What is the preferred treatment for hepatic encephalopathy in patients with hepatic failure, rifaximin or lactulose?

Rifaximin vs Lactulose in Hepatic Failure

Lactulose is the first-line treatment for hepatic encephalopathy, while rifaximin should be used as an add-on therapy to lactulose for prevention of recurrent episodes after the second episode of hepatic encephalopathy. 1, 2

First-Line Treatment Approach

Lactulose Therapy

• Lactulose is FDA-approved for the prevention and treatment of portal-systemic encephalopathy 3
• Initial dosing: 25-30 mL every 1-2 hours until at least two soft bowel movements per day 1, 2
• Maintenance dosing: 30-45 mL orally every 6-8 hours, titrated to maintain 2-3 soft bowel movements daily 2
• Mechanism: Acidifies the gastrointestinal tract, inhibiting ammonia production by coliform bacteria 4
• Clinical response observed in approximately 75% of patients 3

Common Pitfalls with Lactulose

• Overuse of lactulose can lead to serious complications:
  • Aspiration
  • Dehydration
  • Hypernatremia
  • Severe perianal skin irritation
  • Can paradoxically precipitate hepatic encephalopathy 1
• Lack of effect should prompt search for unrecognized precipitating factors 1

Add-on Therapy

When to Add Rifaximin

• Add rifaximin 550 mg twice daily after the second episode of hepatic encephalopathy 1, 2
• Rifaximin is FDA-approved specifically for reduction in risk of overt hepatic encephalopathy recurrence 5
• In clinical trials for hepatic encephalopathy, 91% of patients were using lactulose concomitantly 5

Benefits of Combination Therapy

• Combination therapy with rifaximin and lactulose is associated with:
  • Increased treatment effectiveness (RR 1.30; 95% CI 1.10-1.53) 6
  • Reduced mortality risk compared to lactulose alone (RR 0.57; 95% CI 0.41-0.80) 6
  • Reduced hospitalization rates in treatment-resistant patients 7
  • Significant reduction in ammonia levels in treatment-resistant patients 7

Evidence Analysis and Controversies

While most evidence supports the combination approach for recurrent episodes, some studies show conflicting results:

• A 2017 study found that rifaximin plus lactulose was effective in 96.87% of patients vs. 85.71% with lactulose alone, but this difference was not statistically significant (p=0.3251) 8
• A 2018 randomized controlled trial found no significant difference in effectiveness between combination therapy (67.69%) and lactulose alone (58.46%) (p=0.276) 9

However, the most recent evidence from 2023 shows that add-on rifaximin therapy significantly reduces hospitalization rates and ammonia levels in patients resistant to lactulose 7, supporting the guideline recommendations.

Treatment Algorithm

1. Initial episode of hepatic encephalopathy:

   • Start lactulose therapy (25-30 mL every 1-2 hours until ≥2 soft bowel movements)
   • Adjust to maintenance dose (30-45 mL every 6-8 hours)
   • Identify and treat precipitating factors

2. After second episode of hepatic encephalopathy:

   • Continue lactulose therapy
   • Add rifaximin 550 mg twice daily
   • Monitor for treatment response and adverse effects

3. For treatment-resistant cases:

   • Ensure proper lactulose dosing (not too much, not too little)
   • Confirm rifaximin adherence
   • Consider other adjunctive therapies as per guidelines (BCAA, LOLA)

The evidence clearly supports starting with lactulose as first-line therapy and adding rifaximin for prevention of recurrent episodes, which improves outcomes in terms of mortality and hospitalization rates.