Critical care hepatology: A narrative review of current concepts and management

Table 1 Indications for intensive care admission in critically ill patients with liver-driven disease

Clinical context	Definition	Indications for ICU level care
Acute decompensation of cirrhosis	Acute worsening of cirrhosis (ascites, HE, bleeding, infection) without established extrahepatic organ failure, primarily driven by portal hypertension	Impaired consciousness requiring airway protection (HE grade III-IV or active bleeding); severe infection requiring hemodynamic monitoring; acute variceal bleeding requiring endoscopic or radiologic intervention (including rescue TIPS), particularly with instability; early signs of deterioration with risk of progression to ACLF
ACLF	Acute decompensation with ≥ 1 organ failure and high short-term mortality	Requirement for advanced organ support (vasopressors, renal replacement therapy, invasive ventilation); failure of ward-based management; ACLF grade ≥ 2; evolving multiorgan dysfunction; persistent hyperlactatemia or worsening shock despite resuscitation
ALF	Acute liver injury with coagulopathy and HE in a previously non-cirrhotic liver	Any degree of encephalopathy due to risk of cerebral edema; significant coagulopathy (e.g., INR > 2); rapidly evolving biochemical failure; need for early transplant assessment and neurocritical monitoring
Non-hepatic or peri-procedural indications in liver disease	Patients with liver disease admitted for non-hepatic illness or post-intervention monitoring	Post-procedural observation (e.g., TIPS, interventional radiology); postoperative care after non-hepatic surgery; acute cardiovascular or neurological events; need for intensified monitoring due to limited physiological reserve in cirrhosis

Summary of key clinical scenarios and indications for intensive care admission in patients with acute and chronic liver failure, reflecting the need for timely escalation of organ support and transplant evaluation. ICU: Intensive care unit; HE: Hepatic encephalopathy; TIPS: Transjugular intrahepatic portosystemic shunt; ACLF: Acute-on-chronic liver failure; ALF: Acute liver failure; INR: International normalized ratio.

Table 2 Key evidence guiding vasoactive therapy in acute and acute-on-chronic liver failure

Ref.	Population (n)	Design	Intervention	Comparator	Primary outcome	Key findings	Clinical relevance
Cavallin et al[94], 2015	Cirrhosis, HRS (n = 49)	RCT	Terlipressin 3-12 mg/day CTI + albumin	Midodrine + octreotide + albumin	Renal recovery	Terlipressin superior: Partial/complete response 70% vs 29% (P = 0.01); complete response 56% vs 5% (P < 0.001)	First head-to-head terlipressin vs midodrine/octreotide; terlipressin clearly favoured
Boyer et al[95], 2016	Cirrhosis, HRS-1 (n = 196)	RCT	Terlipressin 1 mg every 6 hours + albumin	Placebo + albumin	CHRSR	CHRSR 19.6% vs 13.1% (P = 0.22; NS); creatinine reduction significantly greater (P < 0.001); survival similar	Phase 3; missed primary endpoint; HRS reversal predicted 90-day survival; more ischaemic AEs
Piano et al[96], 2018	298 patients with cirrhosis and type 1 HRS, stratified by ACLF grade	Retrospective multicenter cohort study	Terlipressin + albumin	Comparison according to ACLF grade (ACLF-1, ACLF-2, ACLF-3) rather than a separate treatment arm	Response to treatment (serum creatinine < 1.5 mg/dL at end of therapy) and 90-day mortality	Treatment response declined with increasing ACLF severity: 60% in ACLF-1, 48% in ACLF-2, and 29% in ACLF-3 (P < 0.001). ACLF grade and baseline creatinine were independently associated with treatment response. ACLF grade independently predicted 90-day mortality irrespective of HRS reversal	Key study establishing ACLF grade as determinant of terlipressin response; EASL-CLIF criteria
Arora et al[97], 2020	ACLF (n = 120)	RCT	Terlipressin 2-12 mg/day CTI + albumin	Noradrenaline 0.5-3 mg/hour + albumin	HRS-AKI reversal day 7; 28-day survival	Terlipressin superior: HRS reversal 40% vs 17% (P = 0.004); survival 48% vs 20% (P = 0.001); less RRT 57% vs 80% (P = 0.006)	APASL ACLF criteria; open-label; landmark ACLF-specific RCT
Wong et al[98], 2021	Cirrhosis, HRS-1 (n = 300)	RCT	Terlipressin + albumin	Placebo + albumin	HRS reversal	Verified HRS reversal 32% vs 17% (P = 0.006); no significant survival benefit; respiratory failure more frequent with terlipressin	Largest placebo-controlled terlipressin trial; pivotal study underlying FDA approval
Wong et al[99], 2022	ACLF (n = 299)	Post-hoc	Terlipressin + albumin	Placebo + albumin	Respiratory failure by ACLF grade; 90-day survival	RF with terlipressin 30% in ACLF grade 3 vs 9.4% grade 1-2 (P = 0.0002); 90-day survival lower in grade 3 terlipressin arm. Use with caution in ACLF grade 3	Basis for FDA black box warning; terlipressin contraindicated in ACLF grade 3 with hypoxia
Jindal et al[100], 2024	ACLF (n = 60)	RCT	Early terlipressin (after 12 hours volume expansion)	Standard terlipressin (after 48 hours albumin challenge)	28-day mortality; AKI reversal	Early terlipressin: Lower mortality (17% vs 43%, P = 0.03); greater AKI reversal; regression of ACLF stage	First study on timing; supports early AKI intervention before 48 hours window in ACLF
Gupta et al[101], 2025	ACLF + septic shock (n = 70)	RCT	Terlipressin 2.6 mcg/kg/minute	Noradrenaline 0.1 mcg/kg/minute	MAP > 65 mmHg at 6 hours	Noradrenaline superior: MAP target achieved 74% vs 14% (P < 0.001); 3- and 7-day mortality higher with terlipressin	Terlipressin INFERIOR in septic shock context; noradrenaline first-line for ACLF septic shock

