What is the recommended adult dose of L‑ornithine for nutritional supplementation and for hepatic encephalopathy (as L‑ornithine‑L‑aspartate), and how should the dose be adjusted in renal impairment or pregnancy?

L-Ornithine Dosing Recommendations

For Hepatic Encephalopathy (as L-Ornithine-L-Aspartate/LOLA)

For overt hepatic encephalopathy requiring intravenous therapy, administer L-ornithine-L-aspartate 30 g/day intravenously, which effectively lowers plasma ammonia concentrations and improves clinical symptoms within 1-4 days. 1

Intravenous Administration

• Standard dose: 30 g/day IV for treatment of hepatic encephalopathy, typically infused over 4 hours daily 1, 2
• Alternative dosing studied: 20 g/day IV dissolved in 250 mL of 5% dextrose water, infused over 4 hours for 5 consecutive days 2
• Combination therapy with lactulose (20-30 g orally 3-4 times per day) leads to faster symptom recovery compared to lactulose alone 1
• IV LOLA at 30 g/day is particularly effective for West-Haven criteria grade 1-2 hepatic encephalopathy, lowering number connection test (NCT)-A time and plasma ammonia more effectively than placebo 1

Oral Administration

• Oral dose: 18 g/day divided into three doses (6 g three times daily) for chronic hepatic encephalopathy 3, 4
• Administered as sachets dissolved in water, taken during or after meals 4
• Treatment duration typically 8 weeks for chronic management, though 14-day courses have been studied 3, 4
• Oral LOLA lowers NCT-A time and plasma ammonia concentrations, though further studies are needed to fully assess efficacy in overt hepatic encephalopathy 1

Clinical Monitoring

• Monitor plasma ammonia levels and number connection test performance to assess response 1
• Expect clinical improvement within 1-4 days with IV therapy 1
• Mental state grade and Portosystemic Encephalopathy Index show significant improvement with treatment 3

For Nutritional Supplementation

For conditional ornithine deficiency or nutritional supplementation, daily doses of approximately 1 g/day of L-ornithine-L-aspartate are safe and should be sufficient to prevent postprandial hyperammonemia and stimulate tissue regeneration. 5

Supplementation Dosing

• Low-dose supplementation: ~1 g/day for food supplement purposes in states of conditional deficiency 5
• This dose is appropriate during disease states, tissue damage, organ insufficiency, excessive metabolic demand, growth, or pregnancy 5
• Doses above 5 g are considered medicinal products rather than food supplements 5

Carnitine Context (Note: Different from Ornithine)

The evidence provided includes carnitine dosing, which is distinct from ornithine:

• For carnitine deficiency prevention: 0.5-1 g/day in at-risk patients (prolonged parenteral nutrition, continuous renal replacement therapy) 6
• Pharmacologic carnitine supplementation: 50-100 mg/kg/day, with adults often receiving 3 g/day 6

Dose Adjustments

Renal Impairment

• No specific dose adjustments for L-ornithine-L-aspartate in renal impairment are established in the available evidence
• The mechanism of action (providing substrates for ammonia metabolism to urea and glutamine) suggests caution may be warranted, but specific guidance is lacking 1
• Note: For carnitine (a different compound), dosing frequency should be reduced in renal insufficiency, though the milligram dose per administration should be maintained 6

Pregnancy

• L-ornithine-L-aspartate safety in pregnancy is not well-established in the provided evidence
• Pregnancy is listed as a condition where ornithine supplementation may be needed due to increased metabolic demand 5
• However, no specific dosing recommendations or safety data for pregnancy are provided in the available guidelines

Safety Profile

• Excellent tolerability: Very good or good tolerability observed in 97.8% of patients receiving oral LOLA 4
• No drug-related adverse events reported in major observational studies 4
• No difference in non-serious adverse events compared to placebo (RR 1.15,95% CI 0.75 to 1.77) 7
• IV infusions well-tolerated with minimal adverse reactions 2

Important Caveats

• The quality of evidence for mortality and serious adverse event benefits is very low, with benefits demonstrated in all trials but not when restricted to low risk of bias trials 7
• Trial Sequential Analyses found insufficient evidence to definitively support or refute beneficial effects on mortality, hepatic encephalopathy, and serious adverse events 7
• LOLA shows no clear advantage over lactulose or rifaximin in head-to-head comparisons, though it may have benefits over probiotics for hepatic encephalopathy 7