What is the preferred treatment for hepatic encephalopathy, Rifaximin (Rifaximin) or Lactulose (Lactulose), in a patient with liver disease?

Treatment of Hepatic Encephalopathy: Rifaximin vs Lactulose

Lactulose is the first-line treatment for initial episodes of overt hepatic encephalopathy, and rifaximin should be added to ongoing lactulose therapy only after a second recurrence of overt HE. 1, 2

Initial Episode of Overt Hepatic Encephalopathy

• Start with lactulose monotherapy at 25 mL (or 20-30 g) syrup every 1-2 hours until the patient achieves at least 2 soft bowel movements per day 1, 2
• Maintenance dosing should be titrated to maintain 2-3 bowel movements daily 1, 2
• For severe HE (West-Haven grade 3-4) when oral administration is not possible, use lactulose enema: 300 mL lactulose mixed with 700 mL water, administered 3-4 times daily and retained for at least 30 minutes 2
• Lactulose demonstrates significantly more frequent resolution of acute or chronic overt HE and reduces mortality compared to placebo 2

Prevention of Recurrence After First Episode

• Continue lactulose indefinitely for secondary prophylaxis after the first episode resolves, which reduces 14-month recurrence risk from 47% to 20% 1, 2
• Do not add rifaximin at this stage—there is no solid data supporting rifaximin monotherapy, and it contradicts FDA labeling 2, 3

After Second Recurrence of Overt HE

• Add rifaximin 550 mg twice daily to ongoing lactulose therapy after a second recurrence of overt HE within 6 months 1, 2, 3
• This combination reduces recurrence from 45.9% to 22.1% (number needed to treat = 4) 2
• Combination therapy reduces mortality compared to lactulose alone (23.8% vs 49.1%) and decreases hospital stay (5.8 vs 8.2 days) 2
• In the pivotal rifaximin trial, 91% of patients were using lactulose concomitantly, and differences in treatment effect for those not using lactulose could not be assessed 1, 3

Critical Pitfalls to Avoid

• Never use rifaximin as monotherapy for initial overt HE episodes—this approach lacks solid evidence and contradicts FDA labeling 1, 2
• Avoid over-dosing lactulose, as excessive use leads to dehydration, hypernatremia, aspiration risk, severe perianal irritation, and can paradoxically precipitate HE 1, 2
• Always identify and treat precipitating factors first (infections, GI bleeding, electrolyte disturbances, constipation, medications), as nearly 90% of patients can be managed by correcting precipitating factors alone 1, 2
• Do not use rifaximin in patients with MELD scores >25, as it has not been studied in this population and systemic exposure increases with severe hepatic dysfunction 2, 3

Special Considerations

• Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19 3
• There is increased systemic exposure to rifaximin in patients with more severe hepatic dysfunction 3
• The FDA label for rifaximin specifically indicates it is for "reduction in risk of overt hepatic encephalopathy recurrence in adults," with the notation that 91% of trial patients were using lactulose concomitantly 3
• Lactulose has been used for over 2 years in controlled studies for chronic portal-systemic encephalopathy, with clinical response observed in about 75% of patients 4

Alternative Agents for Non-Responders

If patients fail to respond to lactulose or lactulose plus rifaximin:

• Consider oral branched-chain amino acids (BCAAs) as an alternative or additional agent 1
• Consider IV L-ornithine L-aspartate (LOLA) as an alternative or additional agent 1
• Neomycin can be considered but carries risks of ototoxicity, nephrotoxicity, and neurotoxicity with long-term use 1, 2
• Metronidazole is another alternative but has significant limitations for long-term use due to similar toxicity risks 1, 2