What is the recommended treatment prescription for a patient with hepatic encephalopathy?

Treatment of Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy, dosed at 20-30 grams orally 3-4 times daily and titrated to achieve 2-3 soft bowel movements per day. 1, 2

Initial Management Approach

Before initiating pharmacological therapy, you must identify and correct precipitating factors—this alone resolves HE in nearly 90% of patients. 2 Common precipitants include:

• Gastrointestinal bleeding 1
• Infection (including spontaneous bacterial peritonitis) 1
• Constipation 1
• Dehydration and electrolyte imbalances 1
• Psychoactive medications (especially benzodiazepines) 1
• Excessive protein intake 1
• Acute hepatic injury 1

For patients with severe HE (West Haven grade ≥3), provide intensive care monitoring for airway protection. 2

First-Line Pharmacological Treatment: Lactulose

Start lactulose 25-30 mL (20-30 grams) orally every 1-2 hours until the patient has at least 2 bowel movements, then adjust to maintain 2-3 soft stools daily. 1, 2, 3 This achieves clinical response in approximately 75% of patients and reduces blood ammonia by 25-50%. 2, 3

Alternative Routes for Lactulose Administration

• Nasogastric tube: Use when oral intake is not possible 1, 3
• Rectal enema: For severe HE (grade ≥3) or when oral/NG routes are inappropriate, administer 300 mL lactulose mixed with 700 mL water, 3-4 times daily, retained for at least 30 minutes 1, 3

Critical Lactulose Pitfall

Avoid excessive lactulose dosing—overuse causes aspiration risk, dehydration, hypernatremia, and severe perianal skin breakdown. 2, 3 The goal is 2-3 soft stools daily, not diarrhea.

Add-On Therapy: Rifaximin

Add rifaximin 550 mg twice daily (or 400 mg three times daily) to lactulose after the second episode of HE or when lactulose alone fails to prevent recurrence. 1, 2, 3, 4 Do not use rifaximin as monotherapy—there is no solid evidence supporting its use alone. 3

The combination of rifaximin plus lactulose:

• Improves recovery within 10 days (76% vs 44% with lactulose alone) 1, 3
• Shortens hospital stays (5.8 vs 8.2 days) 1, 3
• Reduces HE recurrence risk by 58% 2

In the FDA approval trials for rifaximin, 91% of patients were using lactulose concomitantly. 4

Alternative and Adjunctive Therapies

When conventional therapy fails or as additional treatment:

Intravenous L-Ornithine L-Aspartate (LOLA)

• Dose: 30 grams/day IV 1
• Lowers HE grade within 1-4 days (OR 2.06-3.04) and shortens symptom recovery time (1.92 vs 2.50 days) when combined with lactulose 1
• Note: Oral LOLA is ineffective 1, 2

Oral Branched-Chain Amino Acids (BCAAs)

• Dose: 0.25 g/kg/day 1
• Use as alternative or additional therapy for patients nonresponsive to conventional treatment 1, 2
• Note: IV BCAAs are ineffective for acute episodes 2

Albumin

• Dose: 1.5 g/kg/day until clinical improvement or maximum 10 days 1
• Can be used as adjunctive therapy 1

Polyethylene Glycol

• 4 liters orally as a substitute for non-absorbable disaccharides 1

Agents to Avoid

Do not use neomycin or metronidazole as first-line therapy due to significant toxicity:

• Neomycin: nephrotoxicity, ototoxicity, intestinal malabsorption 1, 5
• Metronidazole: peripheral neuropathy with long-term use 1

These are only considered alternative choices when other options have failed. 1

Prevention of Recurrence (Secondary Prophylaxis)

After the first episode of overt HE, 50-70% of patients experience recurrence within one year. 1

Initiate maintenance therapy immediately after the first HE episode:

• Continue lactulose indefinitely, titrated to 2-3 soft stools daily 1, 2
• Add rifaximin 550 mg twice daily after the second episode or if recurrence occurs on lactulose alone 1, 2, 3

Nutritional Management

Do not restrict protein—this worsens malnutrition and sarcopenia, which are risk factors for HE. 1, 2

Recommended nutritional approach:

• Daily energy: 35-40 kcal/kg 1
• Daily protein: 1.2-1.5 g/kg 1
• Small frequent meals (4-6 times daily) including a late-night snack 1, 2
• Avoid prolonged fasting periods 2

Special Considerations

Post-TIPS Hepatic Encephalopathy

Neither rifaximin nor lactulose prevents post-TIPS HE better than placebo—routine prophylaxis is not recommended. 1, 2 If severe HE develops post-TIPS, consider shunt diameter reduction. 1

Liver Transplantation

Consider transplant evaluation for:

• Recurrent intractable HE despite medical therapy 1, 2
• Acute liver failure with HE 1
• Severe HE unresponsive to treatment 1

Important limitation: Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of trial patients had MELD scores >19. 4 There is increased systemic rifaximin exposure in severe hepatic dysfunction. 4

Patient Education

Provide structured 15-minute education sessions covering:

• Medication effects and side effects (including diarrhea from lactulose) 1
• Critical importance of adherence 1
• Early warning signs of recurrent HE 1
• Actions to take if symptoms return 1

This education reduces HE-related hospitalization risk (HR 0.14,95% CI 0.02-0.77). 1