Overview and Definitions
Liver failure exists on a spectrum from acute presentations in previously healthy individuals to acute decompensation superimposed on established chronic liver disease.
Acute Liver Failure (ALF): also termed fulminant hepatic failure, is characterised by rapid onset of hepatic dysfunction (coagulopathy and encephalopathy) within 26 weeks of the initial insult in a patient with no pre-existing liver disease.
Acute-on-Chronic Liver Failure (ACLF): an acute deterioration in a patient with known chronic liver disease or cirrhosis, precipitated by an identifiable trigger, resulting in organ failure and high short-term mortality.
- Decompensated Cirrhosis: the clinical transition from compensated to decompensated cirrhosis is marked by the appearance of variceal haemorrhage, ascites, jaundice, or hepatic encephalopathy.
- Median survival once decompensated is approximately 2 years.
Aetiology
Acute Liver Failure
| Cause | Examples |
|---|---|
| Viral | Hepatitis A, B, D (acute); hepatitis E (especially pregnancy); rarely CMV, HSV |
| Drug/toxin | Paracetamol overdose (most common in Australia/UK), idiosyncratic drug reactions, Amanita phalloides |
| Vascular | Budd-Chiari syndrome, ischaemic hepatitis, sinusoidal obstruction |
| Metabolic | Wilson's disease, acute fatty liver of pregnancy, HELLP syndrome |
| Autoimmune | Autoimmune hepatitis |
- Hepatitis A and E, transmitted via the faeco-oral route, are typically self-limiting, although approximately 1-2% of those infected will develop fulminant hepatic failure.
- Hepatitis B and C are transmitted parenterally and may progress to chronic infection; coinfection with hepatitis D markedly increases the risk of cirrhosis and hepatocellular carcinoma.
Acute-on-Chronic Liver Failure: Common Precipitants
| Precipitant Category | Examples |
|---|---|
| Infection/sepsis | Spontaneous bacterial peritonitis, pneumonia, urinary tract infection |
| Gastrointestinal bleeding | Variceal or non-variceal haemorrhage |
| Hepatotoxin exposure | Alcohol binge, hepatotoxic drugs (NSAIDs, aminoglycosides) |
| Viral superinfection | Hepatitis A or E superimposed on chronic HBV/HCV |
| Procedural | Surgery, TIPSS-related |
Pathophysiology of Key Complications
Hepatic Encephalopathy
- Failure of hepatic clearance leads to accumulation of ammonia and other toxins.
- Cerebral oedema is a particular risk in ALF; it is less prominent in ACLF.
- Cerebral oedema may progress to herniation and is a major cause of death in ALF.
Coagulopathy
- Reduced synthesis of clotting factors I, II, V, VII, IX, and X, combined with thrombocytopaenia (splenic sequestration) and platelet dysfunction.
- The INR is both a marker of severity and a component of transplant scoring.
- Note that routine coagulation tests may not capture the full picture, patients with liver failure often have simultaneous reductions in pro- and anticoagulant factors, resulting in a rebalanced but fragile haemostatic state.
Cardiovascular: Hyperdynamic Circulation
- Cirrhosis produces splanchnic vasodilatation (nitric oxide-mediated), resulting in low SVR, compensatory tachycardia, and elevated cardiac output.
- Effective arterial blood volume is reduced, activating the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system.
$$SVR = \frac{MAP - CVP}{CO} \times 80$$
A low SVR with high CO is the hallmark, complicating vasopressor management.
Hepatorenal Syndrome (HRS)
- Renal vasoconstriction secondary to systemic vasodilation and RAAS activation, in the absence of intrinsic renal pathology.
- HRS type 1 (now termed HRS-AKI) is rapidly progressive; HRS type 2 is associated with refractory ascites.
