What is the recommended management of hepatic encephalopathy, including first‑line therapy, dosing, and secondary measures?

Management of Hepatic Encephalopathy

Lactulose 20–30 g orally 3–4 times daily, titrated to achieve exactly 2–3 soft bowel movements per day, is the first-line treatment for all grades of overt hepatic encephalopathy and should be continued indefinitely after the first episode as secondary prophylaxis. 1, 2, 3

Immediate Assessment and Stabilization

All patients presenting with overt hepatic encephalopathy require a four-pronged approach: (1) stabilize consciousness and protect the airway, (2) exclude alternative causes (intracranial hemorrhage, infection, metabolic derangements), (3) identify and correct precipitating factors, and (4) start empirical lactulose immediately without delay. 2

Identification of Precipitating Factors

Precipitating factors are present in 80–90% of hepatic encephalopathy episodes, and their correction alone resolves the condition in approximately 90% of cases. 1, 2 This systematic search is the cornerstone of management and must be performed in every patient. 2

The most common precipitating factors and their management include:

• Gastrointestinal bleeding: Obtain CBC, perform digital rectal exam, check stool occult blood, and proceed with endoscopy when indicated; treat with blood transfusion, endoscopic hemostasis, and vasoactive medications 1, 2
• Infection: Order CBC with differential, CRP, chest X-ray, urinalysis/culture, blood cultures, and diagnostic paracentesis; initiate empiric broad-spectrum antibiotics immediately if infection is suspected 1, 2
• Constipation: Evaluate clinically and with plain abdominal radiography; manage with enemas or osmotic laxatives 1, 2
• Dehydration: Assess skin turgor, vital signs, and basic metabolic panel; hold diuretics and administer intravenous albumin or isotonic fluids 1, 2
• Electrolyte disturbances: Correct sodium to a target of 140–145 mmol/L along with potassium, magnesium, and phosphate abnormalities 2
• Renal dysfunction: Monitor BUN, serum creatinine, cystatin C, and electrolytes; adjust nephrotoxic medications and optimize volume status 1, 2

Grade-Specific Management

Grades I–II (Mild-to-Moderate Encephalopathy)

Manage on a medical ward with frequent mental status checks, though ICU is preferable; transfer immediately to ICU if level of consciousness declines. 4, 2

• Avoid sedatives (benzodiazepines, opioids) because they worsen encephalopathy and have delayed clearance in liver failure 4, 2
• Perform non-contrast head CT to exclude intracranial hemorrhage and other structural causes 2
• Monitor glucose, potassium, magnesium, and phosphate levels closely 4
• Start lactulose 25 mL orally every 12 hours, titrating to achieve 2–3 soft bowel movements daily 2

Grade I patients exhibit mild alterations in consciousness, subtle personality changes, decreased attention, sleep disturbances, irritability or apathy, and difficulty with complex cognitive tasks. 4, 2 Grade II patients have mild disorientation (especially temporal), pronounced lethargy, inappropriate behavior, asterixis, and dysarthric or slow speech. 4, 2

Grades III–IV (Severe Encephalopathy)

Patients with grade III–IV encephalopathy require immediate ICU admission with endotracheal intubation for airway protection; these patients cannot protect their airway and are at high risk of aspiration. 1, 2

Critical ICU measures include:

• Elevate head of bed to 30 degrees 1, 2
• Minimize stimulation and Valsalva-type maneuvers 2
• Use low-dose propofol only if sedation is absolutely necessary (may reduce cerebral blood flow) 2
• Deliver lactulose via nasogastric tube if oral intake is impossible 1, 2
• Treat seizures with phenytoin rather than benzodiazepines 1, 2

For severe encephalopathy when oral/nasogastric administration is not possible, perform lactulose enema with 300 mL lactulose and 700 mL water 3–4 times per day, retaining the solution in the intestine for at least 30 minutes until clinical improvement occurs. 1

Cerebral edema occurs in 25–35% of grade III patients and 65–75% of grade IV patients. 2 If intracranial hypertension develops, administer intravenous mannitol in a bolus dose of 0.5–1 g/kg, which may be repeated once or twice provided serum osmolality has not exceeded 320 mosm/L. 1

First-Line Pharmacologic Therapy

Lactulose Dosing and Titration

The initial dose is lactulose 20–30 g (25–30 mL) orally 3–4 times per day, which must be titrated to produce exactly 2–3 soft bowel movements per day—not diarrhea. 1, 2, 3 Underdosing leads to treatment failure, while overdosing causes dehydration, hypernatremia, aspiration risk, and severe perianal irritation. 2 An equivalent daily dose of lactitol is 67–100 g. 1

Lactulose achieves clinical response in approximately 75% of patients and resolves overt hepatic encephalopathy in approximately 90% of cases when combined with correction of precipitating factors. 2

When to Add Rifaximin

Add rifaximin 550 mg orally twice daily only after a second breakthrough overt hepatic encephalopathy episode occurs while the patient is on lactulose (typically within 6 months of the first episode); continue both drugs indefinitely. 2, 3 Do not introduce rifaximin after the first overt episode. 3

