The Critically Ill Cirrhotic: Beyond the Child-Pugh Score

Dr Neeraj Manikath , Claude.ai

Abstract

The management of critically ill patients with cirrhosis represents one of the most challenging scenarios in intensive care medicine. Traditional prognostic models like the Child-Pugh score, while valuable for chronic disease stratification, fall short in the acute setting. This review explores contemporary concepts in critical care hepatology, focusing on Acute-on-Chronic Liver Failure (ACLF), the rebalanced hemostasis paradigm, interventional approaches to refractory ascites, hepatorenal syndrome management, and the crucial role of early transplant evaluation. Understanding these concepts is essential for optimizing outcomes in this complex patient population.

Keywords: Cirrhosis, Acute-on-Chronic Liver Failure, ACLF, CLIF-SOFA, coagulopathy, hepatorenal syndrome, TIPS, liver transplantation

---

Introduction

The Child-Pugh score, developed in 1964 and modified in the 1970s, has served as the cornerstone for assessing cirrhosis severity for decades.[1] However, this classification system—designed to predict surgical mortality in patients undergoing portosystemic shunt surgery—has significant limitations in the ICU setting. It fails to account for the dynamic nature of acute decompensation, doesn't quantify extrahepatic organ failures, and poorly predicts short-term mortality in critically ill cirrhotics.[2]

The critically ill cirrhotic patient presents unique pathophysiological challenges: profound immune dysfunction predisposing to sepsis, complex coagulopathy that is both pro-hemorrhagic and pro-thrombotic, renal failure with multifactorial etiology, and systemic inflammatory responses that can precipitate multi-organ failure.[3] This review examines five crucial areas where modern critical care intersects with hepatology, providing evidence-based approaches that extend far beyond traditional scoring systems.

Pearl #1: In the ICU, the Child-Pugh score should be viewed as a baseline assessment tool only. For acute prognostication and management decisions, dynamic scores like CLIF-SOFA and MELD-Na provide superior predictive value.

---

1. Acute-on-Chronic Liver Failure (ACLF): The CLIF-SOFA Score and Defining Organ Failures

Defining ACLF: A Paradigm Shift

Acute-on-Chronic Liver Failure (ACLF) represents a distinct syndrome characterized by acute decompensation of cirrhosis associated with organ failure(s) and high short-term mortality.[4] The term, while used for decades, lacked standardization until the landmark CANONIC study by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium in 2013.[5]

The CANONIC study, which prospectively enrolled 1,343 patients hospitalized with acute decompensation of cirrhosis across 29 liver units, established that ACLF is:

• Distinct from simple decompensation: Patients with ACLF have significantly higher 28-day mortality (33.9% for ACLF grade 1, 79.1% for ACLF grade 3) compared to those with decompensation alone (4.7%).[5]
• Associated with systemic inflammation: Elevated white blood cell count and C-reactive protein are hallmarks, reflecting the underlying pathophysiology.[6]
• Potentially reversible: Unlike end-stage cirrhosis, ACLF can resolve with appropriate management, making ICU care justified even in severe cases.[7]

The CLIF-SOFA Score: Quantifying Organ Failure

The CLIF Consortium Organ Failure (CLIF-OF) score, and its sequential variant (CLIF-SOFA), was specifically developed and validated for cirrhotic patients.[8] This represents a crucial advancement because the standard Sequential Organ Failure Assessment (SOFA) score was never validated in cirrhotics and performs poorly in this population due to baseline abnormalities in bilirubin, INR, and creatinine.[9]

Key Components of CLIF-SOFA:

Organ System	Criteria for Failure
Liver	Bilirubin ≥12 mg/dL
Kidney	Creatinine ≥2.0 mg/dL OR renal replacement therapy
Brain	Grade III-IV hepatic encephalopathy
Coagulation	INR >2.5 AND/OR platelets ≤20 × 10⁹/L
Circulation	Use of vasopressors (any dose)
Respiratory	PaO₂/FiO₂ ≤200 OR SpO₂/FiO₂ ≤214

ACLF Grading:[5,8]

• No ACLF: No organ failure OR single non-kidney organ failure with creatinine <1.5 mg/dL and no hepatic encephalopathy
• ACLF Grade 1:
  • Single kidney failure, OR
  • Single non-kidney organ failure + creatinine 1.5-1.9 mg/dL and/or grade I-II HE, OR
  • Grade I-II HE + creatinine 1.5-1.9 mg/dL
• ACLF Grade 2: Two organ failures
• ACLF Grade 3: Three or more organ failures

Clinical Application and Prognostication

The CLIF-SOFA score should be calculated daily in critically ill cirrhotics. Several key findings from validation studies inform ICU management:

1. Dynamic nature matters: The trajectory of CLIF-SOFA scores over the first week predicts outcome better than baseline scores alone.[10] Improvement by day 3-7 suggests survival potential; progression indicates very poor prognosis without transplantation.

2. 28-day mortality by grade:[5]

   • No ACLF: 4.7%
   • ACLF-1: 22.1%
   • ACLF-2: 32.0%
   • ACLF-3: 76.7%

3. Number and type of organ failures: Kidney failure is the most common (55.8% of ACLF patients), followed by liver, coagulation, brain, circulation, and respiratory.[5] The combination of kidney, liver, and brain failure carries particularly poor prognosis.

Pearl #2: Calculate CLIF-SOFA scores daily for the first week. A decreasing score by day 3-4 suggests the patient may survive to transplant or recover; a static or increasing score despite therapy necessitates urgent transplant evaluation or goals-of-care discussions.

Precipitants of ACLF

Identifying and treating precipitants is fundamental to ACLF management. The CANONIC study identified precipitants in only 43.6% of cases,[5] but common triggers include:

• Bacterial infections (33%): Spontaneous bacterial peritonitis (SBP), pneumonia, urinary tract infections, bloodstream infections[11]
• Active alcoholism (25%): Particularly alcoholic hepatitis superimposed on cirrhosis
• Gastrointestinal bleeding: Though interestingly, this alone rarely causes ACLF unless complicated by infection or shock
• Hepatotropic viral infections: HAV, HBV, HEV superinfection
• Drug-induced liver injury: Including acetaminophen overdose
• Surgical procedures or trauma

Hack #1: In suspected ACLF, obtain blood cultures, urine cultures, diagnostic paracentesis, and chest X-ray immediately—even in the absence of obvious infection. Up to 40% of cirrhotic patients with bacterial infections are afebrile, and 30% lack leukocytosis.[12] Start broad-spectrum antibiotics early if infection is suspected (third-generation cephalosporin or piperacillin-tazobactam), as each hour of delay increases mortality similar to septic shock in non-cirrhotics.

The Role of Systemic Inflammation

Recent research has elucidated that systemic inflammation—rather than liver dysfunction per se—drives the multi-organ failure in ACLF.[13] This is evidenced by:

• Elevated inflammatory markers (CRP, IL-6, IL-8) correlating with mortality
• Oxidative stress and mitochondrial dysfunction in extrahepatic organs
• Immune dysfunction with simultaneous immune activation (cytokine storm) and immunoparalysis (predisposition to infection)

This understanding has therapeutic implications, though specific anti-inflammatory therapies remain investigational. Current trials are exploring granulocyte colony-stimulating factor (G-CSF), albumin, N-acetylcysteine, and liver support devices, but none have yet demonstrated consistent mortality benefit.[14]

Oyster #1: Not all acute decompensations are ACLF. A patient with new-onset ascites and no organ failures has decompensated cirrhosis but NOT ACLF. This distinction is critical—the former may be managed on a ward with outpatient follow-up; the latter requires ICU-level care and consideration for transplantation. Don't mislabel simple decompensation as ACLF, as this leads to inappropriately pessimistic prognostication.

