What is the best approach to manage hepatic encephalopathy in an adult patient with a history of liver disease?

Management of Hepatic Encephalopathy

Start with lactulose 30-45 mL orally every 1-2 hours until achieving 2-3 soft bowel movements daily, and add rifaximin 550 mg twice daily for recurrent episodes or when lactulose alone is insufficient within 24 hours. 1, 2, 3

Immediate Assessment: Identify and Treat Precipitating Factors First

Identifying and treating precipitating factors resolves hepatic encephalopathy in 80-90% of cases, making this the most critical initial step. 1

The most common precipitating factors to systematically evaluate include:

• Gastrointestinal bleeding - Check complete blood count, perform digital rectal examination, and obtain endoscopy if indicated 1
• Infection - Obtain blood cultures, urinalysis with culture, chest X-ray, and diagnostic paracentesis if ascites is present 1
• Constipation - Assess bowel movement frequency 1
• Dehydration and electrolyte imbalances - Check basic metabolic panel, particularly potassium and sodium 1
• Medications - Review for sedatives, benzodiazepines, opioids, and diuretics 4
• Acute kidney injury - Monitor creatinine and urine output 5

Patients with multiple concomitant precipitating factors have significantly worse prognosis and higher mortality, so systematic screening for all factors is essential. 5

Acute Pharmacological Management

First-Line Treatment: Lactulose

• Administer lactulose 30-45 mL (20-30 g) orally every 1-2 hours until the patient has at least 2 bowel movements, then adjust to maintain 2-3 soft stools per day. 1, 3
• Lactulose reduces blood ammonia by 25-50% and produces clinical response in approximately 75% of patients. 3
• For severe encephalopathy (West Haven grade ≥3), consider lactulose enemas in addition to oral therapy. 6
• Lactulose can be taken with or without food. 2

Adding Rifaximin

• Add rifaximin 550 mg orally twice daily when the patient does not improve with lactulose alone within 24 hours. 1, 2
• The combination of lactulose plus rifaximin shows superior efficacy compared to lactulose alone. 1
• Never use rifaximin as monotherapy for acute overt hepatic encephalopathy - always combine with lactulose initially. 7

Airway Protection and Stabilization

• Patients with grade III/IV hepatic encephalopathy require intubation for airway protection. 7
• Position the patient with head elevated at 30 degrees to reduce intracranial pressure. 7
• Consider intensive care unit admission for patients with altered consciousness who cannot protect their airway. 7

Secondary Prophylaxis After First Episode

After the first episode of overt hepatic encephalopathy, start indefinite secondary prophylaxis with lactulose 25 mL twice daily, titrated to 2-3 soft stools per day. 1

• Add rifaximin 550 mg twice daily after a second episode of hepatic encephalopathy. 1
• The combination of lactulose plus rifaximin is associated with a 40% reduction in mortality, fewer 30-day readmissions, and reduced hepatic encephalopathy recurrence from 53% to 34%. 1
• In the FDA approval trials for rifaximin in hepatic encephalopathy, 91% of patients were using lactulose concomitantly. 2

Nutritional Management

Provide adequate protein intake of 1.2-1.5 g/kg/day and energy intake of 35-40 kcal/kg/day, with small frequent meals (4-6 times daily including a nighttime snack). 1

• Never restrict protein long-term, as this worsens sarcopenia and hepatic function. 4, 6
• Weight loss with sarcopenia worsens hepatic encephalopathy, so the nutritional priority is to provide enough protein and energy to favor positive nitrogen balance and increase muscle mass. 4
• Consider replacing animal protein with vegetable and dairy protein while maintaining overall protein intake. 6

Patient and Caregiver Education

Provide structured 15-minute education sessions covering medication effects and side effects, the critical importance of adherence, early warning signs of recurrent hepatic encephalopathy, and specific actions to take. 1

Education should include:

• Effects of lactulose and rifaximin, including potential side effects like diarrhea 4
• Importance of medication adherence 4
• Early signs of recurring hepatic encephalopathy 4
• Actions to take if recurrence begins: anticonstipation measures for mild recurrence and referral to general practitioner or hospital if hepatic encephalopathy occurs with fever 4
• Structured education reduces hepatic encephalopathy-related hospitalization by 86%. 1

Monitoring and Follow-Up

• Schedule frequent outpatient visits to adjust treatment and prevent recurrence of precipitating factors. 4, 6
• Monitor neurological status, gait, and fall risk at each follow-up visit. 4, 1
• Systematically screen all patients with cirrhosis for both overt and covert hepatic encephalopathy using the animal naming test. 1
• Treatment endpoints must cover cognitive performance (improvement in one accepted test as minimum) and daily life autonomy (basic and operational abilities). 4

Advanced Considerations for Refractory Cases

Portosystemic Shunt Occlusion

• Consider embolization of large spontaneous portosystemic shunts (>8 mm) in patients with recurrent hepatic encephalopathy despite optimal medical therapy and a MELD score <11. 1
• Approximately 60% remain hepatic encephalopathy-free at 100 days and 50% at 2 years post-embolization. 1

Liver Transplantation

Evaluate for liver transplantation in patients with recurrent overt hepatic encephalopathy despite optimal medical therapy or severe hepatic encephalopathy unresponsive to treatment. 1

• Overall 1-year survival after the first hepatic encephalopathy episode is only 42%, declining to 23% at 3 years. 1
• 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. 2
• There is increased systemic exposure to rifaximin in patients with more severe hepatic dysfunction. 2

Critical Pitfalls to Avoid

• Never rely solely on ammonia levels for diagnosis or treatment decisions - a normal blood ammonia level in a patient suspected of hepatic encephalopathy calls for consideration of other causes. 4, 6
• Avoid sedative medications which can worsen encephalopathy and interfere with neurological assessment. 7
• Do not assume all altered mental status is hepatic encephalopathy - obtain brain imaging to exclude structural lesions, particularly in patients with focal neurological deficits. 4, 7
• Do not discharge patients without secondary prophylaxis - recurrence risk is high without maintenance lactulose. 7
• Do not delay treatment when infection is present - the encephalopathy will not fully resolve until the precipitating infection is adequately treated. 7