Treatment of Hepatic Encephalopathy: Rifaximin vs Lactulose
Lactulose is the first-line treatment for overt hepatic encephalopathy, and rifaximin should be added to ongoing lactulose therapy after a second recurrence, not used as monotherapy for initial episodes. 1, 2, 3
Initial Treatment of Overt Hepatic Encephalopathy
Start with lactulose as first-line therapy for any initial episode of overt HE. 1, 2
- Lactulose demonstrates significantly more frequent resolution of acute or chronic overt HE and reduces mortality compared to placebo. 1, 4
- Initial dosing: 25-30 mL (20-30 g) lactulose syrup every 1-2 hours until the patient achieves at least 2 soft bowel movements per day. 1, 2
- Maintenance dosing: Titrate to maintain 2-3 bowel movements daily to prevent both under-treatment and complications from overuse. 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. 1
Rifaximin alone is NOT recommended for initial treatment of overt HE. 1, 4 The FDA label explicitly states that in clinical trials for HE, 91% of patients were using lactulose concomitantly, and the treatment effect in patients not using lactulose could not be assessed. 3
Prevention of Recurrent Episodes
Continue lactulose indefinitely after the first episode to prevent recurrence. 2, 4
- Lactulose reduces 14-month recurrence risk from 47% to 20% when used as secondary prophylaxis. 2
Add rifaximin 550 mg twice daily to ongoing lactulose therapy after a second recurrence of overt HE. 1, 2, 4
- Combination therapy (rifaximin plus lactulose) reduces recurrence from 45.9% to 22.1% (number needed to treat = 4). 2
- This combination reduces mortality compared to lactulose alone (23.8% vs 49.1%) and decreases hospital stay (5.8 vs 8.2 days). 2, 5
- Rifaximin added to lactulose reduces the risk of recurrent HE by 58% compared to placebo. 1
Treatment of Covert Hepatic Encephalopathy
Either lactulose or rifaximin can be used for covert HE to improve quality of life and cognitive performance. 1, 4
- Both agents significantly improve cognitive performance and neuropsychiatric testing in covert HE. 1, 4
- Rifaximin may be preferred in covert HE due to fewer gastrointestinal side effects than lactulose. 4
Special Clinical Situations
When lactulose is poorly tolerated or contraindicated, rifaximin alone may be considered based on expert opinion, though this is not supported by strong evidence. 1, 4
For treatment-resistant HE (patients hospitalized or with persistent hyperammonemia despite lactulose), adding rifaximin significantly reduces hospitalization rates (from 41.6% to 22.2%) and ammonia levels. 6
Critical Pitfalls to Avoid
- Do not use rifaximin as monotherapy for initial overt HE episodes - this approach lacks solid evidence and contradicts FDA labeling. 1, 2, 3
- Do not over-dose lactulose - excessive use leads to dehydration, hypernatremia, aspiration risk, severe perianal irritation, and can paradoxically precipitate HE. 2
- Always identify and treat precipitating factors first - nearly 90% of patients can be managed by correcting precipitating factors alone (infections, GI bleeding, electrolyte disturbances, constipation, medications). 1, 4
- Do not use rifaximin in patients with MELD scores >25 - it has not been studied in this population, and systemic exposure increases with severe hepatic dysfunction. 3
- Do not use neomycin or metronidazole long-term - these older antibiotics cause ototoxicity, nephrotoxicity, and peripheral neuropathy. 1, 2
Evidence Quality Note
The most recent French guidelines (2023) analyzed meta-analyses showing rifaximin's benefit but concluded that potential biases in the RCTs prevent recommending rifaximin alone for overt HE. 1 The strongest evidence supports lactulose first-line, with rifaximin added for recurrent episodes despite lactulose therapy. 1, 2, 5