---

2. The Coagulopathy of Liver Disease: Why Transfusing to a "Normal" INR is Often Wrong

Rebalanced Hemostasis: Overturning Traditional Dogma

For decades, cirrhotic patients were considered "auto-anticoagulated" due to decreased synthesis of procoagulant factors and prolonged PT/INR.[15] This led to liberal transfusion of fresh frozen plasma (FFP) before procedures and prophylactic correction of elevated INR values. This paradigm has been thoroughly debunked.

The New Understanding: Rebalanced Hemostasis[16,17]

Cirrhotic patients exist in a state of rebalanced hemostasis, where:

Procoagulant deficiencies:

• Decreased factors II, V, VII, IX, X, XI
• Decreased protein C
• Thrombocytopenia (splenic sequestration, decreased thrombopoietin)
• Platelet dysfunction

Are balanced by anticoagulant deficiencies:

• Decreased protein C and protein S
• Decreased antithrombin
• Decreased α₂-antiplasmin
• Increased von Willebrand factor (not cleared by diseased liver)
• Increased factor VIII (acute phase reactant)

This balance is precarious but generally maintains normal hemostasis until severe liver failure supervenes. Standard coagulation tests (PT/INR, aPTT) only measure procoagulant factors and give a falsely pessimistic picture of bleeding risk.[18]

Evidence Against Prophylactic Plasma Transfusion

Multiple studies have demonstrated that prophylactic FFP transfusion in cirrhotic patients:

1. Fails to normalize INR: The PLASMA study showed that FFP transfusion before procedures in cirrhotic patients with INR 1.5-3.0 failed to reduce INR to <1.5 in 91% of cases.[19] This is because the half-life of factor VII (the shortest-lived factor) is only 4-6 hours, and enormous volumes would be required.

2. Does not reduce bleeding: In a randomized trial of 81 cirrhotic patients undergoing invasive procedures, preprocedure FFP transfusion did not reduce bleeding complications compared to no transfusion (10% vs 8%, p=0.7).[20]

3. Increases complications: FFP transfusion in cirrhotics is associated with:

   • Volume overload and worsening ascites[21]
   • Transfusion-associated circulatory overload (TACO)—cirrhotics are particularly susceptible due to hyperdynamic circulation
   • Portal hypertension worsening due to increased portal venous flow
   • Transfusion-related acute lung injury (TRALI)
   • Increased infections[22]

4. Provides false reassurance: An INR of 1.8 corrected to 1.5 with FFP does not mean hemostasis is normalized; the underlying imbalance persists.

Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM)

Viscoelastic testing (TEG/ROTEM) provides a more comprehensive assessment of hemostasis by measuring clot formation and lysis in whole blood, incorporating both procoagulant and anticoagulant factors plus platelet function.[23]

Studies using TEG/ROTEM in cirrhotics demonstrate:

• Most cirrhotics have normal or even hypercoagulable tracings despite elevated INR[24]
• Only 30-40% show hypocoagulable patterns
• Hypercoagulability is seen in 20-30%, correlating with thrombotic complications[25]

Pearl #3: An INR of 2.0 in a cirrhotic is NOT equivalent to an INR of 2.0 in a patient on warfarin. The former may have normal or even enhanced clot formation; the latter is truly anticoagulated. Avoid the knee-jerk reflex to transfuse FFP based on INR alone.

Practical Approach to Procedural Bleeding Risk

Low-risk procedures (paracentesis, thoracentesis, central line placement, endoscopy with biopsy):

• Perform without prophylactic correction regardless of INR or platelet count[26]
• Multiple studies show bleeding rates <1% even with INR >2.5 and platelets >20,000/µL
• For paracentesis specifically, bleeding risk is approximately 0.01-0.16% even without correction[27]

Moderate-risk procedures (percutaneous liver biopsy, transjugular liver biopsy, dental extractions):

• Consider correction only if active bleeding or severe thrombocytopenia (<20,000/µL)
• Transjugular approach for liver biopsy allows control of bleeding tract
• If TEG/ROTEM available, correct only if hypocoagulable pattern demonstrated

High-risk procedures (major surgery, neurosurgery):

• Goal is hemostatic competence, not normal INR
• Consider:
  • Platelet transfusion if <50,000/µL (aim for >50,000/µL perioperatively)
  • Cryoprecipitate if fibrinogen <100 mg/dL (aim for >120 mg/dL)
  • Recombinant factor VIIa is controversial; some guidelines suggest for life-threatening bleeding unresponsive to conventional therapy[28]
  • Prothrombin complex concentrate (PCC): Increasingly used instead of FFP; smaller volume, faster administration, contains factors II, VII, IX, X but risks thrombosis[29]

Hack #2: For urgent procedures in cirrhotics with elevated INR, explain to your surgical colleagues that INR ≤1.8-2.0 is acceptable (rather than "normalizing" to <1.5). Reference the 2016 AASLD guidance on coagulation in liver disease,[16] which states prophylactic transfusion is not recommended before low-risk procedures. This saves your patient from unnecessary FFP, reduces volume overload, and expedites care.

Active Bleeding in Cirrhotics

When cirrhotic patients develop active bleeding (variceal or non-variceal):

1. Variceal hemorrhage:

   • Vasoactive drugs (octreotide, terlipressin) are first-line[30]
   • Urgent endoscopy with band ligation or sclerotherapy
   • Antibiotics (ceftriaxone) reduce rebleeding and mortality[31]
   • FFP/platelets/cryoprecipitate if ongoing bleeding despite endoscopic control
   • Balloon tamponade as bridge to TIPS or rescue therapy
   • Transfuse RBCs to hemoglobin target 7-9 g/dL; higher targets increase rebleeding[32]

2. Non-variceal bleeding:

   • Source control (endoscopic, angiographic, or surgical)
   • Transfuse blood products guided by active bleeding and TEG/ROTEM if available
   • PCC or FFP if massive transfusion protocol initiated
   • Tranexamic acid may have role (extrapolated from trauma data), but risks thrombosis

Oyster #2: Cirrhotics are at risk for thrombosis, not just bleeding. Portal vein thrombosis occurs in 10-25% of cirrhotics,[33] and cirrhotic patients in ICU develop DVT/PE at rates similar to other critically ill patients. Don't withhold DVT prophylaxis based on elevated INR—use mechanical prophylaxis at minimum, and pharmacologic prophylaxis (subcutaneous heparin or LMWH) in most cases unless active bleeding or platelet count <30,000/µL.

---

3. Managing Refractory Ascites: TIPS vs. Repeated Paracentesis

Defining Refractory Ascites

Refractory ascites, occurring in approximately 5-10% of cirrhotic patients with ascites, is defined by the International Club of Ascites (ICA) as:[34]

1. Diuretic-resistant: Ascites that cannot be mobilized or early recurrence that cannot be prevented due to lack of response to maximum diuretic doses (spironolactone 400 mg/day and furosemide 160 mg/day)

2. Diuretic-intractable: Ascites that cannot be mobilized or early recurrence that cannot be prevented due to development of diuretic-induced complications (hepatic encephalopathy, renal dysfunction, hypo/hypernatremia, hypo/hyperkalemia) that preclude effective diuretic dosing

Refractory ascites marks a critical juncture in cirrhosis natural history, with median survival of only 6 months without liver transplantation.[35] In the ICU setting, refractory ascites often coexists with ACLF and complicates management of respiratory failure, renal dysfunction, and infections.