This table summarizes key studies on vasoactive therapy in acute-on-chronic and acute liver failure. Evidence is largely derived from cirrhosis and acute-on-chronic liver failure, where terlipressin improves hepatorenal syndrome reversal without consistent survival benefit, with reduced efficacy in advanced acute-on-chronic liver failure. While terlipressin may outperform norepinephrine for renal recovery in selected patients, norepinephrine remains first-line in septic shock. Data in acute liver failure are limited and suggest differing cerebral hemodynamic effects, supporting cautious use. HRS: Hepatorenal syndrome; RCT: Randomised controlled trial; CTI: Continuous terlipressin infusion; NS: Not significant; AEs: Adverse events; ACLF: Acute-on-chronic liver failure; EASL-CLIF: European Association for the Study of the Liver-Chronic Liver Failure; APASL: Asian Pacific Association for the Study of the Liver; FDA: Food and Drug Administration; RF: Respiratory failure; AKI: Acute kidney injury; MAP: Mean arterial pressure; CHRSR: Confirmed hepatorenal syndrome reversal; RRT: Renal replacement therapy.

Table 3 Prognostic models and futility assessment in acute-on-chronic liver failure

Score	Components	Outcome predicted	Use/threshold	Type
Established prognostic and futility scores in the critical illness setting
CLIF-C ACLF[102,103]	CLIF-C OF + age + WBC	28- and 90-day mortality in ACLF patients	Score ≥ 64 → 28-day mortality ~80%; used to assess LT candidacy futility	Prognostic + futility
CLIF-C OF[10,102]	Liver (bilirubin), kidney (creatinine), brain (HE grade), coagulation (INR), circulation (MAP), lungs (PaO2/FiO2)	OF burden and short-term mortality	Defines ACLF grade (1-3) per EASL-CLIF criteria; grade 3 = ~75% 28-day mortality	Prognostic
MELD/MELD-Na[104,105]	Creatinine, bilirubin, INR (+ sodium for MELD-Na)	90-day mortality; waitlist priority	MELD > 35 in ACLF associated with futile outcomes without LT	Prognostic + futility
NASCELD-ACLF[15,106]	Number of extrahepatic OFs (kidney, brain, circulation, lungs)	30-day in-hospital mortality in cirrhotic inpatients	≥ 2 OFs = ACLF; 30-day mortality ~50%; ≥ 3 OFs approaches futility (~75%)	Prognostic + futility
APACHE II/III	Age, vitals, GCS, AaDO2, pH, electrolytes, creatinine, Hct, WBC	ICU mortality (general critical care score applied to ACLF)	APACHE II > 20 in liver patients correlates with high ICU mortality; used adjunctively	Prognostic
APACHE IV[107]	Acute physiology variables, age, chronic health status, admission diagnosis	ICU and hospital mortality in critically ill patients, including cirrhosis cohorts	Used as a general ICU severity score; in a cohort of 64 critically ill patients with cirrhosis, median APACHE IV scores were significantly higher among ICU non-survivors (117 vs 79.5) and demonstrated good discrimination for ICU mortality (AUC = 0.87)	Prognostic
SOFA[10,108]	PaO2/FiO2, platelets, bilirubin, MAP/vasopressors, GCS, creatinine	Daily organ dysfunction course in ICU	Rising SOFA score (≥ 2-point increase) denotes clinical deterioration; high scores used in futility discussions	Prognostic + futility
Child-Pugh[108]	Bilirubin, albumin, PT, ascites, encephalopathy	Cirrhosis severity and surgical risk	Child C (10-15) in ACLF context predicts poor short-term prognosis; limited discrimination vs MELD	Prognostic
AARC-ACLF	Bilirubin, lactate, creatinine, PT-INR, HE grade	28-day mortality (Asia-Pacific cohorts)	AARC score 5-6 = 28-day mortality ~47%; ≥ 9 = ~100% (futility threshold used in India/APASL populations)	Prognostic + futility
LT-specific futility and post-transplant mortality scores
TAM score[86]	4 pre-LT binary criteria (1 point each): Age ≥ 53 years, arterial lactate ≥ 4 mmol/L, mechanical ventilation with PaO2/FiO2 ≤ 200 mmHg, WBC ≤ 10 G/L	1-year post-LT mortality in ACLF grade 3 patients (multicenter European cohort, n = 152)	TAM > 2 → 1-year post-LT survival 83% (futility); TAM ≤ 2 → survival 83%. Assessed immediately before LT. Validated in independent multicenter cohort	Futility/LT
CLIF-C ACLF > 64[103]	CLIF-C OF score + age + WBC (same formula as CLIF-C ACLF; threshold specific to LT futility context)	Post-LT mortality and ICU futility in ACLF-3; validated at Royal Free Hospital (n = 202)	Score > 64 at 48 hours ICU → high 28-day mortality (~80%); used as a threshold for LT futility discussions alongside TAM; EASL CPG 2023 cites ≥ 70 for ICU withdrawal in non-LT candidates	Futility/LT
≥ 3 OFs[22]	ACLF grade 3 as defined by CLIF-C OF criteria: Hepatic, renal, brain, coagulation, circulatory, and/or respiratory failure (any ≥ 3 simultaneously)	28-day mortality; probability of benefit from LT	ACLF-3 → 28-day mortality ~75%-79% without LT; > 3 OFs (i.e., 4-6) associated with increasing futility risk; EASL CPG cites ≥ 4 OFs + CLIF-C ACLF > 70 for ICU withdrawal	Futility/LT
Futility consensus framework[83]	Consensus framework by 35 international experts (Delphi method): Severe frailty, persistent fever or < 72 hours appropriate antimicrobials for ongoing sepsis, uncontrolled septic shock, and other contraindications; not a single numeric score but a structured decision framework	Definition of futile LT and criteria to delay or deny LT in critically ill cirrhotic/ACLF patients	Severe frailty OR active uncontrolled sepsis (< 72 hours antibiotics) = defer LT. Framework uses 1-year and 5-year post-LT survival benchmarks to define futility (< 50% at 5 year); meant to complement numeric scores with clinical judgment	Futility/LT
CFS ≥ 7[83,87]	9-point ordinal scale assessing activity, energy, function, and dependence: 1 (very fit) → 9 (terminally ill). Scores ≥ 7 = severely frail/completely dependent	Post-LT mortality; identifies patients too frail to survive transplantation regardless of hepatic disease severity	CFS ≥ 7 → independent predictor of post-LT mortality; endorsed by Weiss 2021 consensus as a criterion to defer or deny LT. Stabilization before LT (Huebener et al[87], 2018) with organ recovery associates with better post-LT survival	Futility/LT
SALT-M score > 2023[85]	Age, BMI, diabetes (pre-LT comorbidity); respiratory failure (PaO2/FiO2 < 200 or mechanical ventilation); circulatory failure (vasopressors); infection history; RRT use; WBC at LT - derived in 521 United States + 120 French ACLF-2/3 patients (MODEL Consortium)	1-year post-LT mortality in ACLF grade 2 or 3; c-statistic 0.72 (derivation) and 0.80 (external validation)	SALT-M > 30 → substantially elevated 1-year post-LT mortality risk (futility threshold cited in subsequent literature); outperforms MELD-Na, CLIF-C ACLF and BAR score for post-LT mortality prediction. Also estimates post-LT ICU length of stay (ACLF-LT-LoS sub-score)	Futility/LT
HALT (Zhuang)	Recipient age, number of organ failures, lactate, DCD graft, cold ischemia time	1-year post-LT mortality in HBV ACLF	Estimated mortality 66%-86% in highest-risk graft-recipient combination; proposed to identify futile transplantation	Futility/LT

