Alternative Treatments for Hyperammonemia When Lactulose is Ineffective
When lactulose is ineffective for treating hyperammonemia, rifaximin should be added as the first-line adjunctive therapy, followed by intravenous L-ornithine L-aspartate (LOLA) if the combination therapy fails. 1
First-Line Approach: Add Rifaximin
- Dosage: 550 mg twice daily 1
- Evidence: Rifaximin is an effective add-on therapy to lactulose for prevention of hepatic encephalopathy recurrence (Grade I, A, 1) 2, 1
- Mechanism: Reduces ammonia production by eliminating ammonia-producing colonic bacteria 3
- Efficacy: Combination therapy with rifaximin and lactulose is associated with:
Second-Line Options (If Rifaximin + Lactulose Fails)
1. Intravenous L-ornithine L-aspartate (LOLA)
- Dosage: 30 g/day intravenously 1
- Evidence: Demonstrated improvement in psychometric testing and postprandial venous ammonia levels in patients with persistent hepatic encephalopathy (Grade I, B, 2) 2
- Important note: Oral supplementation with LOLA is ineffective 2
2. Neomycin
- Evidence: Alternative choice for treatment of overt hepatic encephalopathy (Grade II-1, B, 2) 2
- Caution: Long-term ototoxicity, nephrotoxicity, and neurotoxicity make it unsuitable for continuous long-term use 2
3. Metronidazole
- Evidence: Alternative choice for treatment of overt hepatic encephalopathy (Grade II-3, B, 2) 2
- Caution: Similar to neomycin, long-term toxicity concerns limit extended use 2
4. Oral Branched-Chain Amino Acids (BCAAs)
- Dosage: 0.25 g/kg/day orally 1
- Evidence: Can be used as an alternative or additional agent for patients nonresponsive to conventional therapy (Grade I, B, 2) 2
Advanced Interventions for Severe Cases
1. Albumin Infusion
- Dosage: 1.5 g/kg/day for up to 10 days 1
- Note: While a recent RCT showed no effect on resolution of hepatic encephalopathy, it was related to better post-discharge survival 2, 1
2. Hemodialysis
- Indication: Should be considered in patients with severe hyperammonemia or who are not responsive to medication administration 4
- Efficacy: High levels of ammonia can be reduced quickly when medications are used with hemodialysis 4
3. Sodium Phenylacetate
- Mechanism: Acts as a urea surrogate excreted in urine 2
- Administration: Must be diluted with sterile 10% Dextrose Injection before administration via a central venous catheter 4
- Dosing: Based on weight for smaller patients and body surface area for larger patients 4
4. Probiotics
- Evidence: Open-label study found fewer episodes of hepatic encephalopathy in the probiotic arm compared to placebo, similar to lactulose 2
- Advantage: May have fewer side effects than other treatments
Monitoring and Management
- Monitor mental status, serum ammonia levels, liver function tests, and electrolytes daily 1
- Identify and address potential precipitating factors for hepatic encephalopathy:
- Medication non-compliance
- Infection
- Gastrointestinal bleeding
- Electrolyte disturbances
- Constipation
- Dehydration 1
Important Caveats
- Avoid overuse of lactulose, which can lead to complications such as aspiration, dehydration, hypernatremia, and severe perianal skin irritation 2, 1
- Avoid benzodiazepines, which can worsen encephalopathy 1
- Consider liver transplantation for patients with severe encephalopathy that does not respond to medical treatment 1
- Lactulose enemas can be considered as an alternative administration route when oral administration is not feasible 5
By following this algorithmic approach to managing hyperammonemia when lactulose is ineffective, clinicians can systematically work through evidence-based alternatives to improve patient outcomes and reduce mortality.