In an adult with acute liver failure and severe hyperammonemia (e.g., >150 µmol/L) or a fulminant inflammatory response, should plasma exchange be preferred over continuous renal replacement therapy, and when is CRRT indicated?

Plasma Exchange vs CRRT in Acute Liver Failure

In adults with acute liver failure and severe hyperammonemia (>150 µmol/L), plasma exchange should be preferred over CRRT alone, though CRRT remains essential for managing concurrent acute kidney injury and can effectively reduce ammonia levels when plasma exchange is unavailable. 1, 2

Primary Recommendation for Hyperammonemia

Plasma exchange is the preferred intervention for ALF patients with hyperammonemia (ammonia >150 µmol/L), particularly when high-volume exchange (8-12 L per session) is available. 1, 2 The 2023 Critical Care Medicine guidelines from the Society of Critical Care Medicine provide a conditional recommendation for plasma exchange in this setting, though the evidence quality is low. 1

Evidence Supporting Plasma Exchange

• A multicenter randomized controlled trial (2016) demonstrated that high-volume plasma exchange significantly improved transplant-free survival in 182 adult ALF patients (Hazard Ratio 0.56, p = 0.0083). 2
• Plasma exchange addresses both hyperammonemia and the systemic inflammatory response caused by damage-associated molecular patterns (DAMPs) released from necrotic hepatocytes, which CRRT alone cannot adequately clear. 3
• For Wilson disease-related ALF specifically, immediate plasma exchange is mandatory as a bridge to transplantation, as this condition is uniformly fatal without transplant. 2

Role of CRRT in Acute Liver Failure

CRRT should be initiated when ALF patients develop acute kidney injury or when plasma exchange is unavailable, as it provides effective ammonia clearance and hemodynamic stability. 4, 5, 6

When CRRT is Indicated

• Standard renal indications: severe/refractory hyperkalemia, refractory acid-base imbalances, severe volume overload unresponsive to medical management, or symptomatic uremia. 4, 5
• Hemodynamic instability: CRRT provides superior cardiovascular stability compared to intermittent hemodialysis in critically ill ALF patients. 5, 3
• Hyperammonemia management when plasma exchange unavailable: CRRT effectively reduces ammonia levels, with median concentrations decreasing from 151 µmol/L to 52 µmol/L over 5 days of treatment. 6

Evidence for CRRT Efficacy

• A 2024 meta-analysis of 1,442 patients showed CRRT was associated with improved overall survival (RR 0.83,95% CI 0.70-0.99, p=0.04) and improved transplant-free survival (RR 0.65,95% CI 0.49-0.85, p=0.002). 7
• Ammonia clearance correlates best with cumulative duration of CRRT rather than hourly treatment intensity, suggesting early initiation and prolonged therapy are more important than high-intensity dosing. 6
• Ammonia clearance with CRRT (median 25 mL/min) is significantly less than urea (50 mL/min) or creatinine (42 mL/min) clearance, and there is no significant difference between CVVH, CVVHD, or CVVHDF techniques. 8

Combined Approach: Optimal Strategy

The combination of CRRT with plasma exchange represents the most rational approach, as CRRT removes ammonia while plasma exchange addresses both ammonia and inflammatory mediators (DAMPs). 3

• This combined strategy improves survival for ALF patients not appropriate for transplantation and ensures better stability of vital organs while awaiting liver transplantation. 3
• Both modalities should be viewed as bridges to transplantation rather than curative therapies; simultaneous listing for transplantation is mandatory. 2, 4

Technical Implementation Details

CRRT Prescription Specifics

• Target effluent dose: 20-25 mL/kg/hour (standard dose; higher doses do not improve ammonia clearance). 4, 5
• Buffer selection: MANDATORY use of bicarbonate-buffered (NOT lactate-buffered) dialysate and replacement fluids, as ALF patients have impaired lactate metabolism (strong 1B recommendation). 4, 5
• Timing: Initiate CRRT early (median 4 hours from indication) and continue for prolonged duration to maximize cumulative ammonia removal. 6
• Modality: Continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHDF) are preferred; no significant difference in ammonia clearance between techniques. 5, 8

Plasma Exchange Specifics

• Volume: High-volume exchange (8-12 L per session) is preferred for patients with severe disease (CLIF-C ACLF score ≥13 or Grade 4 encephalopathy). 2
• Availability: Plasma exchange requires experienced operators and appropriate infrastructure; the conditional recommendation allows adaptation to local resources. 2

Critical Decision Algorithm

1. Confirm ALF diagnosis: absence of chronic liver disease + INR ≥1.5 + hepatic encephalopathy. 2
2. Measure ammonia level:
   • If >150 µmol/L AND plasma exchange available → initiate plasma exchange immediately. 1, 2
   • If >150 µmol/L AND plasma exchange unavailable → initiate CRRT with bicarbonate buffer. 4, 5, 6
3. Assess for concurrent AKI or standard CRRT indications → initiate CRRT regardless of ammonia level. 4, 5
4. Consider combined CRRT + plasma exchange for optimal outcomes, particularly in severe cases. 3
5. Simultaneously list for liver transplantation; neither therapy is curative. 2, 4

Critical Pitfalls to Avoid

• Never use lactate-buffered solutions in ALF patients under any circumstances; this risks worsening lactic acidosis. 4, 5
• Do not delay transplant evaluation; refer immediately for listing while initiating extracorporeal support. 4
• Do not rely on lactulose or rifaximin for ALF hyperammonemia; these chronic liver failure therapies have not demonstrated benefit in ALF. 1, 2
• Do not assume higher CRRT intensity improves ammonia clearance; cumulative duration matters more than hourly dose. 6
• Plasma exchange is NOT recommended for acute-on-chronic liver failure (ACLF); limit use to true ALF with hyperammonemia. 2

Anticoagulation Considerations

• Regional citrate anticoagulation can be used cautiously but requires intensive monitoring of ionized calcium and total calcium/ionized calcium ratio due to impaired hepatic citrate metabolism. 5
• ALF patients are often coagulopathic, making heparin-based anticoagulation potentially more hazardous than citrate. 5
• If citrate is too risky, consider CRRT with no anticoagulation or sustained low-efficiency dialysis (SLED). 5