How should hepatic encephalopathy be managed, including first‑line therapy, dosing, adjuncts, and refractory treatment?

Management of Hepatic Encephalopathy

Begin immediate treatment with lactulose 25 mL orally every 12 hours, titrated to produce exactly 2–3 soft stools daily, while simultaneously identifying and correcting precipitating factors—this dual approach resolves hepatic encephalopathy in approximately 90% of patients. 1, 2

Initial Stabilization and Assessment

Airway Protection and ICU Criteria

• Patients with Grade III–IV encephalopathy require immediate endotracheal intubation for airway protection due to inability to protect their airway and high aspiration risk. 3, 2
• Admit all Grade III–IV patients to the ICU with head of bed elevated to 30 degrees to reduce intracranial pressure. 3, 2
• Grade I–II patients can be managed on a medical ward with frequent mental status checks, but transfer immediately to ICU if level of consciousness declines. 2

Exclude Alternative Diagnoses

• Perform head CT to exclude intracranial hemorrhage, drug intoxication, or other structural causes of altered mental status. 1, 2
• A normal blood ammonia level should prompt reevaluation for alternative causes; elevated ammonia does not correlate with encephalopathy severity or prognosis and has limited diagnostic utility. 2

Identify and Correct Precipitating Factors

This is the cornerstone of management—precipitating factors are present in 80–90% of episodes, and their correction alone resolves hepatic encephalopathy in approximately 90% of patients. 1, 2, 4

Systematic Search Protocol

• Gastrointestinal bleeding: Check for melena, hematemesis, perform digital rectal exam, stool occult blood test, complete blood count, and endoscopy if indicated. Treat with blood transfusion, endoscopic hemostasis, and vasoactive medications. 1, 3
• Infection: Obtain CBC with differential, C-reactive protein, chest X-ray, urinalysis/culture, blood cultures, and diagnostic paracentesis. Start empirical broad-spectrum antibiotics if infection is suspected. 1, 3, 4
• Constipation: Assess clinically and with abdominal plain radiograph. Treat with enemas or osmotic laxatives. 1, 4
• Dehydration: Evaluate skin turgor, blood pressure, pulse, and basic metabolic panel. Reduce or hold diuretics; administer intravenous albumin or isotonic fluids. 1, 3
• Electrolyte disturbances: Correct sodium (target 140–145 mmol/L), potassium, magnesium, and phosphate abnormalities. 1, 3
• Renal dysfunction: Check blood urea nitrogen, serum creatinine, cystatin C, and electrolyte panel. Adjust nephrotoxic drugs and optimize volume status. 1
• Medications: Discontinue benzodiazepines, opioids, and other psychoactive drugs—these worsen encephalopathy and have delayed clearance in liver failure. 2

First-Line Pharmacologic Therapy

Lactulose Dosing and Titration

• Start lactulose 25 mL (containing 16.7 grams) orally every 12 hours. 2, 5
• Titrate to produce exactly 2–3 soft stools per day—not diarrhea. Underdosing leads to treatment failure; overdosing causes dehydration, hypernatremia, aspiration risk, and severe perianal irritation. 2, 5
• For acute severe encephalopathy requiring rapid laxation, administer 30–45 mL every 1–2 hours until bowel movement occurs, then reduce to maintenance dosing. 5
• In Grade III–IV patients who cannot take oral medication, administer lactulose 300 mL mixed with 700 mL water or physiologic saline as a retention enema via rectal balloon catheter; retain for 30–60 minutes and repeat every 4–6 hours. 5
• Clinical improvement may occur within 24 hours but may not begin before 48 hours. 5

When Lactulose Fails

• If lactulose is ineffective, systematically search for unrecognized precipitating factors or alternative causes of encephalopathy before escalating therapy. 2, 6

Adjunctive and Second-Line Therapy

Rifaximin

• Add rifaximin 550 mg orally twice daily if lactulose alone is insufficient or after a second episode of overt hepatic encephalopathy. 1, 2, 7
• Rifaximin combined with lactulose reduces recurrence risk by 58% (22.1% vs 45.9%; NNT = 4) and lowers hospitalization risk (13.6% vs 22.6%; NNT = 9). 2
• Do not use rifaximin as monotherapy for acute overt encephalopathy—it is not recommended as first-line treatment based on current evidence quality. 2, 6
• Rifaximin can be taken with or without food. 7

