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

Plasma Exchange (PLEX) for Hepatic Encephalopathy and Liver Failure

Plasma exchange is NOT routinely recommended for acute-on-chronic liver failure (ACLF) with hepatic encephalopathy, as major guidelines explicitly advise against its use outside of research protocols. 1, 2, 3

Guideline-Based Position on PLEX

Primary Recommendation

• The 2023 Critical Care Medicine guidelines provide a conditional recommendation (very low quality evidence) that PLEX may be used either as extracorporeal liver support or standard medical therapy in critically ill ALF or ACLF patients—essentially stating equipoise exists between the two approaches. 1
• The European Association for the Study of the Liver (EASL) explicitly recommends against routine PLEX use for ACLF outside research trials, citing insufficient high-quality evidence despite emerging survival data. 2, 3
• The American Association for the Study of Liver Diseases (AASLD) suggests PLEX only for acute liver failure (ALF) with hyperammonemia (ammonia >150 μmol/L), NOT for ACLF. 2, 3

Critical Distinction: ALF vs ACLF

• PLEX has conditional support only in ALF with severe hyperammonemia, not in ACLF with hepatic encephalopathy. 2, 3
• This distinction is crucial—the pathophysiology and evidence base differ substantially between these entities. 2

When PLEX Might Be Considered (Highly Selective)

PLEX should only be considered in ACLF patients who meet ALL of the following criteria: 2, 3

• Listed for liver transplantation and awaiting organ availability
• Deteriorating despite standard medical therapy (see below)
• At a center with established PLEX expertise and resources
• Ideally enrolled in a research protocol
• Asian Pacific Association for the Study of the Liver (APASL) guidelines are more supportive for bridge-to-transplant scenarios, though this conflicts with Western guidelines 2, 3

Standard Medical Therapy for Hepatic Encephalopathy in ACLF (What to Use Instead)

First-Line Interventions

• Nonabsorbable disaccharides (lactulose or lactitol) are the cornerstone therapy with conditional recommendation and low-quality evidence. 1
• Polyethylene glycol (PEG) as an alternative to lactulose, with conditional recommendation and low-quality evidence. 1
• In a 2022 RCT, combined PEG 3350 plus lactulose resulted in earlier HE resolution (median 4.5 vs 9 days) and improved 28-day survival (93.1% vs 67.7%, P=0.010) compared to lactulose alone in ACLF patients. 4

Adjunctive Therapies

• Oral rifaximin as adjunctive therapy to disaccharides (conditional recommendation, low-quality evidence). 1
• Meta-analysis of 19 RCTs showed rifaximin increased complete encephalopathy reversal (RR 0.59) and reduced mortality (RR 0.50). 1
• L-ornithine L-aspartate (LOLA) with conditional recommendation but very low-quality evidence. 1

Therapies NOT Routinely Recommended

• IV flumazenil, zinc supplementation, glycerol phenylbutyrate, probiotics, and acarbose are NOT routinely recommended (conditional recommendation, very low-quality evidence). 1

Critical Management Algorithm for ACLF with Hepatic Encephalopathy

Step 1: Identify and Treat Precipitating Factors

• Bacterial infections are the most important trigger—empiric broad-spectrum antibiotics should be initiated immediately if sepsis or worsening encephalopathy is present. 5, 6
• Third-generation cephalosporins (cefotaxime, ceftriaxone) are first-line for spontaneous bacterial peritonitis. 5
• For upper GI bleeding, antibiotic prophylaxis (typically third-generation cephalosporins) reduces mortality and should be given within 1 hour of shock onset. 1
• Other precipitants include GI bleeding, constipation, excessive protein intake, dehydration, renal dysfunction, electrolyte imbalance, and psychoactive medications. 1

Step 2: Initiate Standard Hepatic Encephalopathy Therapy

• Start lactulose (titrated to 2-3 soft stools daily) or consider PEG 3350 (2L q12h) followed by lactulose for faster resolution. 1, 4
• Add rifaximin 550mg BID if no improvement after 24-48 hours of disaccharide therapy. 1, 7
• Consider LOLA if available, though evidence is very limited. 1

Step 3: Provide Organ Support

• Organ support is essential in ACLF management—address renal failure, coagulopathy, and hemodynamic instability. 8
• Balanced crystalloids preferred over normal saline for fluid resuscitation. 1
• Do NOT use invasive intracranial pressure monitoring for advanced-grade encephalopathy (conditional recommendation, very low-quality evidence). 1
• Do NOT routinely use induced moderate hypothermia (<34°C) for intracranial hypertension risk (conditional recommendation, very low-quality evidence). 1

Step 4: Early Transplant Evaluation

• Liver transplantation should be considered for severe HE unresponsive to medical therapy, as 28-day mortality approaches 40-90% in ACLF. 1, 8
• The "Golden Window" period is approximately 7 days before complications like sepsis and multiorgan failure become irreversible. 8

Common Pitfalls and Caveats

Avoid These Errors

• Do NOT delay antibiotics in suspected infection—bacterial infections are documented in 60-80% of ALF/ACLF patients and are major triggers for both ACLF and encephalopathy. 5, 6
• Do NOT use PLEX routinely—it lacks evidence in ACLF and diverts resources from proven therapies. 1, 2, 3
• Do NOT use selective bowel decontamination in liver transplant recipients (conditional recommendation, low-quality evidence). 1
• Rifaximin should not be used to lower ammonia in ALF (distinct from ACLF). 5

Monitoring Considerations

• Ammonia levels do not correlate well with HE grades in ACLF and should not guide therapy decisions. 4
• Dynamic prognostic models (AARC liver failure score, CLIF-C ACLF score) are superior to static models for management decisions. 8
• Presence of 4 or more organ failures warrants re-evaluation of continuing aggressive support absent transplant options. 3

Antibiotic Selection in Liver Failure

• Third-generation cephalosporins, piperacillin-tazobactam, and fluoroquinolones (with caution) are safest in liver impairment. 5
• Avoid or reduce doses of rifampicin, isoniazid, and macrolides that require hepatic metabolism. 5
• Piperacillin-tazobactam can precipitate acute encephalopathy in cirrhosis due to decreased renal clearance. 5

Bottom Line

Focus on proven therapies: lactulose/PEG, rifaximin, aggressive infection management, organ support, and early transplant evaluation. 1, 4 Reserve PLEX only for highly selected transplant candidates deteriorating despite standard therapy, preferably within research protocols. 2, 3 The evidence does not support routine PLEX use for hepatic encephalopathy in ACLF. 1, 2, 3