What is the recommended treatment for hepatic encephalopathy?

Treatment of Hepatic Encephalopathy

First-Line Treatment: Lactulose

Lactulose is the first-choice treatment for episodic overt hepatic encephalopathy and should be initiated immediately without delay. 1, 2, 3

• Start lactulose 25 mL orally every 12 hours, titrating the dose to achieve 2-3 soft bowel movements daily 2, 4
• Clinical response occurs in approximately 75% of patients, with blood ammonia levels reduced by 25-50% 1, 3
• For patients unable to take oral medications, administer lactulose via nasogastric tube 2
• Lactulose has demonstrated benefit in resolution of hepatic encephalopathy, reduction of mortality, and reduction of serious adverse events 5

Critical Initial Steps Before Starting Treatment

Identifying and correcting precipitating factors resolves hepatic encephalopathy in nearly 90% of patients and must be done concurrently with lactulose initiation. 2, 4

• Search for and treat: infections, gastrointestinal bleeding, constipation, dehydration, electrolyte disturbances (particularly hypokalemia and hypomagnesemia), and sedative medications 2, 4, 6
• Exclude alternative causes of altered mental status that commonly coexist with hepatic encephalopathy in cirrhotic patients 2, 4
• A normal ammonia level should prompt reevaluation of the diagnosis 5

Intensive Care Considerations

• Patients with higher grades of hepatic encephalopathy (grade III-IV) who cannot protect their airway require ICU monitoring 2
• Patients with grade 0-II encephalopathy can typically be managed on a medicine ward 4
• Avoid sedatives as they worsen encephalopathy and have delayed clearance in liver failure 4

Second-Line Treatment: Adding Rifaximin

Add rifaximin 550 mg twice daily when lactulose alone fails to prevent recurrence of hepatic encephalopathy. 1, 2, 7

• Rifaximin reduces the risk of hepatic encephalopathy recurrence by 58% when added to lactulose 2, 5
• The combination improves recovery within 10 days and shortens hospital stays 2
• Rifaximin should be added after the second episode of hepatic encephalopathy or when lactulose monotherapy fails 2
• In the pivotal trials, 91% of patients were using lactulose concomitantly with rifaximin 7
• Rifaximin can be continued indefinitely for secondary prevention with a good safety profile, with studies showing effectiveness beyond 24 months 5

Do not use rifaximin as monotherapy for initial treatment of overt hepatic encephalopathy. 5

Prevention of Recurrence (Secondary Prophylaxis)

Secondary prophylaxis is strongly recommended after the first episode of overt hepatic encephalopathy, as 50-70% of patients will experience recurrence within one year. 2, 4, 5

• Continue lactulose indefinitely, titrated to 2-3 soft stools daily 2, 4
• Add rifaximin 550 mg twice daily for patients with recurrent episodes despite lactulose therapy 1, 2
• Prophylactic therapy may only be discontinued when precipitating factors are well-controlled, infections treated, variceal bleeding resolved, or liver function significantly improved 4

Alternative and Additional Therapies

For patients nonresponsive to conventional lactulose and rifaximin therapy:

• IV L-ornithine L-aspartate can be used as an alternative or additional agent (note: oral formulation is ineffective) 1, 2
• Oral branched-chain amino acids can be used as alternative or additional therapy (note: IV formulation is ineffective for acute episodes) 1, 2
• Neomycin is an alternative choice, though long-term use carries risks of ototoxicity and nephrotoxicity 1
• Metronidazole is an alternative for short-term therapy, but long-term use risks ototoxicity, nephrotoxicity, and neurotoxicity 1

Special Clinical Scenarios

Post-TIPS Hepatic Encephalopathy

• Neither rifaximin nor lactulose prevents post-TIPS hepatic encephalopathy better than placebo 1, 2
• Routine prophylactic therapy is not recommended 5
• If severe hepatic encephalopathy develops post-TIPS, shunt diameter reduction can reverse it 1

Spontaneous Portosystemic Shunts

• In patients with preserved liver function and recurrent overt hepatic encephalopathy, search for large spontaneous portosystemic shunts that may be amenable to embolization 1, 2

Hepatic Encephalopathy with Upper GI Bleeding

• Lactulose is supported for prevention of hepatic encephalopathy following upper gastrointestinal bleeding 1

Nutritional Management

Avoid protein restriction as it worsens malnutrition and sarcopenia, which are risk factors for hepatic encephalopathy. 2

• Provide small, frequent meals distributed throughout the day with a late-night snack 2, 4
• Avoid prolonged fasting periods which can worsen hepatic encephalopathy 2
• Address malnutrition present in approximately 75% of patients with hepatic encephalopathy 4
• Multivitamin supplementation is generally recommended 4

Liver Transplantation Evaluation

• Recurrent intractable hepatic encephalopathy together with liver failure is an indication for liver transplantation evaluation 2, 4
• The first episode of hepatic encephalopathy should prompt evaluation for liver transplantation 4

Common Pitfalls to Avoid

• Overuse of lactulose can lead to aspiration, dehydration, hypernatremia, and severe perianal skin irritation 2, 5
• Failing to identify precipitating factors is the most common cause of treatment failure 2, 4
• Relying exclusively on ammonia levels for diagnosis or monitoring is not recommended 4, 5
• Using rifaximin as monotherapy for initial treatment is inappropriate 5
• Inadequate lactulose dosing that fails to achieve 2-3 soft stools daily 4