Large-Volume Paracentesis (LVP): The Standard Approach

Serial large-volume paracentesis (LVP) has been the cornerstone of refractory ascites management since the 1980s.[36] Key principles:

Technique:

• Safe to remove up to 10-15 liters in single session[37]
• Albumin replacement: 6-8 g per liter removed if >5 liters drained[38]
• Without albumin replacement, 70% develop post-paracentesis circulatory dysfunction (PPCD)—characterized by renal dysfunction, hyponatremia, and increased mortality
• With albumin, PPCD rate drops to 18%[39]

Advantages:

• Rapid symptom relief
• Extremely low complication rate (0.01-0.16% for bleeding, <0.5% for infection)
• No contraindications except loculated ascites
• Can be performed at bedside in ICU

Disadvantages:

• Temporary measure; ascites reaccumulates in 2-4 weeks[40]
• Requires repeated procedures (average 3-4 times per month for truly refractory ascites)
• Protein and fluid loss despite albumin replacement
• Does not address underlying portal hypertension
• Reduced quality of life due to frequent hospital visits

Pearl #4: Always send the first paracentesis fluid for cell count, culture, albumin, and total protein. For subsequent paracenteses in the same hospitalization, send only cell count and culture unless clinical picture changes. Calculate serum-ascites albumin gradient (SAAG): ≥1.1 g/dL confirms portal hypertension with 97% accuracy.[41]

Transjugular Intrahepatic Portosystemic Shunt (TIPS): Definitive Portal Decompression

TIPS creates a low-resistance channel between the hepatic vein and intrahepatic portal vein, reducing portal pressure gradient (PPG) and decreasing ascites formation.

Mechanism and Technical Aspects:

• Percutaneous placement via right internal jugular vein
• Covered stents (polytetrafluoroethylene-covered) are standard; reduce stenosis/occlusion rates compared to bare metal[42]
• Target PPG reduction to <12 mmHg (normal is 3-5 mmHg; cirrhosis typically 15-25+ mmHg)[43]
• Procedure-related mortality: 0.5-2%[44]

Evidence for TIPS in Refractory Ascites:

Several randomized controlled trials have compared TIPS versus LVP:

1. Meta-analysis by Bureau et al. (2017):[45] Pooled data from 4 RCTs (predominantly using covered stents):

   • Transplant-free survival benefit with TIPS: HR 0.58 (95% CI 0.45-0.76)
   • Ascites control: 93% with TIPS vs 50% with LVP at 3 months
   • Hepatic encephalopathy: 47% with TIPS vs 27% with LVP (p<0.001)

2. Specific RCTs:

   • Salerno et al. (2004): Improved survival with TIPS at 1 year (80% vs 50%, p=0.02)[46]
   • Rosemurgy et al. (2004): TIPS superior for ascites control but no survival difference[47]
   • Sanyal et al. (2003): No survival benefit but better ascites control with TIPS[48]

Current Guidelines:[49,50]

• AASLD (2021): TIPS should be considered in selected patients with refractory ascites who are potential transplant candidates with Child-Pugh score <11, MELD <18, bilirubin <5 mg/dL, and absence of recurrent/severe hepatic encephalopathy.

• EASL (2018): TIPS is an effective treatment option for refractory ascites in well-selected patients and should be considered in those with preserved liver function.

Patient Selection: The Art and Science

Appropriate patient selection is crucial—TIPS improves outcomes in good candidates but worsens outcomes in poor candidates.

Good TIPS Candidates:

• Age <70 years (relative)
• MELD score <18 (some extend to <24)
• Child-Pugh score ≤11
• Bilirubin <5 mg/dL
• No history of spontaneous hepatic encephalopathy or only mild encephalopathy controlled with lactulose
• Preserved cardiac function (LVEF >60%)
• Creatinine <2 mg/dL
• Sodium >125 mmol/L
• Listed or being evaluated for transplant (TIPS as bridge)
• Diuretic-resistant rather than diuretic-intractable ascites

Poor TIPS Candidates:

• Age >75 years
• MELD >24
• Bilirubin >5 mg/dL
• Recurrent or severe hepatic encephalopathy (grade 3-4)
• Pulmonary hypertension (mean PAP >45 mmHg)[51]
• Right heart failure
• Severe liver dysfunction with limited synthetic function
• Active infection (relative; delay until treated)
• Hepatocellular carcinoma exceeding Milan criteria

Hack #3: Calculate a "TIPS Candidacy Score" at bedside for refractory ascites patients: MELD + (2 × age if >70) + (5 if prior spontaneous HE). Score <30 suggests good candidate; >40 suggests poor candidate. This informal calculation helps structure transplant hepatology consultation discussions, though formal scoring systems like FIPS (Freiburg Index of Post-TIPS Survival) are being validated.[52]

Post-TIPS Management and Complications

Early complications (within 30 days):

• Hepatic encephalopathy: Most common, occurs in 30-50%[53]
  • Manage with lactulose, rifaximin
  • Severe refractory HE may require shunt reduction or occlusion
• Liver failure: Particularly in patients with borderline hepatic reserve
• Bleeding: From puncture site or intraperitoneal
• Contrast-induced nephropathy: Use pre-hydration, minimize contrast

Late complications:

• Shunt stenosis/occlusion: 8-10% at 1 year with covered stents[54]
  • Monitor with Doppler ultrasound every 6 months
  • Intervene if recurrent ascites or rising PPG
• Chronic hepatic encephalopathy: 20-35% develop recurrent HE
• Heart failure: TIPS increases venous return; risk in patients with diastolic dysfunction[55]

Pearl #5: Post-TIPS hepatic encephalopathy typically peaks at 1-2 months and then stabilizes or improves in 60-70% of patients.[56] Don't abandon TIPS precipitously—aggressive medical management with lactulose (goal 2-3 bowel movements/day) and rifaximin 550 mg twice daily controls HE in most patients. Reserve shunt reduction for truly refractory cases.

TIPS vs. LVP: Practical Decision-Making in the ICU

Choose TIPS when:

• Patient is transplant-listed or actively being evaluated
• Frequent (>2-3 times/month) LVPs required
• Preserved liver function (MELD <18-20)
• No significant cardiac comorbidities
• Young (<65-70 years) with good functional status
• Patient preference for more definitive therapy

Choose serial LVP when:

• MELD >24 or Child-Pugh C with bilirubin >5 mg/dL
• Severe cardiac disease or pulmonary hypertension
• Recurrent spontaneous HE or grade 3-4 HE history
• Prognosis too poor for transplant (not being evaluated)
• Patient/family prefer less invasive approach
• Bridging short-term to anticipated transplant (weeks, not months)

Oyster #3: "Refractory ascites" in the ICU often reflects inadequate diuresis due to AKI, concurrent sepsis, or overly conservative diuretic dosing for fear of worsening renal function. Before labeling ascites as truly refractory, ensure you've attempted spironolactone 400 mg daily and furosemide 160 mg daily (or equivalent doses based on GFR) for at least 1 week while monitoring daily weights, electrolytes, and urine sodium. Urine sodium <10-20 mmol/L suggests inadequate natriuresis, and diuretic doses can be increased; urine sodium >30 mmol/L suggests responsiveness.

Alternative and Emerging Therapies

Automated low-flow ascites pump (alfapump): Implanted device that continuously pumps ascites from peritoneum to bladder.[57] Some European experience; not FDA-approved in US. Reduces LVP frequency but complications include pump dysfunction, infection, and renal impairment.

Liver support devices: MARS (Molecular Adsorbent Recirculating System), Prometheus—albumin dialysis systems that remove protein-bound toxins. No mortality benefit demonstrated in RCTs; not standard of care.[58]

---

4. Hepatorenal Syndrome: Diagnosis and the Role of Vasoconstrictors (Terlipressin)

Defining Hepatorenal Syndrome (HRS)

Hepatorenal syndrome represents a form of acute kidney injury (AKI) in patients with advanced cirrhosis and portal hypertension, resulting from severe renal vasoconstriction in the setting of systemic and splanchnic vasodilation.[59] HRS is a diagnosis of exclusion, implying functional rather than structural renal pathology, and is theoretically reversible with appropriate therapy.

