What is the management of acute liver failure with hyperammonemia and Acute Kidney Injury (AKI), particularly the role of L-ornithine L-aspartate (LOLA)?

Management of Acute Liver Failure with Hyperammonemia and AKI

In acute liver failure (ALF) with hyperammonemia and AKI, there is insufficient evidence to recommend LOLA, and management should focus on continuous renal replacement therapy (CRRT) initiated early, continuous hemodynamic support, and avoidance of nephrotoxic agents, with liver transplantation evaluation as the definitive treatment. 1

Critical Distinction: ALF vs ACLF

The evidence base diverges sharply between acute liver failure (ALF) and acute-on-chronic liver failure (ACLF):

• For ALF patients with hyperammonemia: There is insufficient evidence to recommend lactulose, rifaximin, or LOLA 1
• For ACLF patients: LOLA is conditionally suggested (very low quality evidence) 1

This distinction is crucial because ALF patients are not preconditioned to cope with hyperammonemia and are more susceptible to intracranial hypertension compared to ACLF patients 1

Management Algorithm for ALF with Hyperammonemia and AKI

1. Renal Replacement Therapy (Primary Intervention)

Initiate CRRT early when ammonia >150 μmol/L, even before Stage 3 AKI develops 1, 2:

• Start within 4-6 hours of ICU admission if hyperammonemia present 2, 3
• Use continuous venovenous hemodiafiltration (CVVHD) as preferred modality (78% of cases) 2
• Target effluent flow rate: 43 mL/kg/hr (median effective dose) 2
• Duration matters more than intensity: Cumulative treatment hours correlate best with ammonia reduction (p=0.03) 2
• Expected ammonia trajectory: 151 μmol/L → 107 μmol/L (day 2) → 75 μmol/L (day 3) → 52 μmol/L (day 5) 2

2. Plasma Exchange (When Available)

Use plasma exchange for hyperammonemia defined as ammonia >150 μmol/L 1:

• Conditional recommendation based on low quality evidence 1
• Particularly important since ammonia >200 μmol/L is strongly associated with cerebral herniation 1
• Intracranial hypertension develops in 55% of ALF patients with ammonia >200 μmol/L 1

3. Encephalopathy Management

Grade I-II encephalopathy 1:

• ICU monitoring with frequent mental status checks 1
• Head CT to exclude intracranial hemorrhage 1
• Avoid sedation if possible; use short-acting benzodiazepines only for unmanageable agitation 1

Grade III-IV encephalopathy 1:

• Intubate for airway protection 1
• Position head elevated at 30 degrees 1
• Use propofol in small doses (long half-life in hepatic failure) 1
• Control seizures with phenytoin 1
• Use endotracheal lidocaine before suctioning to avoid ICP spikes 1

4. Renal Support Considerations

Avoid nephrotoxic agents 1:

• Use continuous modes of hemodialysis when needed 1
• Volume replacement as needed 1
• Pressor support (dopamine, epinephrine, norepinephrine) to maintain adequate mean arterial pressure 1

5. Metabolic Management

Close monitoring required 1:

• Glucose, potassium, magnesium, phosphate 1
• Enteral feedings if possible, otherwise total parenteral nutrition 1

Why LOLA is NOT Recommended in ALF

The 2023 Critical Care Medicine guidelines explicitly state there is insufficient evidence for LOLA in critically ill ALF patients with hyperammonemia 1. This contrasts with ACLF where:

• LOLA has conditional recommendation (very low quality evidence) for ACLF with overt hepatic encephalopathy 1
• Mechanism involves stimulating urea cycle in residual hepatocytes 1, 4
• A systematic review (6 RCTs, n=597) showed possible benefit in ACLF, but evidence quality was very low 1
• Intravenous LOLA at 30 g/day may be effective in ACLF 5
• Oral LOLA is ineffective and should not be used 5

Common Pitfalls to Avoid

Do not delay CRRT waiting for Stage 3 AKI: In Australian/New Zealand cohorts, 75% of ALF patients receiving CRRT did not have Stage 3 AKI at initiation 3. Early CRRT prevented extreme hyperammonemia (>140 μmol/L) in 84% of patients, which was associated with improved transplant-free survival (55% vs 13%, p=0.05) 3

Do not use lactulose in ALF: Unlike cirrhosis, lactulose in ALF showed no difference in encephalopathy severity or overall outcome, with concern for gaseous abdominal distension complicating potential transplantation 1

Do not routinely use invasive ICP monitoring: Conditional recommendation against invasive ICP monitoring in ALF with advanced-grade encephalopathy (very low quality evidence) 1

**Do not use induced moderate hypothermia (<34°C) routinely**: No significant difference in primary outcomes (ICP >25 mmHg: 35% vs 27%, p=0.56) or mortality (41% vs 46%, p=0.75) 1