Hepatopulmonary Syndrome and Portopulmonary Hypertension
- Hepatopulmonary syndrome: intrapulmonary vascular dilatation causing right-to-left shunting and hypoxaemia; characterised by orthodeoxia (worsening $SpO_2$ on sitting upright)
- Portopulmonary hypertension: pulmonary arterial hypertension in the context of portal hypertension; significantly increases perioperative risk
Severity Scoring Systems
Child-Turcotte-Pugh (CTP) Score
| Parameter | 1 point | 2 points | 3 points |
|---|---|---|---|
| Bilirubin ($\mu$mol/L) | <34 | 34-50 | >50 |
| Albumin (g/L) | >35 | 28-35 | <28 |
| INR | <1.7 | 1.7-2.3 | >2.3 |
| Ascites | None | Mild | Moderate-severe |
| Encephalopathy | None | Grade 1-2 | Grade 3-4 |
- Class A: 5-6 points (well-compensated, ~10% perioperative mortality)
- Class B: 7-9 points (significant compromise, ~30% perioperative mortality)
- Class C: 10-15 points (decompensated, ~75-80% perioperative mortality)
MELD Score
$$MELD = 3.78 \times \ln[Bilirubin\;(mg/dL)] + 11.2 \times \ln[INR] + 9.57 \times \ln[Creatinine\;(mg/dL)] + 6.43$$
- Calculated from bilirubin, INR, and serum creatinine
- Higher scores indicate greater mortality risk and more urgent need for transplantation
- Used to prioritise organ allocation on transplant waiting lists
King's College Criteria (ALF, Paracetamol)
Paracetamol-induced ALF:
- Arterial pH < 7.30 after resuscitation, OR
- All three of: INR > 6.5, creatinine > 300 $\mu$mol/L, and grade III-IV encephalopathy
Non-paracetamol ALF:
- INR > 6.5, OR
- Any three of: age < 10 or > 40 years, aetiology (seronegative hepatitis, drug reaction), jaundice-to-encephalopathy interval > 7 days, INR > 3.5, bilirubin > 300 $\mu$mol/L
Management of Acute Liver Failure
General Supportive Care
| System | Management Priority |
|---|---|
| Airway | Early intubation if GCS ≤8 or grade III-IV encephalopathy; RSI with care for full stomach and coagulopathy |
| Ventilation | Lung-protective strategy; target mild hypocarbia ($PaCO_2$ 35-40 mmHg) to modulate ICP |
| Haemodynamics | Volume resuscitation (balanced crystalloid); vasopressors (noradrenaline first-line) for vasodilatory shock |
| Nutrition | Early enteral nutrition; avoid prolonged fasting; restrict protein only if refractory encephalopathy |
| Renal | Continuous renal replacement therapy (CRRT) preferred over intermittent HD (better haemodynamic tolerance) |
| Glucose | Frequent monitoring; 10% dextrose infusion for hypoglycaemia (impaired gluconeogenesis) |
| Infection | Surveillance cultures; broad-spectrum antibiotics for suspected sepsis; antifungal prophylaxis in severe ALF |
Hepatic Encephalopathy and Cerebral Oedema
- Grade III-IV encephalopathy: intubate and consider intracranial pressure (ICP) monitoring
- Head of bed 30°, avoid hypotension (CPP = MAP − ICP; target CPP > 60 mmHg)
- Lactulose (titrate to 2-3 soft stools/day) to reduce ammonia production
- Rifaximin as adjunct (non-absorbable antibiotic reducing gut ammonia production)
- Hypertonic saline (3%) for cerebral oedema; target serum sodium 145-155 mmol/L
- Mannitol 0.5-1 g/kg IV for acute ICP rises if renal function preserved
- Avoid nephrotoxins, benzodiazepines, opioids where possible
Coagulopathy Management
- Do NOT correct coagulopathy with FFP prophylactically, INR is a prognostic marker; its correction masks disease severity and wastes products
- FFP, cryoprecipitate, and platelets indicated for active bleeding or invasive procedures
- Vitamin K IV (phytomenadione 10 mg) if cholestasis may contribute
- Consider recombinant factor VIIa for refractory haemorrhage
Specific Causes
- Paracetamol overdose: N-acetylcysteine (NAC), mainstay treatment; loading dose 150 mg/kg IV over 60 minutes, then infusion; benefits extend beyond paracetamol toxicity into improving microcirculation in ALF of any cause
- Hepatitis B: antiviral therapy (tenofovir or entecavir)
- Autoimmune hepatitis: corticosteroids (prednisolone 40-60 mg/day) if no infection
- Wilson's disease: chelation therapy; urgent transplant evaluation
- Budd-Chiari: anticoagulation, TIPSS, or transplantation
Management of Acute-on-Chronic Liver Failure (ACLF)
Identify and Treat the Precipitant
| Precipitant | Specific Treatment |
|---|---|
| Spontaneous bacterial peritonitis | Cefotaxime 2 g IV 8-hourly; albumin 1.5 g/kg day 1, 1 g/kg day 3 (renal protection) |
| Variceal haemorrhage | Terlipressin/octreotide + banding ± TIPSS; antibiotic prophylaxis (ceftriaxone) |
| Alcoholic hepatitis | Abstinence; corticosteroids (prednisolone 40 mg/day) if Maddrey Discriminant Function ≥32; nutritional support |
| Hepatitis B reactivation | Antivirals (tenofovir, entecavir) |
| HRS-AKI | Terlipressin + albumin (1 g/kg/day up to 100 g); CRRT if refractory |
Ascites Management
- Dietary sodium restriction (80-120 mmol/day)
- Spironolactone (starting dose 100 mg/day, up to 400 mg/day) ± frusemide (40 mg/day, up to 160 mg/day)
- Therapeutic paracentesis for tense or refractory ascites; albumin replacement 6-8 g per litre drained if >5 L removed
- TIPSS for refractory ascites (contraindicated if encephalopathy, severe portal hypertension with bilirubin >50 $\mu$mol/L, or cardiopulmonary contraindications)
Variceal Prophylaxis
- Non-selective beta-blockade (propranolol or carvedilol) for secondary prophylaxis
- Endoscopic band ligation for oesophageal varices
Indications for Liver Transplantation
- Liver transplantation is the definitive management for both acute and chronic liver failure.