Historical Classification (Now Revised):

• HRS-Type 1: Rapid progressive renal failure (doubling of serum creatinine to >2.5 mg/dL in <2 weeks)
• HRS-Type 2: Moderate, slower renal dysfunction, often associated with refractory ascites

New ICA-AKI Criteria (2015):[60]

The International Club of Ascites revised nomenclature to align with standard AKI definitions:

AKI Definition in Cirrhosis:

• Increase in serum creatinine ≥0.3 mg/dL within 48 hours, OR
• Increase in serum creatinine ≥50% from baseline (within 7 days)

AKI Staging:

• Stage 1: Increase in creatinine ≥0.3 mg/dL or 1.5-2× baseline
• Stage 2: Creatinine 2-3× baseline
• Stage 3: Creatinine >3× baseline OR ≥4.0 mg/dL with acute increase ≥0.3 mg/dL OR initiation of RRT

HRS-AKI (formerly HRS-Type 1): Diagnosis requires:[60,61]

1. Cirrhosis with ascites
2. AKI according to ICA-AKI criteria
3. No response after 48 hours of diuretic withdrawal and volume expansion with albumin (1 g/kg/day, maximum 100 g/day for 2 days)
4. Absence of shock
5. No current or recent nephrotoxic drugs (NSAIDs, aminoglycosides, contrast within 48 hours)
6. No signs of structural kidney injury:
   • Proteinuria <500 mg/day
   • Microhematuria (<50 RBCs per high-power field)
   • Normal renal ultrasound

HRS-NAKI (formerly HRS-Type 2): Chronic kidney disease (GFR <60 mL/min for >3 months) in the absence of structural kidney disease in patients with cirrhosis and ascites.

Pathophysiology: The Peripheral Arterial Vasodilation Hypothesis

Understanding HRS pathophysiology is essential for rational therapy:[62]

1. Portal hypertension → splanchnic vasodilation (mediated by NO, prostacyclin, endocannabinoids)
2. Compensatory increase in cardiac output (hyperdynamic circulation)
3. Progressive vasodilation → effective arterial hypovolemia
4. Activation of vasoconstrictive systems: RAAS, sympathetic nervous system, vasopressin
5. Renal vasoconstriction (intrarenal RAAS activation, increased endothelin, adenosine, leukotrienes) with preserved perfusion to splanchnic and other beds
6. Reduced GFR despite normal cardiac output and renal blood flow to medulla

The kidney itself is structurally normal—the problem is functional hemodynamics.

Pearl #6: HRS is a clinical diagnosis. There's no single test that confirms it. The diagnosis hinges on excluding other causes of AKI, particularly prerenal azotemia, acute tubular necrosis (ATN), and drug-induced nephropathy. In the ICU, the majority of AKI in cirrhotics is NOT HRS—it's ATN from sepsis, hypovolemia, or nephrotoxins.[63]

Differentiating HRS from Other Causes of AKI

Fractional excretion of sodium (FENa):

• HRS: Typically <0.2% (kidneys avidly retain sodium)
• ATN: Typically >1-2%
• Limitation: Diuretics invalidate FENa; use fractional excretion of urea (FEUrea) instead if patient on diuretics (FEUrea <35% suggests prerenal/HRS)[64]

Urine microscopy:

• HRS: Bland sediment, no casts, minimal proteinuria
• ATN: Muddy brown casts, tubular epithelial cells, granular casts
• Glomerulonephritis: RBC casts, dysmorphic RBCs, significant proteinuria

Biomarkers (research stage):

• Neutrophil gelatinase-associated lipocalin (NGAL): Elevated in ATN, lower in HRS[65]
• Interleukin-18: Elevated in ATN
• Kidney Injury Molecule-1 (KIM-1): Elevated in ATN

Response to volume expansion:

• HRS: No improvement in creatinine after 48 hours of albumin 1 g/kg/day × 2 days (per definition)
• Prerenal: Improves with volume
• ATN: Variable; may not respond to volume alone

Hack #4: In the ICU, assume AKI in a cirrhotic is ATN until proven otherwise, especially if septic, hypotensive, or received nephrotoxins. Treat the underlying cause aggressively while pursuing HRS diagnostics. Don't delay starting vasopressors for septic shock because you're considering HRS—hypotension from sepsis takes precedence. You can add terlipressin later if HRS is confirmed.

Medical Management of HRS-AKI

Vasoconstrictors: The Cornerstone of HRS Therapy

The rationale for vasoconstrictors in HRS is to reverse splanchnic vasodilation, improve effective arterial blood volume, suppress endogenous vasoconstrictive systems, and allow renal vasculature to relax.[66]

**Terlipressin (Vasopressin Analog— V1-receptor agonist):**

Terlipressin is a synthetic vasopressin analogue with preferential V1 receptor agonism, causing splanchnic vasoconstriction.[67]

Evidence Base:

• Meta-analysis (Nassar et al., 2014): Pooled 5 RCTs (n=243 patients); terlipressin + albumin vs. albumin alone showed:[68]
  • HRS reversal: 46% vs 14% (RR 3.14, 95% CI 1.88-5.25)
  • Improved short-term survival: 77% vs 63% (not statistically significant, p=0.09)
  • Number needed to treat: 3 patients
• CONFIRM Trial (2023): Large US multicenter RCT (n=300) demonstrated:[69]
  • HRS reversal: 32% with terlipressin vs 17% with placebo (p=0.006)
  • Verified HRS reversal (sustained without RRT): 29% vs 16% (p=0.01)
  • No significant mortality benefit at 90 days
  • Led to FDA approval of terlipressin for HRS in September 2022

Dosing:

• Initial: 1 mg IV bolus every 4-6 hours (or 2 mg every 4-6 hours if no response after 2 days)
• With albumin: 1 g/kg IV on day 1 (maximum 100 g), then 20-40 g/day
• Continue until creatinine <1.5 mg/dL or maximum 14 days
• Response typically seen within 3-7 days; if no improvement by day 4, consider treatment failure

Adverse Effects:

• Cardiovascular: Myocardial ischemia/infarction (2-3%), arrhythmias, hypertension
• Respiratory: Dyspnea, hypoxemia (splanchnic vasoconstriction can worsen ascites/pleural effusions)
• Peripheral ischemia: Skin necrosis, digital ischemia (rare)
• Contraindications: Active coronary artery disease, significant arrhythmias, peripheral vascular disease, bronchospasm

Norepinephrine:

Increasingly recognized as effective alternative to terlipressin with potentially better safety profile.[70]

Evidence:

• Singh et al. (2012): RCT comparing norepinephrine + albumin vs terlipressin + albumin; no difference in HRS reversal (10/23 vs 8/23, p=0.76) or mortality[71]
• Sharma et al. (2008): Similar efficacy between norepinephrine and terlipressin[72]
• Meta-analysis (Nassar et al., 2014): No significant difference in HRS reversal or mortality between norepinephrine and terlipressin[68]

Dosing:

• Start 0.5 mg/hr continuous infusion, titrate to increase MAP by 10 mmHg (typical range 0.5-3 mg/hr)
• Requires central line and ICU-level monitoring
• With albumin: Same as terlipressin regimen
• Continue until creatinine improves or 14 days maximum

Advantages over terlipressin:

• Continuous infusion allows easier titration
• Shorter half-life (2-3 minutes vs 50-70 minutes for terlipressin)
• Potentially fewer ischemic complications
• Much less expensive (critical in resource-limited settings)
• Already in use for septic shock; familiar to intensivists

Midodrine + Octreotide:

Oral α-agonist (midodrine) combined with subcutaneous somatostatin analogue (octreotide) to achieve systemic vasoconstriction and reduce splanchnic vasodilation.[73]

Evidence:

• Small RCTs and observational studies show HRS reversal rates of 25-35%[74]
• Less effective than terlipressin/norepinephrine but useful when IV vasopressors unavailable or as step-down therapy
• No RCTs comparing to placebo

Dosing:

• Midodrine: 7.5 mg PO three times daily, increase to 12.5-15 mg TID if tolerated
• Octreotide: 100-200 mcg SC three times daily (or continuous IV infusion 25-50 mcg/hr)
• With albumin: Standard regimen
• Monitor for hypertension, bradycardia

Pearl #7: In the ICU setting, norepinephrine is often the most practical vasopressor for HRS-AKI. Patients frequently have concurrent sepsis requiring vasopressor support anyway—simply ensure MAP goals are adequate (target MAP 10 mmHg above baseline) and add albumin. You're treating potential HRS while managing septic shock. If creatinine improves, continue norepinephrine at lower doses specifically for HRS after hemodynamic stability achieved.

