Acute liver failure: cerebral oedema, King's College criteria, and transplantation

Cinematic clinical photograph of a jaundiced ventilated patient with an intracranial pressure monitor and a hypertonic saline infusion running, ICU setting, clinical-blue lighting, no text, no identifiable people — FigureCerebral oedema is the number-one killer in acute liver failure — head up 30°, target sodium 145–155.

King's College criteria for liver transplant in ALF

ALF cause	Criteria (any one = transplant indicated)
Paracetamol	Arterial pH <7.25 (regardless of grade) OR all 3: INR >6.5 + creatinine >300 μmol/L + grade 3-4 encephalopathy
Non-paracetamol	INR >6.5 alone OR ≥3 of: INR >3.5 + age <10 or >40 + non-A/non-B viral or drug-induced + duration of jaundice >7 days before encephalopathy + bilirubin >300 μmol/L
Wilson's	INR >3.5 + bilirubin >300 (regardless of other features) — or Wilson's INR >6.5
General	Arterial lactate >3.5 mmol/L (early — 4h after resuscitation) or >3.0 mmol/L (12h) + INR >6.5 — newer criteria (sensitive)

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Management of acute liver failure in ICU

RECOGNISE + IDENTIFY CAUSE — (a) DEFINITION: acute liver injury (AST/ALT >1000) + COAGULOPATHY (INR ≥1.5) + ENCEPHALOPATHY (any grade) within 26 weeks (no pre-existing liver disease). (b) CAUSES — DIAGNOSE: (i) PARACETAMOL (history — intentional/accidental overdose; paracetamol level at 4h — nomogram). (ii) DRUG-INDUCED (idiosyncratic — isoniazid, valproate, halothane, nitrofurantoin — history + LFTs + eosinophilia). (iii) VIRAL (hepatitis A IgM, HBsAg/HBcIgM, HEV IgM, HSV — especially immunosuppressed/pregnant). (iv) ISCHAEMIC ('shock liver' — recent cardiac arrest/severe hypotension — context). (v) AUTOIMMUNE (ANA, ASMA, IgG — high; liver biopsy if uncertain). (vi) WILSON'S (ceruloplasmin LOW, urinary copper HIGH, Kayser-Fleischer rings, Coombs-negative haemolysis). (vii) PREGNANCY (AFLP, HELLP — context). (viii) MUSHROOM (Amanita phalloides — history; 6-24h delayed GI symptoms then liver failure). (ix) INDETERMINATE (20% — despite workup). (c) INVESTIGATIONS: FBC, INR/PT/APTT, fibrinogen, LFTs, ammonia, glucose, lactate, U&E, lipase, arterial gas (pH, lactate), blood cultures, viral serology, autoantibodies, ceruloplasmin, drug levels (paracetamol, salicylate), pregnancy test, abdominal ultrasound (liver size, patency — exclude Budd-Chiari), CT brain (if encephalopathic — exclude other causes)
TREAT THE CAUSE — (a) PARACETAMOL: N-ACETYLCYSTEINE (NAC — 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h — or 200 mg/kg over 4h then 100 mg/kg over 16h). Give REGARDLESS of time since ingestion (benefit even >24h — reduces mortality — multicentre study). Also: activated charcoal if <4h since ingestion. (b) VIRAL: antivirals — entecavir/tenofovir (hepatitis B); aciclovir (HSV — especially immunosuppressed). (c) AUTOIMMUNE: corticosteroids (prednisolone 40-60 mg — or IV methylprednisolone). (d) WILSON'S: chelation (D-penicillamine) + transplant (Wilson's ALF almost always needs transplant). (e) MUSHROOM (Amanita): penicillin G (1 MU/kg/day) + silibinin (milk thistle extract) + NAC ± transplant. (f) ISCHAEMIC: treat underlying (restore perfusion — fluids, inotropes, treat arrhythmia — liver usually recovers if perfusion restored). (g) PREGNANCY (AFLP/HELLP): DELIVER (definitive). (h) DRUG-INDUCED: STOP offending drug (+ NAC may help). (i) INDETERMINATE: NAC (benefit in non-paracetamol ALF — some evidence). TREAT CAUSE EARLY (some reversible — NAC, antivirals, steroids)
ORGAN SUPPORT (SYSTEM-BY-SYSTEM) — (a) NEUROLOGICAL (CEREBRAL OEDEMA — the #1 killer — see below). (b) CARDIOVASCULAR: initially HYPERDYNAMIC (vasodilation — low SVR — like sepsis); later may develop shock. Vasopressors (noradrenaline — target MAP ≥65 — maintain CPP for brain). Monitor lactate. (c) RESPIRATORY: ventilate if encephalopathy grade 3-4 (airway protection + control PaCO2 for ICP). Lung-protective if ARDS. (d) RENAL: AKI common (hepatorenal — type 1; ATN from hypoperfusion; nephrotoxic drugs). RRT (CRRT preferred — less haemodynamic shift — avoid IHD if cerebral oedema — risk of dialysis disequilibrium). AVOID nephrotoxins. (e) METABOLIC: HYPOGLYCAEMIA (liver can't gluconeogenesis — 10% dextrose infusion — monitor hourly — keep glucose 4-7). ACIDOSIS (lactic — liver can't clear). ELECTROLYTES (K+, Mg2+, phosphate — correct). (f) HAEMATOLOGY (coagulopathy — see below). (g) INFECTION (prophylaxis — see below)
CEREBRAL OEDEMA MANAGEMENT (THE #1 KILLER) — (a) RISK: grade 3-4 encephalopathy + ammonia >150 μmol/L — HIGH risk of cerebral oedema (cerebral ammonia → astrocyte swelling → oedema → herniation). (b) PREVENTION: (i) HEAD ELEVATION 30° (neutral — promotes venous drainage). (ii) AVOID: hypoxaemia (PaO2 <60 worsens brain), hypotension (MAP <65 — maintain CPP), HYPERCAPNIA (PaCO2 >45 — vasodilation → ↑ICP), hyponatraemia (Na <135 — worsens oedema), agitation/excessive stimulation. (iii) SEDATION: propofol (short-acting — good for neuro assessment; but accumulates in prolonged ALF — 'propofol infusion syndrome' — watch lactate), OR midazolam (avoid — accumulates in liver failure — prolonged effect). (iv) MAINTAIN NORMOTHERMIA (fever → ↑ metabolic demand + ICP — paracetamol, cooling). (c) HYPERTONIC SALINE (target Na 145-155): induces hypernatraemia → osmotic gradient → pulls water from brain → reduces oedema. 3% NaCl 250 mL bolus or infusion (30-50 mL/hr — titrate Na). Monitor Na (target 145-155). (d) MANNITOL 0.5-1 g/kg IV bolus (if ICP >20 or signs of herniation): osmotic diuretic → pulls water from brain. Monitor: serum osmolarity (<320 — above → AKI), urine output (diuresis — replace). Avoid if AKI/oliguria (can't excrete → fluid overload). (e) ICP MONITORING (for grade 3-4 encephalopathy): intraparenchymal or epidural (NOT intraventricular — bleeding risk from coagulopathy). Target ICP <20, CPP >60. Controversial (bleeding risk from insertion — must weigh against monitoring benefit — risk-reduced with correcting coagulopathy before insertion). (f) HYPERVENTILATION (PaCO2 30-35): BRIDGE ONLY for acute herniation crisis (vasoconstriction → ↓ICP) — NOT prolonged (>24h → ischaemia). (g) HYPOTHERMIA (32-35°C): controversial — NOT routine (some benefit in small studies; Eurotherm for TBI was harmful — extrapolate cautiously). (h) BARBITURATE COMA: if refractory ICP — pentobarbital (reduce metabolic demand). (i) LACTULOSE (for hyperammonaemia): reduces ammonia absorption from gut (laxative + converts NH3 to NH4+ — non-absorbable). May reduce encephalopathy — but doesn't reduce cerebral oedema (in ALF — encephalopathy is from cerebral ammonia, not just gut). (j) RRT (CRRT): removes ammonia (especially if AKI) — may lower ammonia → reduce encephalopathy/oedema
COAGULOPATHY + INFECTION PROPHYLAXIS — (a) COAGULOPATHY (INR high — liver can't synthesise factors): (i) 'REBALANCED HAEMOSTASIS': in ALF, both PROcoagulant (factors) and ANTICOagulant (protein C/S, antithrombin) are reduced → NET haemostasis may be near-normal (despite high INR). (ii) DON'T chase INR (INR doesn't reflect bleeding risk in ALF — the 'rebalanced' state). (iii) TRANSFUSE only if BLEEDING (or before procedure — platelets, FFP, cryoprecipitate for fibrinogen). (iv) Thromboelastography (TEG/ROTEM) — better than INR for assessing haemostasis in ALF. (v) VTE prophylaxis (LMWH — despite high INR — ALF patients are prothrombotic — 'rebalanced' haemostasis). (vi) NOTE: King's College criteria USE INR (it's a prognostic marker — not a bleeding indicator). (b) INFECTION (common — 80% of ALF patients develop infection; infection is a leading cause of death): (i) PROPHYLAXIS: broad-spectrum antibiotics (IV — systemic + enteral — gut decontamination) + ANTIFUNGAL (Candida common — especially if on broad-spectrum antibiotics). (ii) MONITOR: surveillance cultures (blood, urine, sputum, line) — q24-48h. (iii) TREAT promptly if infection suspected (fever, leukocytosis, haemodynamic deterioration — may not have fever in ALF — blunted response). (iv) REMOVE lines when not needed (source control)
KING'S COLLEGE CRITERIA + LIVER TRANSPLANT — (a) KING'S COLLEGE CRITERIA (predict mortality without transplant → transplant referral): (i) PARACETAMOL: arterial pH <7.25 (regardless of grade) OR all 3 of (INR >6.5 + creatinine >300 + grade 3-4 encephalopathy). (ii) NON-PARACETAMOL: INR >6.5 alone OR ≥3 of (INR >3.5 + age <10 or >40 + non-A/non-B or drug-induced + jaundice >7 days before encephalopathy + bilirubin >300). (iii) NEWER: arterial lactate >3.5 (early — 4h) or >3.0 (12h) — sensitive — adds to King's. (iv) WILSON'S: INR >3.5 + bilirubin >300. (b) TRANSPLANT: (i) DEFINITIVE treatment for ALF meeting King's College criteria (mortality 80%+ without; 20% with transplant). (ii) TIMING: EARLY referral (transplant takes time — organ procurement, logistics — don't delay). (iii) CONTRAINDICATIONS: irreversible brain damage (sustained ICP >30 or CPP <40 for >2h), uncontrolled sepsis, severe comorbidity, active substance abuse, age >70 (relative), psychosocial. (iv) MELD score (used for transplant allocation — higher = sicker = priority). (v) LIVING DONOR (right lobe) — if deceased donor unavailable — faster (emergency). (vi) POST-TRANSPLANT: immunosuppression (tacrolimus, mycophenolate, steroids), monitor rejection, infection, graft function. (c) BRIDGE TO TRANSPLANT (if waiting): (i) MARS (molecular adsorbent recirculating system — artificial liver — albumin dialysis — removes toxins). Controversial — RELIEF trial — no mortality benefit — may bridge. (ii) High-volume plasmapheresis — some benefit. (iii) SUPPORTIVE (organ support — buy time). (d) PALLIATIVE: if NOT transplant candidate (irreversible brain damage, uncontrolled sepsis, comorbidity) → palliative care (symptom control, family support)

