What are the treatment guidelines for a patient with Acute-on-Chronic Liver Failure (ACLF)?

Management Guidelines for Acute-on-Chronic Liver Failure (ACLF)

Patients with ACLF requiring organ support should be admitted to the ICU immediately, with prognosis reassessed after 3-7 days of full intensive care, and liver transplantation considered as the only definitive life-saving treatment for those with severe disease. 1

Immediate Recognition and ICU Admission

Diagnostic Verification

• Confirm three criteria: (1) liver failure with elevated bilirubin (≥6 mg/dL) AND INR (≥1.5), (2) acute clinical deterioration, and (3) at least one extrahepatic organ failure 2, 3
• Calculate severity scores immediately: CLIF-C ACLF score, MELD-Na, or NACSELD ACLF score, as MELD alone underestimates mortality 3

ICU Admission Criteria

Admit to ICU within 6 hours of diagnosis if any of the following are present: 1

• Need for vasopressor support
• Mechanical ventilation requirement
• Renal replacement therapy
• Massive bleeding
• Grade III-IV hepatic encephalopathy requiring airway protection
• Septic shock

Contraindications to ICU Admission

Do not admit patients with: 1

• Severe pulmonary disease (GOLD criteria 3-4), cardiac disease (NYHA class III-IV), or neurological disease combined with ACLF-3
• Advanced neoplasm with life expectancy <6 months
• Severe frailty with Karnofsky performance status ≤40

Initial Workup and Precipitant Identification

Mandatory Initial Assessment

Perform immediately upon diagnosis: 1

• Blood cultures, ascitic fluid culture, urine culture, rectal and nasal swabs
• Diagnostic paracentesis with cell count and culture
• Chest radiograph
• Urinalysis
• Abdominal ultrasound including renal assessment
• HCV RNA, HBsAg, HBV DNA, HEV RNA
• Serum creatinine, sodium, potassium, C-reactive protein, procalcitonin
• Complete blood count with differential
• Liver function tests: bilirubin, AST, ALT, ALP, GGT, INR, albumin

Common Precipitants to Identify

Search systematically for: 1, 3

• Bacterial infections (present in ~60% of cases) - most common precipitant
• Severe alcohol-related hepatitis
• Hepatitis B reactivation (especially in Asia)
• GI hemorrhage with shock
• Drug-induced liver or kidney injury

Organ System Support

Hepatic Encephalopathy Management

Use nonabsorbable disaccharides as first-line therapy: 1

• Start lactulose immediately, titrate to 2-3 soft bowel movements daily 3
• For Grade 3-4 encephalopathy: administer lactulose enema (300 mL lactulose in 700 mL water) 3
• Add oral rifaximin as adjunctive therapy (conditional recommendation) 1
• Consider L-ornithine L-aspartate (LOLA) as adjunctive therapy 1
• Use enteral polyethylene glycol as alternative to lactulose 1
• Do NOT use benzodiazepines in altered mental status 3
• Do NOT routinely use IV flumazenil, zinc supplementation, glycerol phenylbutyrate, probiotics, or acarbose 1

Circulatory Support

Target mean arterial pressure 50-60 mmHg: 3

• Use balanced crystalloids (lactated Ringer's) or albumin for volume replacement - avoid normal saline 1, 3
• For intraoperative liver transplant volume replacement: use albumin over crystalloid 1
• Initiate vasopressors (norepinephrine, epinephrine, or dopamine) if fluid replacement fails 3
• Do NOT use midodrine or terlipressin for ACLF patients with spontaneous bacterial peritonitis 1

Renal Support

Use continuous renal replacement therapy, NOT intermittent hemodialysis: 3

• Monitor for hepatorenal syndrome development (creatinine ≥2 mg/dL) 2
• Assess volume status carefully before initiating therapy 1

Respiratory Support

Monitor continuously with pulse oximetry: 3, 4

• Do NOT initiate terlipressin if SpO2 <90% 4
• Discontinue terlipressin if SpO2 decreases below 90% during treatment 4
• Avoid terlipressin entirely in ACLF Grade 3 patients due to significant respiratory failure risk 4
• Use low tidal volume and low PEEP strategies if mechanical ventilation required 3