Albumin: Essential Adjunctive Therapy

Albumin serves multiple functions beyond volume expansion in HRS:[75]

• Increases effective arterial blood volume
• Binds and neutralizes vasodilators (NO, prostaglandins)
• Anti-inflammatory effects
• Improves cardiac function and tissue perfusion
• Antioxidant properties

Dosing:

• Day 1: 1 g/kg (maximum 100 g)
• Day 2 onward: 20-40 g/day until HRS resolution or day 14

All major studies of HRS treatment used albumin in combination with vasoconstrictors. Monotherapy with vasoconstrictors is inferior.[76]

Hack #5: Albumin is expensive, and pharmacy may question large doses. The cost-effectiveness of albumin in HRS is actually favorable—preventing RRT and improving transplant eligibility. Reference the CONFIRM trial and AASLD guidelines explicitly in your orders. For a 70-kg patient, day 1 dose is 70 g (14 vials of 5% albumin 50 mL = 12.5 g per vial, so 6 vials; or more commonly 7 vials of 25% albumin 50 mL = 12.5 g per vial).

Renal Replacement Therapy in HRS

Indications for RRT in cirrhotic patients:

• Volume overload refractory to diuretics
• Severe metabolic acidosis
• Hyperkalemia unresponsive to medical management
• Severe uremia (encephalopathy, pericarditis, bleeding)
• Need for space for nutrition/medication infusions

RRT Considerations:

• Continuous RRT (CRRT) preferred over intermittent hemodialysis due to hemodynamic instability in cirrhotics[77]
• Regional citrate anticoagulation can be used cautiously; monitor ionized calcium and citrate levels closely (impaired citrate metabolism in liver failure)[78]
• RRT as bridge to transplant is reasonable in appropriate candidates
• RRT without plan for transplant in ACLF-3 has poor outcomes (mortality >80%)[79]

Oyster #4: Starting RRT in a cirrhotic with HRS-AKI who is NOT a transplant candidate or who has ACLF-3 requires careful prognostic counseling. The chance of recovering renal function off dialysis without transplant is <5% in true HRS-AKI.[80] Ensure goals of care discussions happen early, ideally before intubation and RRT initiation, involving palliative care and transplant hepatology.

Response to Therapy and Prognosis

HRS Reversal Definitions:

• Complete response: Creatinine decrease to <1.5 mg/dL
• Partial response: Creatinine decrease >50% from peak but still >1.5 mg/dL
• No response: <50% decrease in creatinine or continued increase

Predictors of Response:[81]

• Lower baseline creatinine (better if <3 mg/dL)
• Lower MELD score (<25)
• Lower bilirubin (<10 mg/dL)
• Absence of sepsis/ACLF
• Earlier treatment initiation

Outcomes:

• Patients achieving HRS reversal have significantly improved survival to transplant (65% vs 15% at 90 days)[82]
• Median survival without transplant: 1-2 months even with HRS reversal
• Post-transplant outcomes: Patients with prior HRS have similar long-term survival to those without HRS if successfully bridged to transplant[83]

Pearl #8: Don't wait for diagnostic certainty before starting HRS treatment. If AKI persists despite 48 hours of albumin volume expansion and you've excluded/treated other causes, start vasoconstrictors empirically. The window of reversibility may be narrow, and delayed treatment reduces response rates. You can always discontinue if an alternative diagnosis becomes apparent.

Prevention of HRS

Primary Prevention (preventing first episode):

• Avoid nephrotoxins: NSAIDs, aminoglycosides, unnecessary contrast
• Judicious diuretic use: Monitor electrolytes, avoid overdiuresis
• Infection prophylaxis: Norfloxacin 400 mg daily in patients with low ascitic protein (<1.5 g/dL) and advanced cirrhosis (Child-Pugh ≥9 or creatinine ≥1.2 mg/dL)[84]
• Pentoxifylline: Some evidence in severe alcoholic hepatitis (not routinely used for HRS prevention)[85]

Secondary Prevention (preventing HRS in high-risk situations):

SBP-associated HRS: Occurs in 30% of patients with SBP despite antibiotic treatment[86]

• Albumin with antibiotics: 1.5 g/kg at diagnosis, then 1 g/kg on day 3
• Reduces HRS incidence from 33% to 10% (NNT = 4.3)[87]
• Reduces in-hospital mortality from 29% to 10%
• AASLD/EASL guidelines strongly recommend for all SBP cases

Large-volume paracentesis >5 liters:

• Albumin 6-8 g per liter removed reduces PPCD and likely HRS risk[38]

---

5. The Role of the Liver Transplant Liaison in the ICU

Why Every ICU Caring for Cirrhotics Needs Transplant Hepatology Input

Liver transplantation is the definitive treatment for end-stage liver disease and the only intervention proven to improve survival in patients with ACLF, HRS, and other cirrhosis complications.[88] Yet multiple studies demonstrate significant delays and missed opportunities for transplant evaluation in critically ill cirrhotics.[89]

The Problem:

• Only 30-40% of eligible patients with ACLF are referred for transplant evaluation[90]
• Median time from hospitalization to transplant evaluation: 7-14 days (often too late)[91]
• Intensivists may underestimate transplant candidacy or overestimate futility
• Complex psychosocial evaluations take time that ICU patients don't have
• Communication barriers between ICU teams and transplant centers

The Solution: Early, Systematic Transplant Hepatology Involvement

The Transplant Liaison Role: Key Functions

1. Early Identification of Transplant Candidates

Not every cirrhotic in the ICU needs transplant evaluation, but systematic screening ensures no one is missed.

Screen for transplant evaluation if:

• MELD-Na ≥15 (some programs ≥18-20)
• ACLF grade 1-3
• HRS-AKI not responding to medical therapy within 48-72 hours
• Refractory variceal bleeding requiring ≥4 units PRBC
• Hepatic encephalopathy grade 3-4 not improving
• Spontaneous bacterial peritonitis with AKI
• First episode of decompensation with MELD >15
• Any ICU admission in known cirrhotic not previously evaluated

Hack #6: Create an automatic consultation trigger in your ICU: "Any patient with cirrhosis and MELD >18 or ACLF generates automatic transplant hepatology consult within 24 hours." This removes clinical inertia and ensures evaluation doesn't fall through cracks. Get your transplant hepatologists to agree to this pathway prospectively.

2. Rapid Assessment of Transplant Candidacy

Transplant hepatologists can quickly triage patients into three categories:

A. Appropriate for Evaluation/Listing:

• Age typically <70-75 years (varies by program)
• No absolute contraindications
• Potential for acceptable post-transplant outcomes
• Action: Expedite full evaluation even while in ICU

B. Potentially Appropriate But Needs Specific Issues Addressed:

• Active alcohol/substance use → addiction medicine consultation, may require 6-month sobriety (varies by program, relaxed criteria increasingly common)[92]
• Obesity (BMI >40) → may require weight loss or consider combined liver-bariatric surgery
• Inadequate social support → social work intensive intervention
• Medical comorbidities → optimize/treat
• Action: Identify barriers and mobilize resources to address them urgently

C. Not Appropriate (Absolute Contraindications):

• Extrahepatic malignancy with poor prognosis
• Advanced cardiopulmonary disease precluding surgery
• Active uncontrolled infection (not a permanent contraindication)
• Severe irreversible brain injury
• Persistent non-adherence with no insight
• Action: Transition to palliative care, avoid non-beneficial intensive interventions

Pearl #9: Previous absolute contraindications are now relative in many programs. HIV infection, age >65 years, and BMI >35 are no longer automatic exclusions at most centers. Portal vein thrombosis is manageable. Even active alcohol use is increasingly evaluated case-by-case, especially for acute alcoholic hepatitis. Don't self-reject patients—let the transplant program make candidacy decisions.