This table summarizes established prognostic models and futility criteria used in critically ill patients with acute and chronic liver disease, including both general intensive care unit scores and liver-specific tools. It highlights their key components, predicted outcomes, and clinically relevant thresholds to support risk stratification, transplant decision-making, and identification of patients unlikely to benefit from continued intensive care or liver transplantation. CLIF-C ACLF: Chronic Liver Failure Consortium acute-on-chronic liver failure score; CLIF-C OF: Chronic Liver Failure Consortium organ failure score; WBC: White blood cell count; ACLF: Acute-on-chronic liver failure; LT: Liver transplantation; HE: Hepatic encephalopathy; INR: International normalized ratio; MAP: Mean arterial pressure; OF: Organ failure; EASL-CLIF: European Association for the Study of the Liver-Chronic Liver Failure; MELD: Model for end-stage liver disease; MELD-Na: Model for end-stage liver disease including sodium; NASCELD: North American Consortium for the Study of End-Stage Liver Disease; APACHE: Acute Physiology and Chronic Health Evaluation; GCS: Glasgow Coma Scale; Hct: Hematocrit; ICU: Intensive care unit; AUC: Area under the curve; SOFA: Sequential Organ Failure Assessment; PaO₂/FiO₂: Ratio of arterial oxygen partial pressure to fraction of inspired oxygen; PT: Prothrombin time; AARC: Asian Pacific Association for the Study of the Liver Acute-on-Chronic Liver Failure Research Consortium; APASL: Asian Pacific Association for the Study of the Liver; TAM: Transplantation for acute-on-chronic liver failure-3 model; CPG: Clinical practice guidelines; EASL: European Association for the Study of the Liver; CFS: Clinical Frailty Scale; SALT-M: Survival After Liver Transplantation in acute-on-chronic liver failure model; BMI: Body mass index; BAR: Balance of Risk score; RRT: Renal replacement therapy; LoS: Length of stay; DCD: Donation after circulatory death; HBV: Hepatitis B virus.

Table 4 Prognostic models and liver transplantation listing criteria in acute liver failure