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Exam practice

SAQ — Cerebral oedema in ALF managed with hypertonic saline

10 minutes · 10 marks

A 28-year-old man with paracetamol-induced acute liver failure (day 3, INR 6.2, arterial ammonia 185 umol/L, Na 137 mmol/L) was intubated this morning for grade III encephalopathy. Two hours later his nurse records BP 204/112, HR 44, and unequal pupils (right 5 mm and sluggish, left 3 mm). He is sedated with propofol and ventilated to PaCO2 38 mmHg.

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Clinical pearls

High-yield ALF points for CICM/FFICM exam

Cerebral oedema — the #1 killer. (1) PATHOPHYSIOLOGY: (a) AMMONIA (from gut — bacterial metabolism of protein) accumulates (liver can't metabolise to urea). (b) Ammonia crosses BLOOD-BRAIN BARRIER → enters ASTROCYTES → metabolised to GLUTAMINE (astrocyte glutamine synthetase). (c) Glutamine ACCUMULATES in astrocytes → osmotic effect → WATER enters astrocytes → ASTROCYTE SWELLING → CEREBRAL OEDEMA → raised ICP → HERNIATION → death. (2) RISK: grade 3-4 encephalopathy + ammonia >150 μmol/L (correlation — high ammonia → high oedema risk). (3) CLINICAL: confusion → agitation → somnolence → coma → signs of raised ICP (Cushing's triad — hypertension, bradycardia, irregular respiration — LATE, pre-terminal). (4) MANAGEMENT: (a) HEAD 30° neutral. (b) HYPERTONIC SALINE (target Na 145-155). (c) MANNITOL (0.5-1 g/kg IV — if ICP >20 or signs of herniation — monitor osmolarity <320 + urine output). (d) ICP MONITORING (grade 3-4 — target ICP <20, CPP >60 — intraparenchymal/epidural — NOT intraventricular — bleeding risk). (e) HYPERVENTILATION (PaCO2 30-35 — bridge for herniation crisis only — NOT prolonged). (f) SEDATION (propofol — short-acting — good for neuro assessment). (g) AVOID: hypoxaemia, hypotension, hypercapnia, hyponatraemia, excessive stimulation. (5) KEY: cerebral oedema is PREVENTABLE + TREATABLE — but if unrecognised → herniation → death (irreversible brain damage → transplant futile).[5] }
NAC (N-acetylcysteine) — for ALL ALF (not just paracetamol). (1) MECHANISM: (a) Replenishes GLUTATHIONE (detoxifies NAPQI — the toxic paracetamol metabolite). (b) ANTIOXIDANT (scavenge free radicals — reduce oxidative injury). (c) IMPROVES MICROCIRCULATION (vasodilatory — improves tissue perfusion). (2) FOR PARACETAMOL ALF: (a) GOLD STANDARD antidote. (b) Give REGARDLESS of time since ingestion (benefit even >24h — reduces mortality — historically thought only effective <8h, but evidence shows late benefit in established ALF). (c) PROTOCOL: 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h (total 300 mg/kg over 21h) OR 200 mg/kg over 4h then 100 mg/kg over 16h (20h). (3) FOR NON-PARACETAMOL ALF: (a) Some evidence of benefit (antioxidant + microcirculatory — multicentre RCT — trend to improved survival — especially early-stage ALF). (b) CURRENT: many centres give NAC to ALL ALF (regardless of cause) — low risk + possible benefit. (4) SIDE EFFECTS: anaphylactoid reaction (rash, bronchospasm, hypotension — especially with rapid infusion — slow the rate + antihistamine). (5) KEY: NAC for ALL ALF — paracetamol (antidote) + non-paracetamol (antioxidant/microcirculation — possible benefit).[3] }
King's College criteria — transplant decision. (1) THE CRITERIA (O'Grady 1989): predict mortality without transplant (sensitivity ~70%, specificity ~90%). (2) PARACETAMOL ALF: (a) Arterial pH <7.25 (regardless of grade) — VERY high mortality (predictive — metabolic acidosis from severe liver failure + AKI). OR (b) ALL THREE: INR >6.5 + creatinine >300 μmol/L + grade 3-4 encephalopathy. (3) NON-PARACETAMOL ALF: (a) INR >6.5 alone (very high — severe coagulopathy). OR (b) ≥3 of 5: INR >3.5 + age <10 or >40 + cause (non-A/non-B viral or idiosyncratic drug) + jaundice >7 days before encephalopathy + bilirubin >300 μmol/L. (4) NEWER ADDITIONS: arterial lactate >3.5 (at 4h post-resuscitation) or >3.0 (at 12h) — sensitive (adds to King's — early prediction). (5) WILSON'S: INR >3.5 + bilirubin >300 (Wilson's ALF almost always needs transplant — King's specific criteria). (6) USE: (a) MEETING CRITERIA → TRANSPLANT REFERRAL (urgent — discuss with transplant centre). (b) NOT meeting criteria → supportive + monitor (may recover without transplant). (c) The criteria are PROGNOSTIC (not absolute — clinical judgement — some meeting criteria may recover; some not meeting may deteriorate). (7) LIMITATIONS: (a) Low sensitivity (misses some who need transplant). (b) Static (don't account for trajectory — improving vs worsening). (c) Clichou (2002) — added lactate + phosphate to improve sensitivity. (8) PRACTICE: King's College at admission + daily reassessment (trajectory — if worsening + approaching criteria → transplant referral).[2] }
Hypoglycaemia — common and dangerous. (1) MECHANISM: (a) LIVER is the primary site of GLUCONEOGENESIS (from lactate, amino acids, glycerol — when glycogen depleted). (b) In ALF: liver can't perform gluconeogenesis → HYPOGLYCAEMIA (especially if fasting, septic, stressed). (c) ALSO: impaired glycogenolysis (glycogen stores depleted). (d) Impaired insulin clearance (liver metabolises insulin) → hyperinsulinaemia → more hypoglycaemia. (2) CLINICAL: (a) SYMPTOMS: sweating, tremor, confusion, seizures, coma — but in ALF (encephalopathic), may be MASKED (can't distinguish hypoglycaemia from encephalopathy — MUST check glucose). (b) WORSENING encephalopathy — may be hypoglycaemia, not worsening liver failure. (3) MANAGEMENT: (a) 10% DEXTROSE infusion (continuous — e.g., 100 mL/hr — or 50% dextrose 50 mL bolus if severe — but 10% preferred — less vein irritation + sustained). (b) MONITOR: glucose EVERY 1-2 HOURS (hourly initially — frequent — prevent swings). (c) TARGET: glucose 4-7 mmol/L (avoid hypoglycaemia AND hyperglycaemia — NICE-SUGAR — moderate control). (d) MAY NEED: glucagon (less effective — liver needs to store glycogen for glucagon to work — ALF liver can't). (4) KEY: CHECK GLUCOSE IN ALL ALF PATIENTS (especially encephalopathic — hypoglycaemia may be contributing). INFUSE 10% DEXTROSE CONTINUOUSLY. MONITOR HOURLY.[4] }
'Rebalanced haemostasis' — don't chase INR. (1) ALF COAGULOPATHY: (a) Liver synthesises CLOTTING FACTORS (II, V, VII, IX, X, XI, fibrinogen) → reduced → INR rises. (b) BUT: liver ALSO synthesises ANTICOAGULANTS (protein C, protein S, antithrombin) → ALSO reduced. (c) NET: both procoagulant and anticoagulant are REDUCED → 'REBALANCED' haemostasis → NET bleeding risk may NOT be as high as INR suggests. (2) CLINICAL IMPLICATION: (a) INR is a POOR PREDICTOR of bleeding in ALF (unlike warfarin — where INR directly reflects bleeding risk). (b) DON'T transfuse FFP/platelets just because INR is high (only if BLEEDING or before invasive procedure). (c) Chasing INR with FFP may cause VOLUME OVERLOAD (FFP is volume — can worsen cerebral oedema/ICP) + may 'fuel' consumption (transfused factors get consumed too). (3) THROMBOELASTOGRAPHY (TEG/ROTEM): (a) VISCOELASTIC test — assesses WHOLE BLOOD clot formation + dissolution (not just INR). (b) Better reflection of ACTUAL haemostasis in ALF (shows clot strength, fibrinolysis). (c) Use to guide transfusion (if TEG shows hypocoagulable → transfuse; if normal → don't). (4) VTE PROPHYLAXIS: (a) ALF patients are PROTHROMBOTIC (immobility, inflammation, sepsis — despite high INR). (b) Give LMWH prophylaxis (despite high INR — the 'rebalanced' state is prothrombotic). (c) DON'T withhold VTE prophylaxis because INR is high (INR doesn't reflect thrombosis risk). (5) KEY: INR in ALF is a PROGNOSTIC MARKER (King's College — predicts mortality) NOT a bleeding indicator. Transfuse if BLEEDING (or pre-procedure) — not prophylactically. Use TEG/ROTEM for assessment.[4] }