The landmark randomized controlled trial demonstrated that rifaximin added to lactulose decreased recurrence risk from 45.9% to 22.1% (hazard ratio 0.42; 95% CI 0.28–0.64; p<0.001), with a number needed to treat of 4 to prevent one recurrent episode. 2, 3 Hospitalization rate was reduced from 22.6% to 13.6% (NNT = 9). 2, 3

In the pivotal rifaximin trial, 91% of participants received concurrent lactulose, establishing the lactulose + rifaximin combination as the evidence-based standard rather than rifaximin monotherapy. 3 Rifaximin monotherapy is not recommended for initial treatment of overt hepatic encephalopathy because randomized controlled trials provide insufficient evidence to support its use alone. 3 Rifaximin may be considered as monotherapy only when lactulose is poorly tolerated, though this recommendation is based on expert opinion rather than robust trial data. 3

Patients treated with combination rifaximin and lactulose showed better recovery from hepatic encephalopathy within 10 days (76% vs 44%, p=0.004) and shorter hospital stays (5.8 vs 8.2 days, p=0.001) compared to lactulose alone. 1

Secondary Prophylaxis (Prevention of Recurrence)

After the first overt hepatic encephalopathy episode, continue lactulose indefinitely as secondary prophylaxis; this is a Grade A1 strong recommendation. 2, 3 Lactulose reduces 14-month recurrence risk to 20% versus 47% without treatment. 3 Without secondary prophylaxis, 50–70% of patients experience recurrence within one year. 2

Dosing Algorithm for Secondary Prophylaxis

Clinical Scenario	Treatment	Duration
First overt HE episode	Lactulose 20–30 g (30–45 mL) PO 3–4 times daily; titrate to 2–3 bowel movements/day	Indefinite
Second overt HE episode within 6 months (breakthrough on lactulose)	Add rifaximin 550 mg PO twice daily	Indefinite

2, 3

Long-term rifaximin therapy (>24 months) is safe and well tolerated, with no increased risk of adverse events, bacterial resistance, or Clostridioides difficile infection. 2, 3

Adjunctive and Second-Line Therapies

When standard therapy with lactulose ± rifaximin is insufficient, consider the following options:

• Intravenous albumin (1.5 g/kg/day): Combined with lactulose, improves clinical recovery within 10 days (75% vs 53.3%; p=0.03) in patients with grade ≥2 encephalopathy 1, 2
• Intravenous L-ornithine-L-aspartate (LOLA) 30 g/day: Lowers hepatic encephalopathy grade within 1–4 days (OR 2.06–3.04) and shortens duration until symptom recovery (1.92 vs 2.50 days, p=0.002) when combined with lactulose 1, 2
• Oral branched-chain amino acids (BCAAs) 0.25 g/kg/day: May be employed as adjuncts in patients unresponsive to standard therapy 1, 2
• Polyethylene glycol (4 L over 4 hours): Demonstrated superiority to lactulose alone, shortening median time to resolution to 1 day versus 2 days (p=0.01), though further trials are needed 2

Neomycin and metronidazole are not recommended for management of hepatic encephalopathy because of their side effects: intestinal malabsorption, nephrotoxicity, and ototoxicity for neomycin; peripheral neuropathy for metronidazole. 1

Nutritional Management

Do not restrict protein—this worsens malnutrition and sarcopenia, which are risk factors for hepatic encephalopathy. 2 Malnutrition is present in approximately 75% of patients with hepatic encephalopathy. 4

• Provide moderate hyperalimentation with small, frequent meals throughout the day 4, 2
• Include a late-night snack 4, 2
• Avoid fasting periods, which worsen hepatic encephalopathy 2
• Provide multivitamin supplementation 4
• Begin protein intake at 0.5 g/kg/day in severe cases, with progressive increase to 1–1.5 g/kg/day 5

Role of Ammonia Testing

A normal blood ammonia level should prompt reevaluation for alternative causes of altered mental status; elevated ammonia does not correlate with encephalopathy severity or prognosis and has limited utility beyond excluding hepatic encephalopathy when normal. 4, 2 Isolated blood ammonia determination does not provide diagnostic, prognostic, or staging value. 4

Liver Transplantation Evaluation

The first overt episode of hepatic encephalopathy warrants referral to a transplant center for evaluation. 4, 2 Recurrent, intractable overt encephalopathy in the setting of liver failure constitutes a formal indication for liver transplantation. 4, 2 Overall survival after an overt encephalopathy episode is 42% at 1 year and 23% at 3 years. 2

Critical Pitfalls to Avoid

• Failing to systematically search for precipitating factors, which cause 90% of cases 4, 2
• Not titrating lactulose adequately to achieve exactly 2–3 soft stools per day (not diarrhea) 4, 2, 3
• Confusing hepatic encephalopathy with other causes of altered mental status without exclusion of alternative diagnoses 4, 2
• Omitting secondary prophylaxis after the first episode 4, 2, 3
• Relying solely on ammonia levels for diagnosis, staging, or prognosis 4, 2
• Using benzodiazepines or other sedatives, which have delayed clearance and exacerbate encephalopathy 4, 2
• Adding rifaximin after the first overt hepatic encephalopathy episode; guidelines require a second breakthrough episode 2, 3
• Using rifaximin as monotherapy; efficacy is demonstrated only as add-on to lactulose 2, 3
• Restricting protein intake, which worsens outcomes 2