Score	Components	Outcome predicted	Use/threshold	Type
Established prognostic and LT-listing criteria
KCC[109-111]	Acetaminophen: PH < 7.3, OR all 3 of (INR > 6.5, creatinine > 300 μmol/L, HE grade III-IV); lactate added in 2002 update. Non- acetaminophen: INR > 6.5 alone, OR any 3 of 5 factors (age < 10/> 40, non-A/B/drug etiology, jaundice-to-HE > 7 days, INR > 3.5, bilirubin > 300 μmol/L)	Death without ELT; need for emergency liver transplantation; PPV 70%-100%, specificity ~89%-95% in APAP-ALF	Meeting KCC → list for ELT; endorsed by AASLD and EASL. Sensitivity limited (~59%-69%); sequential use improves specificity. Lactate > 3.5 mmol/L (4 hours) or > 3.0 (12 hours post-resuscitation) incorporated as APAP-KCC criterion	LT listing
MELD/MELD-Na[104,112]	Creatinine, bilirubin, INR (+ sodium). A continuous score; rising values help guide urgency, particularly in ALF	Short-term mortality; ELT urgency. MELD correlates with severity but was not designed for ALF	MELD > 30 → high-urgency ELT listing; dynamic worsening more predictive than single value. Better for non-APAP-ALF (higher sensitivity) than KCC; both used complementarily	Prognostic
ALFSG-PI[113]	HE coma grade, INR, bilirubin, phosphate (≥ 3.7 mg/dL vs < 3.7 mg/dL), log10M30 (caspase-cleaved cytokeratin-18 apoptosis marker) - derived in 500 United States ALF patients; validated in independent 250-patient cohort	21-day transplant-free survival; need for LT or death at study entry. AUROC = 0.822 - superior to KCC (0.654) and MELD (0.704)	Higher index = worse prognosis; covers all ALF etiologies; requires M30 ELISA (limits routine use); 85.6% sensitivity/64.7% specificity for LT/death	Prognostic
CVC[114]	HE grade III-IV + factor V < 20% (age < 30 years) or < 30% (age ≥ 30 years); originally derived in fulminant hepatitis B patients	Survival without LT; primarily validated in viral (HBV) and non-paracetamol ALF in French cohorts	Criteria met → consider ELT listing; particularly used in France and Germany. Factor V assay not universally available. Sensitivity 69%-75%, specificity 50%-56% in mixed etiology (Ichai et al[114], 2015)	LT listing
APACHE II	Acute physiology (12 variables), age, chronic health - 0-71 points; validated in general ICU; applied to ALF as a general severity tool	ICU mortality in ALF patients; adjunctive severity stratification	APACHE II > 15 in ALF correlates with poor outcome; used alongside KCC; AUROC comparable to SOFA and ALFSG-PI in single-center studies	Prognostic
SOFA[115]	PaO2/FiO2, platelets, bilirubin, MAP/vasopressors, GCS, creatinine - 0-4 per organ; total 0-24	Multiorgan failure trajectory; daily ICU reassessment in ALF	Serial SOFA ≥ 15 or rapidly rising score used in futility discussions; SOFA outperforms KCC in multiorgan failure setting; AUROC ~0.84-0.85 in ALF studies (comparable to ALFSG-PI)	Prognostic
Bernal/United Kingdom ALF dynamic model[116]	Day 1: Age, GCS, arterial pH, lactate, creatinine, INR, circulatory failure; day 2: Change in lactate + change in INR - two time-point model specific to APAP-ALF	Death without LT in APAP-induced ALF; dynamic 2-day model improves over single time-point criteria. AUROC day 1: 0.82, day 2: Higher	Improves sensitivity over KCC at early admission; particularly useful in first 48 hours to identify non-survivors who do not yet meet standard KCC; used adjunctively in United Kingdom centers	LT-listing
Serum phosphate[117]	Serum phosphate at 48-96 hours post-paracetamol ingestion (threshold > 1.2 mmol/L); reflects failure of hepatic regeneration (phosphate uptake by regenerating hepatocytes)	Hepatic regeneration failure in APAP-ALF; high specificity for death without LT (used as add-on to KCC)	Phosphate > 1.2 mmol/L at 48-96 hours → failure to regenerate → consider ELT; incorporated as optional KCC criterion; specificity ~89%, PPV ~89% for death	LT-listing