- The liver is the second most commonly transplanted organ after the kidney.
ALF, Transplant Indications
- King's College Criteria (above) remain the most widely used prognostic tool.
- Listing for transplantation should occur early as deterioration can be rapid.
- The window for transplantation in ALF is narrow.
Chronic Liver Disease / ACLF, Transplant Indications
| Indication | Notes |
|---|---|
| Decompensated cirrhosis | Variceal haemorrhage, refractory ascites, spontaneous bacterial peritonitis, hepatic encephalopathy |
| MELD score ≥15 | Survival benefit from transplantation demonstrated above this threshold |
| Hepatocellular carcinoma | Milan criteria: single lesion ≤5 cm, or ≤3 lesions all ≤3 cm, no vascular invasion |
| Hepatopulmonary syndrome | $PaO_2$ < 60 mmHg on room air |
| Portopulmonary hypertension | Moderate-severe (mPAP 35-45 mmHg), relative contraindication if mPAP > 50 mmHg |
| Recurrent cholangitis (PSC) | Unresponsive to endoscopic therapy |
Contraindications to Transplantation
| Absolute | Relative |
|---|---|
| Active extrahepatic malignancy | Age >70 years |
| Active sepsis / uncontrolled infection | Obesity (BMI >35) |
| Severe cardiopulmonary disease | Renal impairment (may require combined liver-kidney) |
| Ongoing substance misuse without rehabilitation | Social support concerns |
| Non-compliance with medical therapy | HIV infection (now often relative) |
Five-year patient survival following liver transplantation is approximately 73%.
Anaesthetic Implications
Preoperative Assessment for Patients with Liver Disease
- A consultant anaesthetist should consider liver disease severity, functional reserve, and end-organ involvement in all patients.
- Elective surgery is contraindicated in patients with acute hepatitis or liver failure.
- Patients with chronic hepatitis can safely undergo elective surgery, but hepatotoxic drugs must be avoided and hepatic perfusion maintained.
CTP class and MELD score predict perioperative mortality risk and guide decision-making regarding the appropriateness of elective, urgent, or emergency surgery.
Drug Considerations
Advanced liver disease impairs elimination of many drugs, requiring dose adjustment:
| Drug Class | Implications in Liver Failure |
|---|---|
| Neuromuscular blockers | Vecuronium and rocuronium have prolonged duration (increased Vd, reduced hepatic clearance); atracurium/cisatracurium preferred |
| Opioids | Morphine, pethidine, and fentanyl accumulate; increased bioavailability due to reduced first-pass; opioids worsen encephalopathy and constipation |
| Benzodiazepines | Prolonged effect; precipitate encephalopathy; avoid if possible |
| NSAIDs | Worsen renal function (reduce prostaglandin-mediated afferent arteriolar tone), increase bleeding risk, and may precipitate HRS, contraindicated |
| Volatile anaesthetics | Reduce MAP and cardiac output in a dose-dependent manner, thereby reducing portal blood flow; isoflurane, sevoflurane, and desflurane preserve the hepatic arterial buffer response, maintaining total hepatic blood flow; preferred over halothane |
Intraoperative Monitoring and Management
- Arterial line mandatory for haemodynamic monitoring and serial ABG/glucose/lactate measurement
- Central venous access for vasoactive drug infusion and CVP monitoring; consider PA catheter or TOE for complex cases
- Maintain MAP >65 mmHg (higher if pre-existing portal hypertension)
- Avoid hypoxia, hypercapnia, and hypotension, all increase hepatic ischaemia
- Anticipate massive haemorrhage in patients with coagulopathy and portal hypertension; have cell salvage, massive transfusion protocol, and viscoelastic testing (TEG/ROTEM) available
- Regional anaesthesia: consider if coagulation status permits (INR ≤1.5, platelets ≥80 × $10^9$/L for neuraxial blocks); avoid in severe coagulopathy
Liver Transplantation Anaesthesia: Unique Challenges
Anaesthetic management for liver transplantation is particularly challenging due to:
- Unpredictable, potentially massive blood loss
- Coagulation abnormalities requiring real-time viscoelastic guidance
- Electrolyte and acid-base disturbances (metabolic acidosis, hyperkalaemia with reperfusion)
- Haemodynamic instability, particularly at reperfusion (post-reperfusion syndrome: >30% drop in MAP for >1 minute)
- Pulmonary complications: hepatopulmonary syndrome, portopulmonary hypertension
- Renal dysfunction, patients undergoing liver transplantation are at significant risk for perioperative AKI given pre-existing hepatorenal physiology
- Neurological: encephalopathy, cerebral oedema management
Postoperative Priorities
- Tight glucose control (hepatic gluconeogenesis impaired)
- Continued vasopressor support as required
- Early enteral nutrition
- Lactulose and rifaximin for encephalopathy prophylaxis
- Vigilance for primary non-function of the graft (rising bilirubin, worsening coagulopathy, haemodynamic instability)
- Immunosuppression initiation and monitoring in transplant recipients