What is the preferred treatment between lactulose and rifaximin (Rifaximin) for hepatic encephalopathy?

Treatment of Hepatic Encephalopathy: Lactulose vs. Rifaximin

Lactulose is the first-line treatment for hepatic encephalopathy, while rifaximin should be added to lactulose (not used alone) for prevention of recurrent episodes after a second episode of overt hepatic encephalopathy. 1

First-Line Treatment: Lactulose

Initial Management

• Lactulose is recommended as first-line therapy for episodic overt hepatic encephalopathy (OHE) 1
• Initial dosing: 25 mL of lactulose syrup every 1-2 hours until at least two soft or loose bowel movements per day are produced 1, 2
• Maintenance dosing: Titrate to maintain 2-3 soft bowel movements daily (typically 30-45 mL orally every 6-8 hours) 2

Mechanism and Efficacy

• Lactulose works by acidifying the gastrointestinal tract, which inhibits ammonia production by coliform bacteria 3
• FDA-approved for prevention and treatment of portal-systemic encephalopathy 4
• Clinical response observed in approximately 75% of patients 4
• Reduces blood ammonia levels by 25-50%, which generally parallels improvement in mental state 4

Cautions with Lactulose

• Avoid excessive dosing which can lead to complications:
  • Aspiration risk
  • Dehydration
  • Hypernatremia
  • Severe perianal skin irritation
  • Paradoxical worsening of hepatic encephalopathy 1, 2

Second-Line/Add-on Treatment: Rifaximin

When to Add Rifaximin

• Add rifaximin to lactulose after a second episode of OHE within 6 months of the first episode 1
• Recommended dose: 550 mg twice daily 5
• FDA-approved specifically for reduction in risk of overt hepatic encephalopathy recurrence in adults 5

Evidence for Combination Therapy

• Rifaximin added to lactulose is the best-documented agent to maintain remission in patients who have already experienced one or more bouts of OHE while on lactulose 1
• Recent meta-analysis (2022) found combination therapy with rifaximin and lactulose was associated with:
  • Increased treatment effectiveness (RR 1.30; 95% CI 1.10-1.53)
  • Reduced mortality risk (RR 0.57; 95% CI 0.41-0.80) compared to lactulose alone 6
• A 2023 study showed rifaximin add-on therapy in lactulose-resistant patients significantly reduced hospitalization rates (from 41.6% to 22.2%) and ammonia levels 7

Treatment Algorithm

1. First Episode of OHE:

   • Start lactulose (25 mL every 1-2 hours until 2 soft bowel movements)
   • Titrate to maintain 2-3 bowel movements daily
   • Continue lactulose as secondary prophylaxis after resolution 1

2. Second Episode of OHE within 6 months:

   • Continue lactulose at effective dose
   • Add rifaximin 550 mg twice daily 1, 5

3. Treatment-Resistant HE:

   • Consider additional therapies if no response to lactulose + rifaximin:
     • Oral branched-chain amino acids (BCAAs) 1
     • IV L-ornithine L-aspartate (LOLA) 1

Important Clinical Considerations

• Always identify and treat precipitating factors for HE (Grade II-2, A, 1) 1
• Rifaximin should not be used as monotherapy; 91% of patients in clinical trials were using lactulose concomitantly 5
• 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 5
• For patients with recurrent or persistent HE, liver transplantation should be considered 1
• In patients with severe HE (grade 3-4), ICU admission should be considered for airway protection 1, 2

While some studies have shown comparable results between lactulose and rifaximin, the established treatment pathway based on the strongest evidence remains clear: start with lactulose as first-line therapy and add rifaximin for prevention of recurrence after a second episode of OHE.