When is a Lactulose (LOLA) infusion indicated in patients with Hepatic Encephalopathy?

LOLA Infusion in Hepatic Encephalopathy

LOLA (L-ornithine L-aspartate) infusion should be used in critically ill patients with acute-on-chronic liver failure (ACLF) who have overt hepatic encephalopathy, particularly when standard treatments like lactulose are insufficient. 1

Indications for LOLA Infusion

LOLA is primarily indicated in the following scenarios:

1. Overt hepatic encephalopathy in ACLF patients:

   • When patients have progressed to clinically evident hepatic encephalopathy
   • As an adjunctive therapy to standard treatments (lactulose and rifaximin)
   • When rapid reduction of ammonia levels is needed

2. Treatment algorithm:

   • First-line: Lactulose (oral or enema) 2
   • Second-line: Add rifaximin when lactulose alone is insufficient
   • Third-line: Consider LOLA infusion when patients continue to have symptoms despite above treatments

Mechanism and Evidence

LOLA works as a substrate for the urea cycle and stimulates enzymatic activity in residual hepatocytes, leading to increased urea excretion and reduced ammonia levels 1. A systematic review of six randomized controlled trials (n=597) suggested LOLA may have beneficial effects on:

• Mortality
• Hepatic encephalopathy severity
• Reduction of serious adverse events

However, it's important to note that the quality of evidence supporting LOLA use is very low, as acknowledged by current guidelines 1.

Administration Protocol

When administering LOLA:

• Use intravenous formulation for critically ill patients
• Monitor ammonia levels before and during treatment
• Continue standard treatments (lactulose, rifaximin) concurrently
• Assess neurological status frequently to evaluate response

Special Considerations

Acute Liver Failure vs. ACLF

• In acute liver failure (ALF), there is insufficient evidence to make a definitive recommendation regarding LOLA use 1
• LOLA is more established for use in ACLF patients with overt hepatic encephalopathy

Grading of Encephalopathy

• For Grade I-II encephalopathy: Oral treatments may be sufficient
• For Grade III-IV encephalopathy: Consider LOLA infusion as part of intensive management
• Patients with Grade III-IV should be managed in an ICU setting with consideration for airway protection 1

Combination Therapy

LOLA should be used as part of a comprehensive approach that includes:

• Identification and treatment of precipitating factors
• Lactulose administration (25-45 mL every 1-2 hours initially until bowel movements occur) 2
• Rifaximin (550 mg twice daily) in patients not responding to lactulose alone 3
• Nutritional support with appropriate protein intake (1.2-1.5 g/kg/day) 3

Pitfalls and Caveats

1. Do not rely solely on LOLA: Always use in combination with standard treatments
2. Regional availability: LOLA is more commonly used outside the United States 1
3. Monitor for improvement: If no response is seen, consider alternative diagnoses or additional interventions
4. Avoid overuse of lactulose: Excessive lactulose can lead to complications including aspiration, dehydration, and hypernatremia 1
5. Consider liver transplantation: For patients with recurrent intractable hepatic encephalopathy 1

LOLA represents an additional therapeutic option in the management of hepatic encephalopathy, particularly for critically ill patients with ACLF who have not adequately responded to first-line treatments.