Is Plasma Exchange (PLEX) advisable in a patient with Acute-on-Chronic Liver Failure (ACLF) and severe hepatic encephalopathy?

Is Plasma Exchange (PLEX) Advisable in ACLF?

Plasma exchange is NOT routinely recommended for ACLF based on current major society guidelines, though it may be considered in highly selected critically ill ACLF patients as a bridge to transplantation when standard therapies fail, ideally within a research protocol. 1, 2

Guideline-Based Framework

Primary Recommendations Against Routine Use

• The EASL 2023 guidelines explicitly recommend against routine use of plasma exchange for ACLF outside of research trials, citing insufficient high-quality evidence despite emerging data showing potential survival benefit. 1, 2

• The AASLD 2024 guidelines suggest plasma exchange ONLY for acute liver failure (ALF) with hyperammonemia (ammonia >150 μmol/L), NOT for ACLF, with a conditional recommendation based on low-quality evidence. 1, 2

• The Critical Care Medicine 2023 guidelines state: "We suggest using plasma exchange in critically ill ALF patients who develop hyperammonemia" (conditional, low quality evidence), but this recommendation does not extend to ACLF. 1, 3

Critical Distinction: ALF vs. ACLF

• PLEX has stronger evidence and guideline support in ALF with hyperammonemia, but this does NOT translate to ACLF. 1, 3

• ALF patients are more vulnerable to cerebral edema and intracranial hypertension from hyperammonemia compared to ACLF patients, which is why PLEX may be more beneficial in ALF. 3

• Traditional therapies for chronic liver failure (lactulose, rifaximin) have not demonstrated benefit in ALF, whereas they remain first-line for hepatic encephalopathy in ACLF. 3, 4

When PLEX Might Be Considered in ACLF (Highly Selected Cases)

Specific Clinical Scenario

PLEX might be considered only in the following narrow circumstances: 2

• Patient is listed for liver transplantation and awaiting organ availability
• Deteriorating despite standard medical therapy (lactulose, rifaximin, albumin, antibiotics, organ support)
• At a center with PLEX expertise and resources
• Ideally enrolled in a research protocol

Geographic Variation in Guidelines

• Asian Pacific Association for the Study of the Liver (APASL) and Chinese guidelines are more supportive of PLEX as a promising treatment for ACLF patients awaiting transplants, but this conflicts with Western guidelines. 2

Research Evidence vs. Guideline Recommendations

The Evidence-Practice Gap

There is a notable disconnect between recent research findings and guideline recommendations:

• A 2025 meta-analysis of 23 studies (5,336 ACLF patients) showed PLEX was associated with significant reduction in mortality at 30 days (RR 0.70), 90 days (RR 0.81), and 1 year (RR 0.85). 5

• A 2024 meta-analysis confirmed improved 30-day (RR 1.36) and 90-day (RR 1.21) survival with PLEX in ACLF. 6

• However, when analyzing only randomized controlled trials in the subgroup analysis, no survival differences were found between PLEX and standard medical therapy in ACLF. 6

Why Guidelines Remain Conservative

• The EASL guidelines explicitly reject routine PLEX use despite emerging data, citing insufficient high-quality randomized controlled trial evidence. 2

• Most positive studies are observational cohorts with significant risk of selection bias. 5, 6

• The definition of ACLF varied across studies, making generalization difficult. 1

Standard Management Remains First-Line

Priority Interventions for ACLF with Hepatic Encephalopathy

Focus on evidence-based standard therapies: 1

• Lactulose (oral or rectal) targeting 2-3 soft stools daily, or polyethylene glycol if ileus risk exists 1

• Rifaximin as adjunctive therapy (though role in acute ACLF setting remains unclear) 1

• Early identification and treatment of precipitating factors: infections (empiric antibiotics), GI bleeding, electrolyte disorders, acute kidney injury 1

• Organ support: vasopressors for hypotension, airway protection for Grade 3-4 encephalopathy, renal replacement therapy for AKI-HRS 1

• Early referral to transplant center for eligible patients, as late referral may make transplantation impossible due to rapid ACLF progression 1

Clinical Algorithm for Decision-Making

Step 1: Confirm ACLF Diagnosis and Severity

• Use CLIF-C ACLF score or APASL criteria to define ACLF 1
• Assess for hepatic encephalopathy using West Haven criteria (Grade 3-4 indicates severe) 1

Step 2: Initiate Standard Medical Therapy

• Lactulose/polyethylene glycol for hepatic encephalopathy 1
• Treat precipitating factors (infections, bleeding, electrolytes) 1
• Provide organ support as needed 1

Step 3: Assess Transplant Candidacy

• If transplant candidate: Early listing and referral to transplant center 1
• If NOT transplant candidate: Continue standard medical therapy; PLEX is not recommended 1, 2

Step 4: Consider PLEX Only If ALL Criteria Met

• Listed for transplantation 2
• Deteriorating despite 3-7 days of full standard therapy 1
• Center has PLEX expertise 2
• Preferably within research protocol 1, 2

Important Caveats

What NOT to Do

• Do not use PLEX routinely or as first-line therapy in ACLF. 1, 2

• Do not confuse ALF recommendations (where PLEX has stronger support) with ACLF. 1, 3

• Do not delay liver transplant evaluation while pursuing PLEX, as ACLF progresses rapidly. 1

Safety Considerations

• PLEX is generally safe with most common adverse effects being skin rash and allergic reactions (14% incidence). 5

• Procedure-related adverse events occur in approximately 2% of procedures. 7

Reassessment of Futility

• Presence of 4 or more organ failures or CLIF-C ACLF score >70 points at 3-7 days after ICU admission should prompt re-evaluation of continuing organ support in the absence of transplant options. 1