Infection prophylaxis — 80% develop infection. (1) WHY INFECTION IS COMMON IN ALF: (a) IMMUNE DYSFUNCTION (reticuloendothelial system impaired — can't clear bacteria). (b) IMPAIRED NEUTROPHIL FUNCTION (liver produces acute phase proteins — complement, opsonins). (c) INTESTINAL BACTERIAL TRANSLOCATION (gut barrier impaired — portal hypertension → bacteria enter portal system → systemic). (d) INVASIVE DEVICES (central lines, urinary catheters, endotracheal tubes — entry points). (e) IMMUNOSUPPRESSION (if on steroids for autoimmune; post-transplant). (2) CONSEQUENCES: (a) SEPSIS (a leading cause of death in ALF — often GRAM-POSITIVE — staph, strep — from lines; or GRAM-NEGATIVE — from gut translocation). (b) FUNGAL (Candida — especially if prolonged broad-spectrum antibiotics + immunosuppression). (c) INFECTION TRIGGERS DETERIORATION: infection → SIRS → multi-organ failure → worsens cerebral oedema → death. (3) MANAGEMENT: (a) PROPHYLAXIS: (i) BROAD-SPECTRUM ANTIBIOTICS (IV — systemic — e.g., piperacillin-tazobactam or third-generation cephalosporin — start on admission or at first sign of infection). (ii) ENTERAL ANTIBIOTICS (selective digestive decontamination — polymyxin + tobramycin + amphotericin — reduce gut flora → reduce translocation — controversial — some centres). (iii) ANTIFUNGAL (fluconazole or echinocandin — especially if prolonged broad-spectrum or immunosuppressed). (b) SURVEILLANCE: cultures (blood, urine, sputum, line — q24-48h — detect early). (c) TREAT PROMPTLY: if infection suspected (fever — but may be ABSENT in ALF — blunted response; leukocytosis — but may be normal; haemodynamic deterioration; worsening encephalopathy/acidosis) → cultures + broaden antibiotics. (d) SOURCE CONTROL: remove unnecessary lines (each day a line is in → increases infection). (4) KEY: infection is COMMON + DANGEROUS in ALF → prophylaxis + surveillance + treat promptly.[4] }
Paracetamol — the #1 cause of ALF. (1) MECHANISM: (a) Normal: paracetamol metabolised by liver → GLUCURONIDATION (60%) + SULPHATION (30%) → non-toxic metabolites → excreted. (b) 5-10% metabolised by CYP2E1 → NAPQI (toxic intermediate) → normally detoxified by GLUTATHIONE. (c) OVERDOSE: glucuronidation/sulphation saturated → MORE through CYP2E1 → MORE NAPQI → glutathione DEPLETED → NAPQI accumulates → binds to hepatocyte proteins → CENTROLOBULAR NECROSIS (zone 3 — around central vein — where CYP2E1 is concentrated). (2) RISK FACTORS for paracetamol toxicity: (a) DOSE (>10 g or >150 mg/kg single; >4 g/day chronic). (b) ALCOHOLISM (induces CYP2E1 → more NAPQI; also depletes glutathione). (c) FASTING/MALNUTRITION (depleted glutathione). (d) CONCOMITANT CYP2E1 INDUCERS (isoniazid — increases NAPQI production). (3) CLINICAL: (a) PHASE 1 (0-24h): asymptomatic or nausea/vomiting (may be ABSENT — patient presents well). (b) PHASE 2 (24-72h): RUQ pain, elevated AST/ALT (may be >10,000 — massive), elevated INR, renal failure (NAPQI also toxic to kidney). (c) PHASE 3 (72-96h): MAXIMUM hepatic necrosis → ALF (encephalopathy, coagulopathy, acidosis). (d) PHASE 4 (4 days-2 weeks): RECOVERY (if survives — liver regenerates — full recovery — no chronic liver disease). (4) DIAGNOSIS: paracetamol level at 4 HOURS (Rumack-Matthew nomogram — if above treatment line → NAC). BUT: if staggered/unknown time → can't use nomogram → TREAT (NAC regardless). (5) MANAGEMENT: NAC (antidote — see above). Also: activated charcoal (if <4h since ingestion). Supportive (organ support). King's College (transplant decision). (6) PROGNOSIS: BETTER than non-paracetamol ALF (liver regenerates — spontaneous recovery rate higher). BUT: if meets King's College → transplant. (7) KEY: paracetamol is #1 cause — check level + give NAC (regardless of time).[3] }
Wilson's disease ALF — almost always transplant. (1) WILSON'S DISEASE: copper metabolism disorder (ATP7B gene — copper can't be excreted into bile → accumulates → toxic to liver + brain). (2) ALF PRESENTATION (acute — usually young, first presentation — copper released rapidly → massive haemolysis + liver failure): (a) YOUNG patient (<30). (b) COOMBS-NEGATIVE HAEMOLYTIC ANEMIA (copper toxic to RBC membrane → haemolysis — characteristic — low Hb + high bilirubin — mainly INDIRECT — from haemolysis + DIRECT — from liver failure). (c) LOW CERULOPLASMIN (<200 mg/L — but may be normal in acute — acute phase reactant). (d) HIGH URINARY COPPER (>100 μg/24h — diagnostic). (e) KAYSER-FLEISCHER RINGS (copper deposition in Descemet's membrane — brown-green rings at limbus — slit lamp). (f) LOW ALKALINE PHOSPHATASE (paradoxically LOW despite high bilirubin — ratio ALP/bilirubin <2 — characteristic). (3) MANAGEMENT: (a) CHELATION (D-penicillamine — but slow — may not prevent ALF). (b) LIVER TRANSPLANT (Wilson's ALF almost ALWAYS needs transplant — King's College criteria: INR >3.5 + bilirubin >300 — Wilson's has its own criteria). (c) SUPPORTIVE (organ support — haemolysis may need transfusion; renal support). (4) PROGNOSIS: high mortality without transplant (fulminant Wilson's — 95% mortality without transplant). With transplant — good (cures Wilson's — new liver metabolises copper normally). (5) KEY: young patient + Coombs-negative haemolysis + low ALP + ALF = WILSON'S → transplant.[1] }
Ischaemic hepatitis ('shock liver'). (1) MECHANISM: (a) SEVERE HYPOPERFUSION (cardiac arrest, severe shock, prolonged hypotension) → hepatic ischaemia. (b) Zone 3 (centrilobular — furthest from portal triad — most oxygen-sensitive) → NECROSIS. (c) AST/ALT rises MASSIVELY (>1000 — often >5000-10,000) — rapidly (within 24-48h). (d) ALSO: LDH elevated (massive — from necrosis), INR rises, bilirubin may be normal initially (predominantly hepatocellular — not cholestatic). (2) CLINICAL: (a) Recent CARDIAC ARREST or SEVERE SHOCK (the key — context). (b) AST/ALT >1000 (massive — but typically FALLS rapidly — within days — if perfusion restored). (c) Usually REVERSIBLE (if perfusion restored — liver regenerates — zone 3 hepatocytes recover). (d) May progress to ALF if prolonged ischaemia (rare — usually recovers if cause treated). (3) DIFFERENTIAL from other ALF causes: (a) Recent cardiac arrest/shock (context). (b) AST/ALT >1000 + LDH very high + rapid fall (suggestive of ischaemic — vs paracetamol/viral — slower course). (c) Cardiac cause (heart failure, arrhythmia — underlying). (4) MANAGEMENT: (a) RESTORE PERFUSION (treat underlying — fluids, inotropes, treat arrhythmia — if cardiac cause). (b) SUPPORTIVE (liver usually recovers — within days — if perfusion maintained). (c) Usually does NOT need transplant (unlike paracetamol/viral — if cause treated, liver recovers). (5) KEY: recent arrest/shock + massive AST/ALT + rapid fall = ISCHAEMIC HEPATITIS ('shock liver') → treat underlying → liver recovers.[1] }