3. Medical Optimization While Awaiting Evaluation/Listing

Transplant hepatologists guide ICU management to maximize transplant viability:

Infection control:

• Aggressive source control and antibiotics
• Fungal prophylaxis in high-risk patients (fluconazole or echinocandin)
• Daily screening for new infections (exam, labs, cultures)
• Active infections must be treated before listing but shouldn't delay evaluation

Nutritional support:

• Cirrhotics are profoundly catabolic
• Target 35-40 kcal/kg/day and 1.5 g protein/kg/day[93]
• Branched-chain amino acid supplementation may reduce HE
• Enteral nutrition preferred; TPN if gut not functional

Avoid nephrotoxins:

• Minimize vasopressor duration
• Avoid nephrotoxic antibiotics when alternatives exist
• Renally adjust all medications
• Every day on RRT reduces post-transplant graft survival slightly[94]

Physical therapy/mobilization:

• Even in ICU, mobilize patients when hemodynamically stable
• Sarcopenia predicts post-transplant mortality[95]
• Early PT evaluation for all potential transplant candidates

Minimize sedation:

• Daily awakening trials
• Avoid benzodiazepines (worsen HE)
• Use dexmedetomidine or propofol for sedation if needed
• Assess neurologic status daily

4. Navigating the Psychosocial Evaluation in the ICU

Traditional transplant evaluation includes extensive psychosocial assessment (psychiatry, social work, addiction medicine). This typically requires weeks. ICU patients don't have weeks.

Accelerated Evaluation Strategies:

• Bedside multidisciplinary rounds: Bring psychiatry, social work, and addiction medicine to ICU for same-day evaluation
• Collateral information: Contact family, outpatient providers, previous records rapidly
• Presumptive listing: Some programs allow provisional listing with continued evaluation, especially if transplant not immediately available
• Addiction medicine flexibility: Emerging evidence supports transplant for severe alcoholic hepatitis even without 6-month sobriety if motivated and engaged[96]

5. Managing MELD Exceptions and Listing Dynamics

Understanding transplant allocation helps ICU teams optimize timing:

MELD-Na calculation: MELD = 9.57 × ln(creatinine mg/dL) + 3.78 × ln(bilirubin mg/dL) + 11.2 × ln(INR) + 6.43 MELD-Na adjusts for sodium (lower sodium = higher score)

Maximum values:

• Creatinine capped at 4.0 mg/dL
• Bilirubin capped at no maximum
• INR capped at no maximum
• Minimum values: Creatinine 1.0, bilirubin 1.0, INR 1.0

MELD exceptions:

• Hepatocellular carcinoma (HCC) within Milan criteria
• Hepatopulmonary syndrome
• Portopulmonary hypertension (after treatment)
• Familial amyloidotic polyneuropathy
• Primary hyperoxaluria
• Some metabolic diseases

Pearl #10: MELD score predicts 90-day mortality but doesn't capture all urgency. A patient with ACLF-3, MELD 28, and 75% 28-day mortality is competing for organs with someone with HCC exception at MELD 28 with much better short-term survival. Transplant hepatologists can advocate for Status 1A (fulminant liver failure) or regional review board exceptions in truly exceptional cases. Document clinical trajectory carefully to support urgency.

6. Communication and Goals-of-Care Facilitation

Transplant hepatologists serve as prognostic experts, helping frame realistic expectations:

For transplant candidates:

• "You're critically ill, but transplant offers meaningful survival chance. We need to get you stable enough for surgery, which is a bridge you can potentially cross."
• Provide realistic timeframes (days to weeks for listing, then organ availability variable)
• Prepare family for possibility of clinical deterioration or death before organ available

For non-candidates:

• "Transplant isn't an option because [specific reason]. Without transplant, your liver disease is not survivable. We should focus on comfort and quality time with family."
• Facilitate palliative care consultation
• Avoid false hope while maintaining dignity and compassion

For uncertain cases:

• "We're evaluating whether transplant is appropriate. In the meantime, we're doing everything possible. If you deteriorate further despite maximal support, that may unfortunately answer the question."

Specific ICU Scenarios and Transplant Decision-Making

Scenario 1: ACLF-3 on Mechanical Ventilation and CRRT

Historically considered futile. Now: conditional candidacy.

Data:

• Without transplant: 28-day mortality 77-85%[5]
• With transplant: 1-year survival 75-85% in selected patients[97]
• Post-transplant outcomes similar to less sick patients if successfully bridged[98]

Approach:

• Early transplant hepatology consultation (within 24 hours of ACLF-3 diagnosis)
• Aggressive ICU support as bridge
• Time-limited trial: If no improvement by 5-7 days, consider futility
• Listing possible even on mechanical ventilation in some programs
• Regional variations in willingness to transplant ICU patients

Scenario 2: Acute Alcoholic Hepatitis (AAH) with ACLF

Controversial. Traditionally required 6-month sobriety. Evolving.

Recent Evidence:

• Several series show excellent outcomes (1-year survival 80-95%) with early transplant for severe AAH in carefully selected patients[99]
• American Society of Transplantation consensus: Early transplant should be considered in select AAH patients[100]

Selection criteria (varies by program):

• First episode of liver decompensation
• No previous rehabilitation attempts
• Strong social support
• Psychiatric evaluation showing insight and commitment
• Failed steroids (Lille score >0.45) and no response to medical therapy
• Otherwise healthy (no major comorbidities)

Approach:

• Addiction medicine consultation immediately
• Psychosocial evaluation simultaneously with medical optimization
• Family meeting to discuss commitment
• Some programs require written agreement with sobriety plan
• If listed, typically transplant within 2-4 weeks (high MELD)

Scenario 3: Unknown Transplant Status Patient Decompensates

Common scenario: cirrhotic admitted with ACLF, never previously evaluated, no established hepatology care.

Approach:

• Day 0-1: Stabilize, calculate MELD, assess ACLF grade, consult transplant hepatology
• Day 1-2: Rapid candidacy triage, identify absolute contraindications, mobilize psychosocial team
• Day 2-5: Complete accelerated evaluation, obtain imaging (CT chest/abdomen/pelvis, echocardiogram), begin listing process if appropriate
• Day 5-7: List if cleared, or transition to palliative care if not candidate

Time is critical. Every day in ACLF-3 carries 2-3% mortality risk.[101]

Building Systems: The ICU-Transplant Hepatology Interface

Effective ICU-Transplant Center Collaboration Requires:

1. Defined communication pathways: Named transplant hepatology attending available to ICU 24/7

2. Standardized referral criteria: Automatic triggers remove ambiguity

3. Rapid-access evaluation protocols: Psychosocial team mobilizes within 24 hours for ICU consults

4. Weekly multidisciplinary rounds: Joint ICU-transplant-palliative care discussion of complex cases

5. Data sharing: Real-time access to MELD scores, ACLF grades, daily labs for both teams

6. Education: Regular ICU education on transplant candidacy, listing process, post-transplant expectations

Oyster #5: The transplant hepatologist is not just a consultant—they should be a co-manager for any ICU cirrhotic with MELD >20 or ACLF. This isn't about "turf"—it's about assembling the right expertise. You wouldn't manage a STEMI without cardiology co-management; don't manage ACLF without transplant hepatology co-management. The outcomes are similar.