Coagulation Management

Do NOT use prophylactic FFP - reserve only for active bleeding or procedures: 3

Intracranial Pressure Management (for ALF, not ACLF)

• Do NOT use invasive intracranial pressure monitoring for ALF patients with advanced-grade encephalopathy 1
• Do NOT routinely use induced moderate hypothermia (<34°C) for ALF patients at risk of intracranial hypertension 1

Infection Management

Spontaneous Bacterial Peritonitis

Administer appropriate antibiotics within 1 hour of shock onset: 1

• Use empiric broad-spectrum antibiotics without delay in high-risk patients 3
• Do NOT perform large volume paracentesis in ACLF patients with SBP 1

Transplant Recipients

• Use systemic antifungal prophylaxis in liver transplant recipients with risk factors for invasive fungal infections 1
• Do NOT use antifungal prophylaxis in low-risk liver transplant recipients 1
• Do NOT use selective bowel decontamination for critically ill liver transplant recipients 1

Variceal Bleeding Management

Use transjugular intrahepatic portosystemic shunt (TIPS) for recurrent variceal bleeding after failed medical and endoscopic intervention: 1

HBV-Related ACLF Specific Management

Start nucleos(t)ide analogues (NAs) immediately in all HBV-related ACLF patients: 1

• Use drugs with high resistance barrier: entecavir or tenofovir 1
• Consider tenofovir alafenamide instead of tenofovir disoproxil fumarate in patients with acute kidney injury 1
• Consider liver transplantation for severe presentation (MELD >30, ACLF-2 or ACLF-3) despite early antiviral treatment, especially without early virologic response (<2-log reduction) 1

Prognostic Assessment and Transplant Evaluation

Timing of Prognosis Assessment

Reassess prognosis after 3-7 days of full organ support: 1

• ACLF is dynamic - one-fifth of patients with ACLF-3 can resolve the syndrome 1
• Monitor organ function frequently as patients can rapidly develop new organ failures 3

Liver Transplantation Criteria

Refer immediately to transplant center for ACLF Grade 2-3: 3

• Liver transplantation is the only life-saving treatment that radically improves long-term prognosis 5
• Consider expedited transplantation for severe presentation despite optimal medical therapy 1
• Be aware that TERLIVAZ-related adverse reactions (respiratory failure, ischemia) may make patients ineligible for transplantation 4
• For patients with MELD ≥35, benefits of TERLIVAZ may not outweigh risks 4

Futility Criteria

Consider withdrawal of organ support and palliative care if: 1

• 4 organ failures present after 3-7 days of full organ support

• CLIF-C ACLF score >70 points with no transplant option
• Four or more organ failures after one week of adequate intensive treatment 3

Extracorporeal Support

Either use extracorporeal liver support or standard medical therapy - no clear superiority established: 1

• Insufficient evidence for routine plasma exchange in ACLF outside research trials 6
• May consider plasma exchange only as bridge to transplantation in highly selected critically ill patients when standard therapies fail 6

Serial Monitoring Requirements

Perform daily assessments of: 2, 3

• Liver function tests (bilirubin, INR, albumin)
• Renal function (creatinine, urine output)
• Neurological status for encephalopathy progression
• Serial lactate levels
• Inflammatory markers (white blood cell count, C-reactive protein)

Palliative Care Integration

All ACLF patients require palliative care consultation regardless of transplant status: 3

• Define prognosis and determine goals of care
• Document advance directives
• Identify surrogate decision-maker within 48 hours of admission
• Have goals of care discussion for: mechanical ventilation >48 hours, ICU stay >48 hours, hemodialysis initiation 3

Critical Pitfalls to Avoid

• Do NOT deny ICU admission solely based on presence of cirrhosis - outcomes are comparable to non-cirrhotic patients with similar disease severity 1
• Do NOT use normal saline for volume resuscitation - use balanced crystalloids or albumin 1, 3
• Do NOT delay antibiotics in suspected infection - administer within 1 hour of shock onset 1
• Do NOT overlook alcohol consumption - even moderate intake can trigger acute deterioration 2
• Do NOT use starches - risk of coagulopathy and renal failure 1