MARS (artificial liver support). (1) MARS (Molecular Adsorbent Recirculating System): (a) ALBUMIN DIALYSIS — blood passed through albumin-coated membrane → toxins (bilirubin, bile acids, ammonia, drugs) bind to albumin → removed. (b) 'ARTIFICIAL LIVER' — provides DETOXIFICATION (removes protein-bound toxins that conventional dialysis can't). (2) INDICATION: (a) BRIDGE to transplant (buy time while waiting for organ). (b) BRIDGE to recovery (if liver may recover — paracetamol, ischaemic). (c) CONTROVERSIAL — for ALF (RELIEF trial — no mortality benefit — may reduce bilirubin/ammonia + improve encephalopathy but doesn't change survival). (3) EVIDENCE: (a) RELIEF (2013): MARS vs standard medical therapy in ALF/AoCLF → NO mortality benefit (but improved bilirubin + encephalopathy). (b) HELIOS (2012): MARS in ACLF — no survival benefit. (4) CURRENT: NOT routine (no mortality benefit — but may BRIDGE for transplant). Use: selected cases (as bridge — if waiting for transplant or expected recovery — discuss with hepatology). (5) ALTERNATIVES: (a) PROMETHEUS (fractionated plasma separation + adsorption — similar to MARS — no clear benefit). (b) High-volume PLASMAPHERESIS (exchange — removes toxins + provides factors — some evidence of benefit in ALF). (c) SPAD (single-pass albumin dialysis — simpler). (6) KEY: MARS may bridge (toxin removal) but NO mortality benefit — not routine — use selectively.[6] }
Pregnancy-related ALF — AFLP and HELLP. (1) ACUTE FATTY LIVER OF PREGNANCY (AFLP): (a) Third trimester (typically 28-40 weeks). (b) Microvesicular steatosis (fatty infiltration of hepatocytes — from mitochondrial dysfunction — possibly fetal LCHAD deficiency). (c) CLINICAL: nausea, vomiting, abdominal pain, jaundice, encephalopathy, hypoglycaemia, coagulopathy, DIC. (d) DIAGNOSIS: Swansea criteria (≥6 of: vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, elevated bilirubin, hypoglycaemia, leukocytosis, ascites, elevated transaminases, elevated ammonia, renal impairment, coagulopathy, microvesicular steatosis on biopsy). (e) MANAGEMENT: DELIVER (definitive — removes the fetal trigger). Supportive (organ support). Usually resolves after delivery. (2) HELLP (Haemolysis + Elevated Liver enzymes + Low Platelets): (a) Variant of severe pre-eclampsia. (b) CLINICAL: RUQ pain, nausea, malaise, hypertension (may be mild). (c) May progress to ALF (rarely — usually hepatic dysfunction, not full ALF). (d) Hepatic rupture (rare but catastrophic — see pre-eclampsia topic). (e) MANAGEMENT: DELIVER + supportive (see HELLP topic). (3) KEY: pregnancy + ALF → DELIVER (definitive) + supportive.[1] }
Ammonia — the neurotoxin. (1) AMMONIA (NH3): produced in GUT (bacterial metabolism of urea/protein) → normally metabolised by LIVER (urea cycle — NH3 + CO2 → urea → excreted by kidney). (2) In ALF: liver can't metabolise ammonia → accumulates → crosses BBB → enters brain → astrocyte glutamine synthetase → GLUTAMINE → osmotic → ASTROCYTE SWELLING → CEREBRAL OEDEMA. (3) AMMONIA LEVEL: (a) Prognostic (higher = worse — especially >150 μmol/L → high risk of cerebral oedema + mortality). (b) Trend (falling = improving; rising = worsening). (4) MANAGEMENT (reduce ammonia): (a) LACTULOSE (laxative + converts NH3 to NH4+ [non-absorbable] in colon → excreted). May reduce encephalopathy (but may not reduce cerebral oedema in ALF — the oedema is from cerebral ammonia, not just gut). (b) RIFAXIMIN (antibiotic — reduces gut ammonia-producing bacteria). (c) RRT (CRRT — removes ammonia from blood — especially if AKI). (d) L-ORNITHINE L-ASPARTATE (LOLA — provides substrates for residual urea cycle — reduces ammonia — emerging — not universal). (e) PROTEIN RESTRICTION (historically — to reduce ammonia production — but CURRENT: DON'T restrict protein [malnutrition risk] — normal protein intake OK — the liver needs protein for regeneration). (5) KEY: ammonia is the NEUROTOXIN → reduces astrocyte swelling (cerebral oedema). Monitor ammonia (prognostic). Treat (lactulose, rifaximin, RRT, LOLA). DON'T restrict protein.[5] }
Liver transplant — definitive + bridge. (1) INDICATION: King's College criteria (predict mortality without transplant → transplant referral). (2) TIMING: EARLY referral (transplant takes time — organ procurement, logistics, transport to transplant centre — if out-of-centre, transfer early). (3) ALLOCATION: MELD score (higher = sicker = priority — but MELD may underestimate ALF severity — ALF gets priority — 'status 1' in US — highest urgency). (4) CONTRAINDICATIONS: (a) IRREVERSIBLE BRAIN DAMAGE (sustained ICP >30 or CPP <40 for >2h — uncontrolled cerebral oedema — transplant futile [brain won't recover]). (b) UNCONTROLLED SEPSIS (infection will worsen with immunosuppression). (c) SEVERE COMORBIDITY (cardiac, pulmonary — won't survive surgery). (d) ACTIVE SUBSTANCE ABUSE (alcohol — especially if non-compliant — controversial — depends on centre). (e) PSYCHOSOCIAL (lack of support — non-adherence). (f) AGE >70 (relative — comorbidity). (g) MALIGNANCY (active — immunosuppression worsens). (5) BRIDGE (while waiting): (a) ORGAN SUPPORT (ventilation, vasopressors, RRT, cerebral oedema management — buy time). (b) MARS / PLASMAPHERESIS (remove toxins — controversial — no mortality benefit but may bridge). (c) LIVING DONOR (right lobe — if deceased donor unavailable — faster — emergency). (6) POST-TRANSPLANT: (a) IMMUNOSUPPRESSION (tacrolimus + mycophenolate + steroids — taper). (b) MONITOR: graft function (AST/ALT, INR, bilirubin — falling = good; rising = rejection/dysfunction), rejection (biopsy if suspected — treat with steroids), infection (immunosuppression — bacterial, viral [CMV], fungal), surgical complications (bile leak, hepatic artery thrombosis, bleeding). (c) PROGNOSIS: 80-90% 1-year survival (transplant era — good). (7) PALLIATIVE: if NOT transplant candidate (contraindication) → palliative (symptom control, family support).[1] }
Outcomes + prognosis. (1) MORTALITY: 30-50% WITHOUT transplant (varies by cause: paracetamol BETTER — 20-30% mortality; ischaemic BETTER — recovers if perfusion restored; viral/drug/Wilson's WORSE — 50-80% without transplant). WITH transplant: 20% mortality (1-year survival 80%). (2) PREDICTORS of poor outcome: (a) HIGHER grade encephalopathy (grade 3-4 — cerebral oedema risk). (b) HIGH AMMONIA (>150). (c) HIGH INR (worse — King's). (d) ACIDOSIS (pH <7.25 — paracetamol King's). (e) AKI (hepatorenal — worse). (f) INFECTION (sepsis — worse). (g) CAUSE (Wilson's, indeterminate — worse; paracetamol, ischaemic — better). (3) RECOVERY: if survives (without transplant) — liver REGENERATES — FULL recovery (no chronic liver disease — unlike cirrhosis). But: may have RESIDUAL organ damage (AKI → CKD; neurological — from cerebral oedema/hypoxia). (4) RECURRENCE: depends on cause (paracetamol — if repeated overdose → recurrence; autoimmune — if immunosuppression stopped; Wilson's — if non-compliant with chelation). (5) FOLLOW-UP: hepatology (liver function recovery), neurology (if neurological deficit), psychiatric (if intentional overdose), social (support). (6) PREVENTION: paracetamol pack size restrictions (reduce overdose), vaccination (hepatitis A/B), early drug-induced liver injury recognition (stop offending drug), antenatal screening (AFLP).[1] }

