In a cirrhotic patient with hyperammonemia (ammonia 98 µg/dL) and developing hepatic encephalopathy, what is the first‑line medication?

Treatment of Hyperammonemia and Developing Hepatic Encephalopathy in Cirrhosis

Lactulose is the best first-line medication for treating elevated ammonia (98 µg/dL) and developing hepatic encephalopathy in this cirrhotic patient. 1, 2, 3

Initial Treatment Approach

Start lactulose immediately at 20-30 g (30-45 mL) orally every 1-2 hours until the patient achieves at least 2 bowel movements per day. 1, 4, 2 Once this initial response is achieved, titrate the dose to maintain 2-3 soft bowel movements daily. 1, 4

Mechanism and Efficacy

• Lactulose works by acidifying the colon through bacterial degradation to acetic and lactic acids, converting ammonia (NH3) to non-absorbable ammonium (NH4+), which is then trapped and eliminated in stool. 1, 4
• Clinical studies demonstrate that lactulose reduces blood ammonia levels by 25-50% and improves mental state in approximately 75% of patients with hepatic encephalopathy. 3
• The overall response rate to lactulose-based therapy is 82.5%, with meta-analyses showing a relative risk of 0.62 (95% CI, 0.46–0.84) for symptom improvement compared to placebo. 1

When to Add Rifaximin

If the patient has recurrent episodes of hepatic encephalopathy or inadequate response to lactulose alone, add rifaximin 550 mg twice daily (or 400 mg three times daily). 1, 2

• Combination therapy with rifaximin plus lactulose shows superior outcomes: 76% recovery within 10 days versus 44% with lactulose alone (P=0.004), and shorter hospital stays (5.8 vs. 8.2 days, P=0.001). 1
• Rifaximin is particularly effective for secondary prophylaxis, reducing HE recurrence from 46% to 22% (NNT=4). 4

Alternative Routes of Administration

If the patient cannot take oral medications or has severe encephalopathy (West-Haven grade 3-4), use lactulose enema: 300 mL lactulose mixed with 700 mL water (total 1 liter), administered 3-4 times daily. 1, 5 The enema solution must be retained for at least 30 minutes to be effective. 1, 5

• Nasogastric tube administration is an option if the patient can protect their airway but cannot swallow. 1
• Critical pitfall: Do NOT give oral lactulose if there are signs of ileus or significant abdominal distention, as this may worsen the clinical picture and increase aspiration risk. 5 In such cases, polyethylene glycol (4 liters orally) is preferred, or use lactulose enema. 5

Adjunctive Therapies for Refractory Cases

If the patient fails to respond adequately to lactulose and rifaximin:

• Consider intravenous L-ornithine-L-aspartate (LOLA) 30 g/day, which provides substrates for ammonia metabolism to urea and glutamine. 1, 2 Combination of lactulose plus IV LOLA shows faster symptom recovery (1.92 vs. 2.50 days, P=0.002) compared to lactulose alone. 1
• Oral branched-chain amino acids (BCAAs) 0.25 g/kg/day can be used as an ancillary option, particularly in patients with muscle wasting. 1, 2

Critical Monitoring and Pitfalls

• Monitor for lactulose-related complications: dehydration, hypernatremia, severe perianal irritation, and aspiration risk (especially in patients with altered mental status). 5, 4
• Do not over-rely on ammonia levels for dosing decisions—ammonia levels are variable and do not guide lactulose titration; clinical improvement in mental status is the primary endpoint. 5, 4
• Ensure adequate hydration to prevent electrolyte disturbances, particularly hypernatremia. 5

Identify and Treat Precipitating Factors

While initiating lactulose, simultaneously investigate common triggers:

• Infection: Obtain blood cultures, urinalysis with culture, chest X-ray, and consider diagnostic paracentesis if ascites is present. Start empiric antibiotics if infection is suspected. 5
• GI bleeding: Check hemoglobin and consider urgent endoscopy if bleeding is suspected. 5
• Medications: Review and discontinue sedatives, opioids, or diuretics that may precipitate encephalopathy. 6
• Electrolyte disturbances: Correct hypokalemia, hyponatremia, or other metabolic derangements. 6

Avoid These Medications

Neomycin and metronidazole are NOT recommended due to significant adverse effects: intestinal malabsorption, nephrotoxicity, and ototoxicity (neomycin), and peripheral neuropathy (metronidazole). 1, 2