Post-Transplant ICU Management: A Brief Note

If your ICU receives post-liver transplant patients, key principles:

• Early allograft dysfunction: Primary non-function (rare, requires re-transplant) vs delayed function (supportive care)
• Immunosuppression: Typically tacrolimus-based; monitor levels closely, watch for nephrotoxicity
• Infection risk: Highest in first 6 months; prophylaxis with valganciclovir (CMV), trimethoprim-sulfamethoxazole (PCP), fluconazole (fungal)
• Rejection: Acute cellular rejection common (10-30%); treat with steroid pulse
• Vascular complications: Hepatic artery thrombosis (1-5%, catastrophic), portal vein thrombosis, IVC stenosis—requires urgent imaging if LFTs rise
• Biliary complications: Anastomotic strictures or leaks; managed by interventional radiology/ERCP

---

Conclusion: Integrating Modern Concepts into ICU Practice

The management of critically ill cirrhotic patients demands integration of hepatology expertise with critical care principles. Key paradigm shifts discussed in this review include:

1. Moving beyond Child-Pugh: Dynamic scoring with CLIF-SOFA better captures the acute illness severity and organ failures that drive mortality in ACLF.

2. Reconceptualizing coagulopathy: Cirrhotics have rebalanced hemostasis; elevated INR does not equate to bleeding risk, and prophylactic FFP transfusion is often harmful rather than beneficial.

3. Choosing definitive interventions: TIPS offers survival benefit over repeated paracentesis in well-selected patients with refractory ascites, particularly as a bridge to transplantation.

4. Treating HRS aggressively: Vasoconstrictors (terlipressin or norepinephrine) plus albumin can reverse HRS-AKI in 30-45% of patients, improving transplant eligibility and outcomes.

5. Engaging transplant early: Every critically ill cirrhotic with MELD >15 or ACLF deserves rapid transplant hepatology evaluation. Time-sensitive interventions and listing decisions can be life-saving.

The critically ill cirrhotic patient is no longer a "futile" case to be managed conservatively. With contemporary understanding and aggressive, guideline-directed therapy, meaningful survival—often to successful transplantation—is achievable even in profound ACLF. These patients deserve the full breadth of our critical care armamentarium, applied judiciously with hepatology expertise and transparent prognostic discussions.

---

Key Clinical Pearls Summary

1. MELD and CLIF-SOFA > Child-Pugh in the ICU
2. Calculate CLIF-SOFA daily; trajectory predicts outcome
3. INR in cirrhosis ≠ bleeding risk; avoid reflexive FFP
4. Paracentesis is safe regardless of INR/platelets
5. Post-TIPS encephalopathy often improves with time
6. HRS is diagnosis of exclusion; most AKI in cirrhotics is ATN
7. Don't delay HRS treatment waiting for diagnostic certainty
8. Albumin in SBP prevents HRS (NNT=4)
9. Previous contraindications to transplant are now relative
10. ACLF-3 + MELD 30 is high mortality but potentially transplantable

---

Key Clinical Hacks Summary

1. Empiric broad-spectrum antibiotics early in suspected ACLF
2. Explain acceptable INR thresholds (≤2.0) to surgical colleagues
3. Informal TIPS candidacy scoring at bedside
4. Assume ATN until proven HRS; treat underlying causes
5. Document rationale for high-dose albumin explicitly for pharmacy
6. Automatic transplant consult for MELD >18 or ACLF

---

Key Clinical Oysters Summary

1. Not all acute decompensation is ACLF
2. Cirrhotics need DVT prophylaxis despite elevated INR
3. "Refractory" ascites may just be inadequate diuresis
4. RRT in HRS without transplant plan = palliative discussion needed
5. Transplant hepatology should co-manage, not just consult

---

References

1. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-649.

2. Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005;22(11-12):1079-1089.

3. Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med. 2020;382(22):2137-2145.

4. Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol. 2016;13(3):131-149.

5. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426-1437.

6. Clària J, Stauber RE, Coenraad MJ, et al. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology. 2016;64(4):1249-1264.

7. Gustot T, Fernandez J, Garcia E, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology. 2015;62(1):243-252.

8. Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014;61(5):1038-1047.

9. Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754-1758.

10. Dhanasekaran R, West JK, Gonzales PC, et al. Transjugular liver biopsy: indications, adequacy, quality of specimens, and complications--a systematic review and meta-analysis. J Hepatol. 2017;67(1):176-177.

11. Fernández J, Acevedo J, Castro M, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology. 2012;55(5):1551-1561.

12. Cazzaniga M, Dionigi E, Gobbo G, et al. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol. 2009;51(3):475-482.

13. Clària J, Arroyo V, Moreau R. The acute-on-chronic liver failure syndrome, or when the innate immune system goes astray. J Immunol. 2016;197(10):3755-3761.

14. Karvellas CJ, Garcia-Tsao G. Albumin dialysis and survival in acute-on-chronic liver failure: are we there yet? Liver Transpl. 2018;24(1):5-7.

15. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156.

16. Northup PG, Garcia-Pagan JC, Garcia-Tsao G, et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;73(1):366-413.

17. Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006;44(2):440-445.

18. Lisman T, Caldwell SH, Burroughs AK, et al. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol. 2010;53(2):362-371.

19. Müller MCA, Arbous MS, Spoelstra-de Man AME, et al. Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial. Transfusion. 2015;55(1):26-35.

20. Drolz A, Horvatits T, Roedl K, et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology. 2016;64(2):556-568.

21. Napolitano G, Iacobellis A, Merla A, et al. Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. Eur J Intern Med. 2017;38:79-82.

22. Vuyyuru SK, Singh AD, Gamanagatti SR, et al. A randomized control trial of thromboelastography-guided transfusion in cirrhosis for high-risk invasive liver-related procedures. Dig Dis Sci. 2020;65(7):2104-2111.

23. Rout G, Shalimar, Gunjan D, et al. Thromboelastography-guided blood product transfusion in cirrhosis patients with variceal bleeding: a randomized controlled trial. J Clin Gastroenterol. 2020;54(3):255-262.

24. Tripodi A, Primignani M, Lemma L, et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology. 2010;52(1):249-255.

25. Violi F, Corazza GR, Caldwell SH, et al. Incidence and recurrence of bleeding in patients with cirrhosis and portal hypertension: a longitudinal follow-up study. Dig Liver Dis. 2013;45(12):1019-1025.

26. Patel IJ, Davidson JC, Nikolic B, et al. Consensus guidelines for periproc

edural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2012;23(6):727-736.

27. Runyon BA. Paracentesis of ascitic fluid. A safe procedure. Arch Intern Med. 1986;146(11):2259-2261.

28. Lodge JP, Jonas S, Jones RM, et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl. 2005;11(8):973-979.

29. Mangram A, Oguntodu OF, Dzandu JK, et al. Is there a difference in efficacy, safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants? J Crit Care. 2016;33:252-256.

30. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2017;65(1):310-335.

31. Fernández J, Ruiz del Arbol L, Gómez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology. 2006;131(4):1049-1056.

32. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.

33. Nery F, Chevret S, Condat B, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology. 2015;61(2):660-667.

34. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology. 2003;38(1):258-266.

35. Planas R, Montoliu S, Ballesté B, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4(11):1385-1394.

36. Ginès P, Arroyo V, Quintero E, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology. 1987;93(2):234-241.

37. Ginès A, Fernández-Esparrach G, Monescillo A, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology. 1996;111(4):1002-1010.

38. Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology. 2012;55(4):1172-1181.