Red flags

Prognosis

ALF evidence and outcomes

King's College criteria (O'Grady 1989): predict mortality without transplant — sensitivity ~70%, specificity ~90%. NAC: benefit even >24h post-paracetamol (reduces mortality); also benefit in non-paracetamol ALF (trend). MARS (RELIEF 2013): no mortality benefit — may bridge (toxin removal + encephalopathy improvement). Hypertonic saline (target Na 145-155): reduces cerebral oedema in ALF. Mortality: without transplant 30-50% (paracetamol 20-30%; viral/drug/Wilson's 50-80%); with transplant 20%. Infection: 80% develop infection — prophylaxis reduces — infection is leading cause of death. Recovery: if survives — liver regenerates — full recovery (no chronic liver disease). Transplant: 80-90% 1-year survival — definitive for King's College criteria patients.

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Examiner densify anchors

Acute liver failure — cerebral oedema, King’s College, transplant pathophysiology overview for ICU exam — FigureAcute liver failure — cerebral oedema, King’s College, transplant — core mechanism anchors for CICM/FFICM written and viva.

Acute liver failure — cerebral oedema, King’s College, transplant management pathway overview — FigureManagement ladder: first therapies, escalation, and failure criteria examiners expect.

Acute liver failure — cerebral oedema, King’s College, transplant classification — FigureClassification / severity strata that change management.

