has been used since the 1960s, even without a strong evidence-base for efficacy.  Currently, in the AASLD guidelines for hepatic encephalopathy, updated in 2014, lactulose is recommended as first line therapy for the treatment of episodic overt hepatic encephalopathy (Grade II-1,B,1 which means controlled trials without randomization, moderate evidence strength, strong recommendation)1.  It's notable that there is a cost appeal of lactulose compared to alternative or add-on therapies such as rifaximin and this is considered in their recommendation.

Before addressing possible alternatives to lactulose, I'd be remiss to not mention the importance of identifying and correcting all precipitating factors.  This is still the cornerstone of of management of this condition and a placebo controlled study found correction of precipitating factors alone to be effective in 90% of patients.

HELP trial2

A recently published study prospectively compared lactulose versus polyethylene glycol 3350-electrolyte solution (PEG) in 50 patients admitted to the hospital with hepatic encephalopathy.  On the first day only, they administered either PEG 4 liters (orally or by NG tube) over 4 hours or standard lactulose 20-30 grams orally or by NG tube ≥3 times per day (or 200 grams by rectal tube).  The primary outcome was an improvement in the hepatic encephalopathy scoring algorithm (HESA) of 1 after 24 hours.  Secondary outcomes included time to improvement of hepatic encephalopathy, length of stay, and ammonia levels.  After the first day, both groups were allowed to receive lactulose as per standard of care.

Both groups had similar characteristics with the only statistically significant difference of a higher BUN in the PEG group.  At 24 hours in the lactulose group, 13/25 (52%) had a 1 point improvement in HESA score compared to 21/23 (91%) in the PEG group (p<0.01).  There was a mean improvement of HESA scores of 0.7 in the lactulose group and 1.5 in the PEG group (p=0.002) and a shorter length of stay in the PEG group by 4 days but it did not reach statistical significance (p=0.07).

One surprising finding was that the improvement in ammonia concentrations from baseline to 24 hours was greater in the lactulose group, even though these patients did not clinically improve as quickly.  In terms of adverse events, neither group had an event definitely attributed to the study drug.  Monitoring of serum electrolytes and renal function was performed and there were no significant changes or differences between groups except that 6 patients in each group experienced moderate hypokalemia.  The authors did not comment about lactulose titration to bowel movements, though the primary outcome was measured after 24 hours which is too short an interval to titrate lactulose anyway.

About lactulose and PEG3

Lactulose is a nonabsorbable synthetic disaccharide of galactose and fructose that is resistant to intestinal disaccharidase activity but does undergo hydrolysis in the colon to short-chain fatty acids.  Once in the colon, lactulose has several mechanisms by which it is proposed to treat hepatic encephalopathy.  One is that it draws water into the lumen of the colon due to the osmotic gradient.  Another is that by reducing the pH, it traps ammonia in the ion form as ammonium (a process referred to as "ion trapping").  Lastly, it is a prebiotic that stimulates the growth of healthy intestinal microflora.  It has sweet flavor which patients may not like but you can dilute it with water or fruit juice.  It is typically dosed 20-30 grams 3 or 4 times a day and titrated to 2 to 3 soft stools per day.

PEG 3350-electrolyte solution (refers to the molecular weight ~3350 Da) is also poorly absorbed and it is retained into the lumen of the colon.  It is the most frequently used medication for colonic cleansing prior to radiologic, endoscopic, or surgical procedures.  It is available in a variety of trade and generic names and generally contains an isotonic mixture of electrolytes to reduce electrolyte disturbances.  It has a salty taste which patients may not like.  Some products come with flavor packets that can be added or some recommend adding something like Crystal Light in addition to refrigerating the solution to improve palatability.  Examples of this do not include MiraLax or GlycoLax (these only contain PEG, no electrolytes, no other inactive ingredients).  

Some examples of the electrolyte-containing product include:
  • Colyte
  • MoviPrep
  • Others

Take home points:

  • PEG 3350-electrolyte solution improved clinical resolution in the HELP study more quickly and more pronounced compared to lactulose, even though ammonia concentrations did not follow suit
  • A one-time dose of PEG 3350-electrolyte solution 4 liters administered over 4 hours was the dose used in the HELP study
  • If prescribing, make sure to choose the PEG solution that contains electrolytes (see examples above)

1.  Vilstrup H, Amodio P, Bajaj J, et al.  Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.  Hepatology  2014;60(2):715-35.
2.  Rahimi RS, Singal AG, Cuthbert JA, et al.  Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy.  JAMA Intern Med  2014.
3.  Sharkey KA, Wallace JL. Chapter 46. Treatment of Disorders of Bowel Motility and Water Flux; Anti-Emetics; Agents Used in Biliary and Pancreatic Disease. In:Brunton LL, Chabner BA, Knollmann BC. eds.  Goodman & Gillman's The Pharmacological Basis of Therapeutics, 12e.  New York, NY: McGraw-Hill;2011.

photo by EraPhernalia Vintage . . . (playin' hook-y ;o)


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