Alternative and Adjunctive Agents

• Intravenous albumin (1.5 g/kg/day) combined with lactulose improves recovery rate within 10 days (75% vs 53.3%, P=0.03) in patients with Grade ≥2 encephalopathy. 1
• Oral branched-chain amino acids (BCAAs) can be used as an adjunctive agent for patients nonresponsive to conventional therapy. 1, 2
• Intravenous L-ornithine L-aspartate (LOLA) can be used as an alternative or additional agent for refractory cases. 1, 2
• Polyethylene glycol (4 liters over 4 hours) showed superiority over lactulose alone in one trial (median time to resolution 1 day vs 2 days, P=0.01), but further studies are required. 1
• Neomycin and metronidazole are alternative antibiotics but carry risks of ototoxicity, nephrotoxicity, and neurotoxicity with long-term use. 2, 8, 9

Secondary Prophylaxis (Prevention of Recurrence)

After the first overt episode, continue lactulose indefinitely as secondary prophylaxis—this is a Grade A1 strong recommendation. 1, 2

Maintenance Regimen

• Continue lactulose at the dose that produces 2–3 soft stools daily. 2
• Add rifaximin 550 mg twice daily after a second episode or when recurrence occurs despite lactulose alone. 1, 2
• Rifaximin can be continued for more than 24 months with a good safety profile. 2, 6
• 50–70% of patients will experience recurrence within one year without secondary prophylaxis. 1, 6

Nutritional Management

• Do not restrict protein—this worsens malnutrition and sarcopenia, which are risk factors for hepatic encephalopathy. 2
• Provide moderate hyperalimentation with small, frequent meals throughout the day, including a late-night snack. 2
• Avoid fasting periods, which worsen encephalopathy. 2
• Start low-dose enteral nutrition once life-threatening metabolic derangements are controlled, regardless of encephalopathy grade. 3

Supportive Care in ICU Setting

• Maintain adequate mean arterial pressure with vasopressors as needed. 3
• Check frequently for glucose, sodium, potassium, magnesium, phosphate, and arterial blood gases. 3, 2
• Minimize stimulation and Valsalva-type maneuvers. 2
• Use low-dose propofol only if sedation is absolutely necessary (may reduce cerebral blood flow). 2
• Treat seizures with phenytoin rather than benzodiazepines. 2
• Cerebral edema occurs in 25–35% of Grade III patients and 65–75% of Grade IV patients. 2

Liver Transplantation Evaluation

• Refer to a transplant center for evaluation after the first overt episode of hepatic encephalopathy. 3, 2
• Recurrent, intractable overt encephalopathy with liver failure is a formal indication for liver transplantation. 1, 2, 6
• Patients with acute liver failure and hepatic encephalopathy have poor prognosis and should be considered for transplantation. 1
• Overall survival after an episode of overt hepatic encephalopathy is 42% at 1 year and 23% at 3 years. 1

Critical Pitfalls to Avoid

• Failing to systematically search for precipitating factors, which are responsible for approximately 90% of cases. 2
• Not titrating lactulose to achieve exactly 2–3 soft stools per day—this is the most common dosing error. 2
• Confusing hepatic encephalopathy with other causes of altered mental status without exclusion of alternative diagnoses. 2
• Omitting secondary prophylaxis after the first episode. 2
• Relying solely on ammonia levels for diagnosis, staging, or prognosis—they lack clinical utility beyond excluding hepatic encephalopathy when normal. 2
• Using benzodiazepines or opioids, which have delayed clearance and exacerbate encephalopathy. 2
• Restricting protein intake, which worsens outcomes. 2
• Starting hepatic encephalopathy-specific therapy before instituting optimal standard of care for at least 24–48 hours, unless using a placebo-controlled trial design. 1

Special Considerations

• Caution in severe hepatic impairment (Child-Pugh Class C): There is increased systemic exposure to rifaximin in patients with severe hepatic impairment. Clinical trials were limited to patients with MELD scores <25. 7
• Clostridium difficile risk: Although concerns exist about C. difficile infection with long-term rifaximin use, recent studies found no increased risk compared with control groups. 1
• Flumazenil (benzodiazepine antagonist) may temporarily improve consciousness in severe hepatic encephalopathy but does not improve survival and is not recommended as first-line therapy. 1