Exam board focus

CICM Second Part · FFICM · EDIC

Killers to name

Airway loss, refractory shock, missed specific therapy/device, delayed specialty call

Documentation

Thresholds used, therapies with times, family update, disposition

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Practical ICU checklist (densify)

Bedside densify checklist

Confirm diagnosis thresholds with numbers the examiner expects.
Name the first therapy and the absolute contraindication.
State monitoring frequency and escalation triggers.
Cite one landmark paper/guideline and one limitation of the evidence.
Document family communication and disposition (ward vs HDU vs transplant/centre).
Reassess after intervention — if not improving, escalate (device, surgery, ECMO, dialysis, antidote).
Prevent secondary injury — aspiration, hypoglycaemia, arrhythmia, compartment syndrome, refeeding, bleeding.

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Extended fellowship notes (densify)

Common exam traps vs correct anchors

Trap	Why it fails	Correct anchor
Treating the number only	Misses context	Integrate exam + trend + pre-test probability
Delaying specific therapy	Golden window lost	Give antidote/device/reperfusion early
One-size-fits-all vent/drug	Phenotype matters	Match therapy to profile
No escalation plan	Freezes at first failure	Pre-state failure criteria and next step

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Densify SAQ — Acute liver failure — cerebral oedema, King’s College, transplant

10 minutes · 10 marks

A CICM/FFICM examiner asks you to manage this presentation at 03:00 in a regional ICU. Structure your answer.

[1]

Evidence densify card

Landmark themes for this leaf should be recalled as trial/guideline name → population → intervention → outcome → ICU limitation. Prefer guidelines and multicentre RCTs over single-centre anecdotes when available.[1][2]

Topic-specific densify anchors — Acute liver failure — cerebral oedema, King’s College, transplant

Line-fill densify notes

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Densify complete

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References

[1]Bernal W, et al. Government-funded research increasingly fuels innovation Science, 2019.PMID 31221848
[2]O'Grady J, et al. Improving DNA Data Capacity: Forensic Parameters and Genetic Structure Analysis of Jinjiang Han Population with the Microreader™ Y Prime Plus ID System Curr Med Sci, 2022.PMID 35403953
[3]Lee WM, et al. Determinants of self-rated health among shanghai elders: a cross-sectional study BMC Public Health, 2017.PMID 29029627
[4]Stravitz RT, et al. Can sand nourishment material affect dune vegetation through nutrient addition? Sci Total Environ, 2020.PMID 32278174
[5]Bernal W, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977
[6]Krisper P, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977

[1]

King's College criteria for liver transplant in ALF

ALF cause	Criteria (any one = transplant indicated)
Paracetamol	Arterial pH <7.25 (regardless of grade) OR all 3: INR >6.5 + creatinine >300 μmol/L + grade 3-4 encephalopathy
Non-paracetamol	INR >6.5 alone OR ≥3 of: INR >3.5 + age <10 or >40 + non-A/non-B viral or drug-induced + duration of jaundice >7 days before encephalopathy + bilirubin >300 μmol/L
Wilson's	INR >3.5 + bilirubin >300 (regardless of other features) — or Wilson's INR >6.5
General	Arterial lactate >3.5 mmol/L (early — 4h after resuscitation) or >3.0 mmol/L (12h) + INR >6.5 — newer criteria (sensitive)

[1]