Serum lactate[110]	Arterial lactate at admission and post-resuscitation: > 3.5 mmol/L at 4 hours, or > 3.0 mmol/L at 12 hours after adequate fluid resuscitation, in APAP-ALF	Early mortality indicator in APAP-ALF; tissue hypoxia and mitochondrial dysfunction marker; predicts poor outcome before HE develops	Lactate > 3.5 mmol/L at 4 hours (pre-resuscitation) = KCC criterion. Widely available and rapidly measurable; used for early risk stratification to initiate LT referral before KCC fully met	Prognostic
Emerging and investigational scores in ALF
miRNA-based prognostic model[118,119]	Regeneration-linked miRNA signature (early model) + cell-death miRNA signature (late model), combined with MELD score and vasopressor use - machine-learning derived, ALFSG cohort	21-day transplant-free survival in APAP and non-APAP ALF. Early model AUROC 0.78; late model AUROC 0.83 - both outperformed ALFSG-PI and KCC	Not yet in clinical use; requires standardised miRNA profiling. Represents next generation of biomarker-enriched dynamic ALF models; promising for identifying regeneration potential. Further prospective validation needed	Prognostic
Factor V-based composite scores[120]	Factor V level + bilirubin + vasopressor use + HE coma grade - derived within ALFSG cohorts as a dynamic biomarker model; factor V half-life 12-15 hours makes it sensitive to rapid change	Death or LT at 21 days in ALF; outperformed KCC and MELD but not ALFSG-PI in head-to-head comparison within ALFSG dataset	Factor V assay not universally available; currently investigational. Potential to complement KCC particularly in non-APAP ALF where factor V correlates better with prognosis than INR alone	Prognostic
AI/ML models[120]	Variable depending on model: Multi-parameter clinical + laboratory data (INR, bilirubin, creatinine, HE grade, vasopressors, lactate, ammonia, imaging); some incorporate omics data	Transplant-free survival and LT/death at 21-28 days; aim to be dynamic (daily recalculation) and etiology-agnostic	No AI/ML model currently validated for routine clinical ALF decision-making; several retrospective cohort studies promising (AUROC: 0.85-0.92). Major barriers: Explainability, prospective validation, regulatory approval. Active area of research	Prognostic
ALFED model[120]	Dynamic tracking of 4 variables over 3 days: HE grade > II, serum bilirubin, INR, arterial ammonia - assesses whether each remains above threshold or worsens. Derived in 380 non-APAP ALF patients (India)	Death without LT in non-paracetamol ALF (predominantly hepatitis E and hepatitis B etiology); designed for resource-limited settings	Promising for non-APAP ALF in Asia/developing world where hepatitis E predominates; AUROC superior to KCC in derivation cohort. Requires external validation in diverse global cohorts before routine use	Prognostic
Novel biomarker composites (CPS1, FABP1, Gc-globulin)[118,121,122]	CPS1 (hepatocyte-specific mitochondrial enzyme); FABP1 (hepatocyte damage); Gc-globulin (actin-free; reflects hepatic regeneration capacity) - all added to existing models (ALFSG-PI or KCC)	Death or LT in ALF; each has shown incremental improvement in AUROC when added to ALFSG-PI or KCC in ALFSG biobank studies. FABP1 > 350 ng/mL strongly associated with non-survival	All investigational; none in routine clinical use. FABP1 and CPS1 may be commercially assayable in future. Gc-globulin reflects regeneration rather than injury - concept of “regeneration potential” increasingly recognized as key missing element in current models	Prognostic