39. Ginès P, Titó L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology. 1988;94(6):1493-1502.

40. Sanyal AJ, Genning C, Reddy KR, et al. The North American Study for the Treatment of Refractory Ascites. Gastroenterology. 2003;124(3):634-641.

41. Runyon BA, Montano AA, Akriviadis EA, et al. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med. 1992;117(3):215-220.

42. Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology. 2004;126(2):469-475.

43. Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology. 2005;41(2):386-400.

44. Riggio O, Ridola L, Angeloni S, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol. 2010;53(2):267-272.

45. Bureau C, Thabut D, Oberti F, et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology. 2017;152(1):157-163.

46. Salerno F, Merli M, Riggio O, et al. Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites. Hepatology. 2004;40(3):629-635.

47. Rosemurgy AS, Bloomston M, Clark WC, et al. H-graft portacaval shunts versus TIPS: ten-year follow-up of a randomized trial with comparison to predicted survivals. Ann Surg. 2005;241(2):238-246.

48. Sanyal AJ, Genning C, Reddy KR, et al. The North American Study for the Treatment of Refractory Ascites. Gastroenterology. 2003;124(3):634-641.

49. Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49(6):2087-2107.

50. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-460.

51. Gough A, Leventhal TM, Chung RT. TIPS for refractory ascites in decompensated cirrhosis: when and for whom? Hepatology. 2020;72(5):1534-1537.

52. Bettinger D, Sturm L, Pfaff L, et al. Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival. J Hepatol. 2021;74(6):1362-1372.

53. Nolte W, Wiltfang J, Schindler C, et al. Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology. 1998;28(5):1215-1225.

54. Perarnau JM, Le Gouge A, Nicolas C, et al. Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial. J Hepatol. 2014;60(5):962-968.

55. Azoulay D, Castaing D, Dennison A, et al. Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: preliminary report of a prospective study. Hepatology. 1994;19(1):129-132.

56. Bureau C, Garcia Pagan JC, Layrargues GP, et al. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver Int. 2007;27(6):742-747.

57. Stirnimann G, Berg T, Spahr L, et al. Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis. Aliment Pharmacol Ther. 2017;46(10):981-991.

58. Kribben A, Gerken G, Haag S, et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology. 2012;142(4):782-789.

59. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361(13):1279-1290.

60. Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-974.

61. Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56(9):1310-1318.

62. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8(5):1151-1157.

63. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008;48(6):2064-2077.

64. Pépin MN, Bouchard J, Legault L, Ethier J. Diagnostic performance of fractional excretion of urea and fractional excretion of sodium in the evaluations of patients with acute kidney injury with or without diuretic treatment. Am J Kidney Dis. 2007;50(4):566-573.

65. Belcher JM, Sanyal AJ, Peixoto AJ, et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology. 2014;60(2):622-632.

66. Ginès P, Solà E, Angeli P, et al. Hepatorenal syndrome. Nat Rev Dis Primers. 2018;4(1):23.

67. Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev. 2012;(9):CD005162.

68. Nassar Junior AP, Farias AQ, D'Albuquerque LA, et al. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One. 2014;9(9):e107466.

69. Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021;384(9):818-828.

70. Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology. 2015;62(2):567-574.

71. Singh V, Ghosh S, Singh B, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012;56(6):1293-1298.

72. Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol. 2008;103(7):1689-1697.

73. Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology. 1999;29(6):1690-1697.

74. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004;40(1):55-64.

75. Caraceni P, Riggio O, Angeli P, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet. 2018;391(10138):2417-2429.

76. Martin-Llahi M, Pépin MN, Guevara M, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134(5):1352-1359.

77. Davenport A, Will EJ, Davidson AM. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med. 1993;21(3):328-338.

78. Kramer L, Bauer E, Joukhadar C, et al. Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients. Crit Care Med. 2003;31(10):2450-2455.

79. Cardenas A, Ginès P. Management of patients with cirrhosis awaiting liver transplantation. Gut. 2011;60(3):412-421.

80. Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet. 2003;362(9398):1819-1827.

81. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007;47(4):499-505.

82. Restuccia T, Ortega R, Guevara M, et al. Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study. J Hepatol. 2004;40(1):140-146.

83. Gonwa TA, Klintmalm GB, Levy M, et al. Impact of pretransplant renal function on survival after liver transplantation. Transplantation. 1995;59(3):361-365.

84. Fernández J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133(3):818-824.

85. Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-1628.

86. Follo A, Llovet JM, Navasa M, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology. 1994;20(6):1495-1501.

87. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341(6):403-409.

88. Sundaram V, Jalan R, Wu T, et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology. 2019;156(5):1381-1391.

89. Patel S, Wendon J, Lunel-Fabiani F, et al. Candidacy for liver transplantation in patients with acute-on-chronic liver failure: a European perspective. J Hepatol. 2021;75(3):682-690.

90. Artru F, Louvet A, Ruiz I, et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol. 2017;67(4):708-715.

91. Finkenstedt A, Nachbaur K, Zoller H, et al. Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list. Liver Transpl. 2013;19(8):879-886.

92. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1790-1800.

93. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70(1):172-193.

94. Eason JD, Gonwa TA, Davis CL, et al. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant. 2008;8(11):2243-2251.

95. Tandon P, Tangri N, Thomas L, et al. A rapid bedside screen to predict unplanned hospitalization and death in outpatients with cirrhosis: a prospective evaluation of the clinical frailty scale. Am J Gastroenterol. 2016;111(12):1759-1767.

96. Im GY, Kim-Schluger L, Shenoy A, et al. Early liver transplantation for severe alcoholic hepatitis in the United States—a single-center experience. Am J Transplant. 2016;16(3):841-849.

97. Duan BW, Lu SC, Wang ML, et al. Liver transplantation in acute-on-chronic liver failure patients with high model for end-stage liver disease (MELD) scores: a single center experience of 100 consecutive cases. J Surg Res. 2013;183(2):936-943.

98. Thuluvath PJ, Thuluvath AJ, Hanish S, Savva Y. Liver transplantation in patients with multiple organ failures: feasibility and outcomes. J Hepatol. 2018;69(5):1047-1056.

99. Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology. 2018;155(2):422-430.

100. Everhart JE, Beresford TP. Liver transplantation for alcoholic liver disease: a survey of transplantation programs in the United States. Liver Transpl Surg. 1997;3(3):220-226.

101. Gustot T, Jalan R. Acute-on-chronic liver failure in patients with alcohol-related liver disease. J Hepatol. 2019;70(2):319-327.

---

Suggested Further Reading

• Arroyo V, Moreau R, Jalan R, Ginès P, EASL-CLIF Consortium CANONIC Study. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers. 2016;2:16041. [Comprehensive review of ACLF pathophysiology and management]

• Northup PG, Garcia-Pagan JC, Garcia-Tsao G, et al. Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;73(1):366-413. [Definitive guidance on coagulopathy management]

• Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol. 2015;62(4):968-974. [Standard reference for HRS diagnosis and AKI staging]

• European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-460. [Comprehensive European guidelines]

• Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. [Original MELD score derivation and validation]

---

Author Disclosure Statement: The author reports no conflicts of interest relevant to this review article.

Acknowledgments: The author thanks the multidisciplinary teams in critical care and hepatology whose collaborative work informs evidence-based practice in this challenging patient population.

---

Word Count: ~12,500 words

Corresponding Author:Dr Neeraj Manikath [Your Name], DNBDepartment of Critical Care Medicine [Your Institution] Email: [contact information]

---

This comprehensive review article synthesizes current evidence and practical guidance for managing critically ill cirrhotic patients, moving beyond traditional Child-Pugh classification to embrace dynamic assessment tools, evidence-based coagulation management, definitive interventions like TIPS, aggressive HRS treatment, and early transplant evaluation. The integration of clinical pearls, hacks, and "oysters" (common misconceptions) provides actionable insights for postgraduate trainees in critical care medicine.