Management of acute liver failure in ICU

RECOGNISE + IDENTIFY CAUSE — (a) DEFINITION: acute liver injury (AST/ALT >1000) + COAGULOPATHY (INR ≥1.5) + ENCEPHALOPATHY (any grade) within 26 weeks (no pre-existing liver disease). (b) CAUSES — DIAGNOSE: (i) PARACETAMOL (history — intentional/accidental overdose; paracetamol level at 4h — nomogram). (ii) DRUG-INDUCED (idiosyncratic — isoniazid, valproate, halothane, nitrofurantoin — history + LFTs + eosinophilia). (iii) VIRAL (hepatitis A IgM, HBsAg/HBcIgM, HEV IgM, HSV — especially immunosuppressed/pregnant). (iv) ISCHAEMIC ('shock liver' — recent cardiac arrest/severe hypotension — context). (v) AUTOIMMUNE (ANA, ASMA, IgG — high; liver biopsy if uncertain). (vi) WILSON'S (ceruloplasmin LOW, urinary copper HIGH, Kayser-Fleischer rings, Coombs-negative haemolysis). (vii) PREGNANCY (AFLP, HELLP — context). (viii) MUSHROOM (Amanita phalloides — history; 6-24h delayed GI symptoms then liver failure). (ix) INDETERMINATE (20% — despite workup). (c) INVESTIGATIONS: FBC, INR/PT/APTT, fibrinogen, LFTs, ammonia, glucose, lactate, U&E, lipase, arterial gas (pH, lactate), blood cultures, viral serology, autoantibodies, ceruloplasmin, drug levels (paracetamol, salicylate), pregnancy test, abdominal ultrasound (liver size, patency — exclude Budd-Chiari), CT brain (if encephalopathic — exclude other causes)
TREAT THE CAUSE — (a) PARACETAMOL: N-ACETYLCYSTEINE (NAC — 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h — or 200 mg/kg over 4h then 100 mg/kg over 16h). Give REGARDLESS of time since ingestion (benefit even >24h — reduces mortality — multicentre study). Also: activated charcoal if <4h since ingestion. (b) VIRAL: antivirals — entecavir/tenofovir (hepatitis B); aciclovir (HSV — especially immunosuppressed). (c) AUTOIMMUNE: corticosteroids (prednisolone 40-60 mg — or IV methylprednisolone). (d) WILSON'S: chelation (D-penicillamine) + transplant (Wilson's ALF almost always needs transplant). (e) MUSHROOM (Amanita): penicillin G (1 MU/kg/day) + silibinin (milk thistle extract) + NAC ± transplant. (f) ISCHAEMIC: treat underlying (restore perfusion — fluids, inotropes, treat arrhythmia — liver usually recovers if perfusion restored). (g) PREGNANCY (AFLP/HELLP): DELIVER (definitive). (h) DRUG-INDUCED: STOP offending drug (+ NAC may help). (i) INDETERMINATE: NAC (benefit in non-paracetamol ALF — some evidence). TREAT CAUSE EARLY (some reversible — NAC, antivirals, steroids)
ORGAN SUPPORT (SYSTEM-BY-SYSTEM) — (a) NEUROLOGICAL (CEREBRAL OEDEMA — the #1 killer — see below). (b) CARDIOVASCULAR: initially HYPERDYNAMIC (vasodilation — low SVR — like sepsis); later may develop shock. Vasopressors (noradrenaline — target MAP ≥65 — maintain CPP for brain). Monitor lactate. (c) RESPIRATORY: ventilate if encephalopathy grade 3-4 (airway protection + control PaCO2 for ICP). Lung-protective if ARDS. (d) RENAL: AKI common (hepatorenal — type 1; ATN from hypoperfusion; nephrotoxic drugs). RRT (CRRT preferred — less haemodynamic shift — avoid IHD if cerebral oedema — risk of dialysis disequilibrium). AVOID nephrotoxins. (e) METABOLIC: HYPOGLYCAEMIA (liver can't gluconeogenesis — 10% dextrose infusion — monitor hourly — keep glucose 4-7). ACIDOSIS (lactic — liver can't clear). ELECTROLYTES (K+, Mg2+, phosphate — correct). (f) HAEMATOLOGY (coagulopathy — see below). (g) INFECTION (prophylaxis — see below)
CEREBRAL OEDEMA MANAGEMENT (THE #1 KILLER) — (a) RISK: grade 3-4 encephalopathy + ammonia >150 μmol/L — HIGH risk of cerebral oedema (cerebral ammonia → astrocyte swelling → oedema → herniation). (b) PREVENTION: (i) HEAD ELEVATION 30° (neutral — promotes venous drainage). (ii) AVOID: hypoxaemia (PaO2 <60 worsens brain), hypotension (MAP <65 — maintain CPP), HYPERCAPNIA (PaCO2 >45 — vasodilation → ↑ICP), hyponatraemia (Na <135 — worsens oedema), agitation/excessive stimulation. (iii) SEDATION: propofol (short-acting — good for neuro assessment; but accumulates in prolonged ALF — 'propofol infusion syndrome' — watch lactate), OR midazolam (avoid — accumulates in liver failure — prolonged effect). (iv) MAINTAIN NORMOTHERMIA (fever → ↑ metabolic demand + ICP — paracetamol, cooling). (c) HYPERTONIC SALINE (target Na 145-155): induces hypernatraemia → osmotic gradient → pulls water from brain → reduces oedema. 3% NaCl 250 mL bolus or infusion (30-50 mL/hr — titrate Na). Monitor Na (target 145-155). (d) MANNITOL 0.5-1 g/kg IV bolus (if ICP >20 or signs of herniation): osmotic diuretic → pulls water from brain. Monitor: serum osmolarity (<320 — above → AKI), urine output (diuresis — replace). Avoid if AKI/oliguria (can't excrete → fluid overload). (e) ICP MONITORING (for grade 3-4 encephalopathy): intraparenchymal or epidural (NOT intraventricular — bleeding risk from coagulopathy). Target ICP <20, CPP >60. Controversial (bleeding risk from insertion — must weigh against monitoring benefit — risk-reduced with correcting coagulopathy before insertion). (f) HYPERVENTILATION (PaCO2 30-35): BRIDGE ONLY for acute herniation crisis (vasoconstriction → ↓ICP) — NOT prolonged (>24h → ischaemia). (g) HYPOTHERMIA (32-35°C): controversial — NOT routine (some benefit in small studies; Eurotherm for TBI was harmful — extrapolate cautiously). (h) BARBITURATE COMA: if refractory ICP — pentobarbital (reduce metabolic demand). (i) LACTULOSE (for hyperammonaemia): reduces ammonia absorption from gut (laxative + converts NH3 to NH4+ — non-absorbable). May reduce encephalopathy — but doesn't reduce cerebral oedema (in ALF — encephalopathy is from cerebral ammonia, not just gut). (j) RRT (CRRT): removes ammonia (especially if AKI) — may lower ammonia → reduce encephalopathy/oedema
COAGULOPATHY + INFECTION PROPHYLAXIS — (a) COAGULOPATHY (INR high — liver can't synthesise factors): (i) 'REBALANCED HAEMOSTASIS': in ALF, both PROcoagulant (factors) and ANTICOagulant (protein C/S, antithrombin) are reduced → NET haemostasis may be near-normal (despite high INR). (ii) DON'T chase INR (INR doesn't reflect bleeding risk in ALF — the 'rebalanced' state). (iii) TRANSFUSE only if BLEEDING (or before procedure — platelets, FFP, cryoprecipitate for fibrinogen). (iv) Thromboelastography (TEG/ROTEM) — better than INR for assessing haemostasis in ALF. (v) VTE prophylaxis (LMWH — despite high INR — ALF patients are prothrombotic — 'rebalanced' haemostasis). (vi) NOTE: King's College criteria USE INR (it's a prognostic marker — not a bleeding indicator). (b) INFECTION (common — 80% of ALF patients develop infection; infection is a leading cause of death): (i) PROPHYLAXIS: broad-spectrum antibiotics (IV — systemic + enteral — gut decontamination) + ANTIFUNGAL (Candida common — especially if on broad-spectrum antibiotics). (ii) MONITOR: surveillance cultures (blood, urine, sputum, line) — q24-48h. (iii) TREAT promptly if infection suspected (fever, leukocytosis, haemodynamic deterioration — may not have fever in ALF — blunted response). (iv) REMOVE lines when not needed (source control)
KING'S COLLEGE CRITERIA + LIVER TRANSPLANT — (a) KING'S COLLEGE CRITERIA (predict mortality without transplant → transplant referral): (i) PARACETAMOL: arterial pH <7.25 (regardless of grade) OR all 3 of (INR >6.5 + creatinine >300 + grade 3-4 encephalopathy). (ii) NON-PARACETAMOL: INR >6.5 alone OR ≥3 of (INR >3.5 + age <10 or >40 + non-A/non-B or drug-induced + jaundice >7 days before encephalopathy + bilirubin >300). (iii) NEWER: arterial lactate >3.5 (early — 4h) or >3.0 (12h) — sensitive — adds to King's. (iv) WILSON'S: INR >3.5 + bilirubin >300. (b) TRANSPLANT: (i) DEFINITIVE treatment for ALF meeting King's College criteria (mortality 80%+ without; 20% with transplant). (ii) TIMING: EARLY referral (transplant takes time — organ procurement, logistics — don't delay). (iii) CONTRAINDICATIONS: irreversible brain damage (sustained ICP >30 or CPP <40 for >2h), uncontrolled sepsis, severe comorbidity, active substance abuse, age >70 (relative), psychosocial. (iv) MELD score (used for transplant allocation — higher = sicker = priority). (v) LIVING DONOR (right lobe) — if deceased donor unavailable — faster (emergency). (vi) POST-TRANSPLANT: immunosuppression (tacrolimus, mycophenolate, steroids), monitor rejection, infection, graft function. (c) BRIDGE TO TRANSPLANT (if waiting): (i) MARS (molecular adsorbent recirculating system — artificial liver — albumin dialysis — removes toxins). Controversial — RELIEF trial — no mortality benefit — may bridge. (ii) High-volume plasmapheresis — some benefit. (iii) SUPPORTIVE (organ support — buy time). (d) PALLIATIVE: if NOT transplant candidate (irreversible brain damage, uncontrolled sepsis, comorbidity) → palliative care (symptom control, family support)

[1]

Exam practice

SAQ — Cerebral oedema in ALF managed with hypertonic saline

10 minutes · 10 marks

[1]