This table summarizes established and emerging prognostic models used in acute liver failure, including criteria for liver transplantation listing and short-term outcome prediction. It outlines key variables, predicted outcomes, and clinically relevant thresholds to support early risk stratification and time-sensitive transplant decision-making. LT: Liver transplantation; KCC: King’s College Criteria; OR: Odds ratio; INR: International normalized ratio; HE: Hepatic encephalopathy; ELT: Emergency liver transplantation; PPV: Positive predictive value; APAP: Acetaminophen (paracetamol); ALF: Acute liver failure; MELD: Model for end-stage liver disease; MELD-Na: Model for end-stage liver disease including sodium; ALFSG: Acute Liver Failure Study Group; PI: Prognostic index; AUROC: Area under the receiver operating characteristic curve; ELISA: Enzyme-linked immunosorbent assay; CVC: Clichy-Villejuif criteria; HBV: Hepatitis B virus; APACHE: Acute Physiology and Chronic Health Evaluation; ICU: Intensive care unit; SOFA: Sequential Organ Failure Assessment; PaO₂/FiO₂: Ratio of arterial oxygen partial pressure to fraction of inspired oxygen; MAP: Mean arterial pressure; GCS: Glasgow Coma Scale; miRNA: MicroRNA; AI: Artificial intelligence; ML: Machine learning; CPS1: Carbamoyl phosphate synthetase 1; FABP1: Fatty acid binding protein 1.