What is the first-line treatment for hepatic encephalopathy secondary to hyperammonemia?

First-Line Treatment for Hepatic Encephalopathy Secondary to Hyperammonemia

Non-absorbable disaccharides (lactulose) are the first-line treatment for hepatic encephalopathy secondary to hyperammonemia. 1, 2, 3

Treatment Algorithm

Initial Management

1. Identify and treat precipitating factors 1, 2

   • Gastrointestinal bleeding
   • Infection
   • Constipation
   • Excessive protein intake
   • Dehydration
   • Renal dysfunction
   • Electrolyte imbalances
   • Psychoactive medications
   • Acute hepatic injury

2. Initiate lactulose therapy 1, 2, 3

   • Initial dosing: 30-45 mL every 1-2 hours until 2 bowel movements occur
   • Maintenance dosing: 25-30 mL (20-30 g) orally every 12 hours
   • Target: 2-3 soft stools per day
   • For severe HE (West Haven criteria grade ≥3) or when oral intake is inappropriate: administer lactulose enema

Add-on Therapies

1. Rifaximin 1, 2

   • Add to lactulose if inadequate response or recurrent episodes
   • Dosage: 550 mg orally twice daily or 400 mg three times daily
   • Reduces risk of HE recurrence by 58% compared to placebo

2. Additional supportive therapies 1, 2

   • Oral branched-chain amino acids (BCAAs)
   • Intravenous L-ornithine L-aspartate (LOLA)
   • Intravenous albumin (1.5 g/kg/day)

Alternative Therapies

1. Antibiotics 1, 2, 4

   • Neomycin (alternative when lactulose is not tolerated)
   • Metronidazole (short-term use only)
   • Note: Long-term use limited by ototoxicity, nephrotoxicity, and neurotoxicity

2. Other options 1, 2

   • Polyethylene glycol (PEG) as osmotic laxative
   • Flumazenil (for HE caused by benzodiazepines)

Nutritional Management

• Daily energy intake: 35-40 kcal/kg
• Protein intake: 1.2-1.5 g/kg
• Small frequent meals (4-6 times/day including night snack)
• Avoid long-term protein restriction 1, 2

Severe Cases

• For patients with severe HE unresponsive to medical treatment, consider liver transplantation 1
• For rapidly deteriorating neurological status with ammonia levels >150 μmol/l, consider continuous kidney replacement therapy (CKRT), specifically high-dose continuous venovenous hemodialysis (CVVHD) 1

Monitoring

• Frequent neurological evaluations
• Monitor ammonia levels
• Ensure adequate bowel movements (2-3 per day)
• Assess for medication side effects (particularly diarrhea with lactulose)

Clinical Pearls and Pitfalls

• Lactulose works by acidifying the gastrointestinal tract, which inhibits ammonia production by coliform bacteria 5, 6
• The combination of lactulose and rifaximin is more effective than lactulose alone for preventing recurrence 2
• Avoid excessive lactulose administration as it can lead to dehydration, hypernatremia, and worsening encephalopathy
• Enemas are recommended for severe HE when oral intake is inappropriate 1
• Patient education about medication effects, adherence, and early signs of recurrence is crucial for long-term management 2

Lactulose has been shown to reduce blood ammonia levels by 25-50%, which generally correlates with improvement in mental status 3. This approach has demonstrated clinical response in approximately 75% of patients, which is at least as satisfactory as neomycin therapy while having fewer serious side effects 3, 7.