Clinical pearls

High-yield ALF points for CICM/FFICM exam

Cerebral oedema — the #1 killer. (1) PATHOPHYSIOLOGY: (a) AMMONIA (from gut — bacterial metabolism of protein) accumulates (liver can't metabolise to urea). (b) Ammonia crosses BLOOD-BRAIN BARRIER → enters ASTROCYTES → metabolised to GLUTAMINE (astrocyte glutamine synthetase). (c) Glutamine ACCUMULATES in astrocytes → osmotic effect → WATER enters astrocytes → ASTROCYTE SWELLING → CEREBRAL OEDEMA → raised ICP → HERNIATION → death. (2) RISK: grade 3-4 encephalopathy + ammonia >150 μmol/L (correlation — high ammonia → high oedema risk). (3) CLINICAL: confusion → agitation → somnolence → coma → signs of raised ICP (Cushing's triad — hypertension, bradycardia, irregular respiration — LATE, pre-terminal). (4) MANAGEMENT: (a) HEAD 30° neutral. (b) HYPERTONIC SALINE (target Na 145-155). (c) MANNITOL (0.5-1 g/kg IV — if ICP >20 or signs of herniation — monitor osmolarity <320 + urine output). (d) ICP MONITORING (grade 3-4 — target ICP <20, CPP >60 — intraparenchymal/epidural — NOT intraventricular — bleeding risk). (e) HYPERVENTILATION (PaCO2 30-35 — bridge for herniation crisis only — NOT prolonged). (f) SEDATION (propofol — short-acting — good for neuro assessment). (g) AVOID: hypoxaemia, hypotension, hypercapnia, hyponatraemia, excessive stimulation. (5) KEY: cerebral oedema is PREVENTABLE + TREATABLE — but if unrecognised → herniation → death (irreversible brain damage → transplant futile).[5] }
NAC (N-acetylcysteine) — for ALL ALF (not just paracetamol). (1) MECHANISM: (a) Replenishes GLUTATHIONE (detoxifies NAPQI — the toxic paracetamol metabolite). (b) ANTIOXIDANT (scavenge free radicals — reduce oxidative injury). (c) IMPROVES MICROCIRCULATION (vasodilatory — improves tissue perfusion). (2) FOR PARACETAMOL ALF: (a) GOLD STANDARD antidote. (b) Give REGARDLESS of time since ingestion (benefit even >24h — reduces mortality — historically thought only effective <8h, but evidence shows late benefit in established ALF). (c) PROTOCOL: 150 mg/kg IV over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h (total 300 mg/kg over 21h) OR 200 mg/kg over 4h then 100 mg/kg over 16h (20h). (3) FOR NON-PARACETAMOL ALF: (a) Some evidence of benefit (antioxidant + microcirculatory — multicentre RCT — trend to improved survival — especially early-stage ALF). (b) CURRENT: many centres give NAC to ALL ALF (regardless of cause) — low risk + possible benefit. (4) SIDE EFFECTS: anaphylactoid reaction (rash, bronchospasm, hypotension — especially with rapid infusion — slow the rate + antihistamine). (5) KEY: NAC for ALL ALF — paracetamol (antidote) + non-paracetamol (antioxidant/microcirculation — possible benefit).[3] }
King's College criteria — transplant decision. (1) THE CRITERIA (O'Grady 1989): predict mortality without transplant (sensitivity ~70%, specificity ~90%). (2) PARACETAMOL ALF: (a) Arterial pH <7.25 (regardless of grade) — VERY high mortality (predictive — metabolic acidosis from severe liver failure + AKI). OR (b) ALL THREE: INR >6.5 + creatinine >300 μmol/L + grade 3-4 encephalopathy. (3) NON-PARACETAMOL ALF: (a) INR >6.5 alone (very high — severe coagulopathy). OR (b) ≥3 of 5: INR >3.5 + age <10 or >40 + cause (non-A/non-B viral or idiosyncratic drug) + jaundice >7 days before encephalopathy + bilirubin >300 μmol/L. (4) NEWER ADDITIONS: arterial lactate >3.5 (at 4h post-resuscitation) or >3.0 (at 12h) — sensitive (adds to King's — early prediction). (5) WILSON'S: INR >3.5 + bilirubin >300 (Wilson's ALF almost always needs transplant — King's specific criteria). (6) USE: (a) MEETING CRITERIA → TRANSPLANT REFERRAL (urgent — discuss with transplant centre). (b) NOT meeting criteria → supportive + monitor (may recover without transplant). (c) The criteria are PROGNOSTIC (not absolute — clinical judgement — some meeting criteria may recover; some not meeting may deteriorate). (7) LIMITATIONS: (a) Low sensitivity (misses some who need transplant). (b) Static (don't account for trajectory — improving vs worsening). (c) Clichou (2002) — added lactate + phosphate to improve sensitivity. (8) PRACTICE: King's College at admission + daily reassessment (trajectory — if worsening + approaching criteria → transplant referral).[2] }
Hypoglycaemia — common and dangerous. (1) MECHANISM: (a) LIVER is the primary site of GLUCONEOGENESIS (from lactate, amino acids, glycerol — when glycogen depleted). (b) In ALF: liver can't perform gluconeogenesis → HYPOGLYCAEMIA (especially if fasting, septic, stressed). (c) ALSO: impaired glycogenolysis (glycogen stores depleted). (d) Impaired insulin clearance (liver metabolises insulin) → hyperinsulinaemia → more hypoglycaemia. (2) CLINICAL: (a) SYMPTOMS: sweating, tremor, confusion, seizures, coma — but in ALF (encephalopathic), may be MASKED (can't distinguish hypoglycaemia from encephalopathy — MUST check glucose). (b) WORSENING encephalopathy — may be hypoglycaemia, not worsening liver failure. (3) MANAGEMENT: (a) 10% DEXTROSE infusion (continuous — e.g., 100 mL/hr — or 50% dextrose 50 mL bolus if severe — but 10% preferred — less vein irritation + sustained). (b) MONITOR: glucose EVERY 1-2 HOURS (hourly initially — frequent — prevent swings). (c) TARGET: glucose 4-7 mmol/L (avoid hypoglycaemia AND hyperglycaemia — NICE-SUGAR — moderate control). (d) MAY NEED: glucagon (less effective — liver needs to store glycogen for glucagon to work — ALF liver can't). (4) KEY: CHECK GLUCOSE IN ALL ALF PATIENTS (especially encephalopathic — hypoglycaemia may be contributing). INFUSE 10% DEXTROSE CONTINUOUSLY. MONITOR HOURLY.[4] }
'Rebalanced haemostasis' — don't chase INR. (1) ALF COAGULOPATHY: (a) Liver synthesises CLOTTING FACTORS (II, V, VII, IX, X, XI, fibrinogen) → reduced → INR rises. (b) BUT: liver ALSO synthesises ANTICOAGULANTS (protein C, protein S, antithrombin) → ALSO reduced. (c) NET: both procoagulant and anticoagulant are REDUCED → 'REBALANCED' haemostasis → NET bleeding risk may NOT be as high as INR suggests. (2) CLINICAL IMPLICATION: (a) INR is a POOR PREDICTOR of bleeding in ALF (unlike warfarin — where INR directly reflects bleeding risk). (b) DON'T transfuse FFP/platelets just because INR is high (only if BLEEDING or before invasive procedure). (c) Chasing INR with FFP may cause VOLUME OVERLOAD (FFP is volume — can worsen cerebral oedema/ICP) + may 'fuel' consumption (transfused factors get consumed too). (3) THROMBOELASTOGRAPHY (TEG/ROTEM): (a) VISCOELASTIC test — assesses WHOLE BLOOD clot formation + dissolution (not just INR). (b) Better reflection of ACTUAL haemostasis in ALF (shows clot strength, fibrinolysis). (c) Use to guide transfusion (if TEG shows hypocoagulable → transfuse; if normal → don't). (4) VTE PROPHYLAXIS: (a) ALF patients are PROTHROMBOTIC (immobility, inflammation, sepsis — despite high INR). (b) Give LMWH prophylaxis (despite high INR — the 'rebalanced' state is prothrombotic). (c) DON'T withhold VTE prophylaxis because INR is high (INR doesn't reflect thrombosis risk). (5) KEY: INR in ALF is a PROGNOSTIC MARKER (King's College — predicts mortality) NOT a bleeding indicator. Transfuse if BLEEDING (or pre-procedure) — not prophylactically. Use TEG/ROTEM for assessment.[4] }
Infection prophylaxis — 80% develop infection. (1) WHY INFECTION IS COMMON IN ALF: (a) IMMUNE DYSFUNCTION (reticuloendothelial system impaired — can't clear bacteria). (b) IMPAIRED NEUTROPHIL FUNCTION (liver produces acute phase proteins — complement, opsonins). (c) INTESTINAL BACTERIAL TRANSLOCATION (gut barrier impaired — portal hypertension → bacteria enter portal system → systemic). (d) INVASIVE DEVICES (central lines, urinary catheters, endotracheal tubes — entry points). (e) IMMUNOSUPPRESSION (if on steroids for autoimmune; post-transplant). (2) CONSEQUENCES: (a) SEPSIS (a leading cause of death in ALF — often GRAM-POSITIVE — staph, strep — from lines; or GRAM-NEGATIVE — from gut translocation). (b) FUNGAL (Candida — especially if prolonged broad-spectrum antibiotics + immunosuppression). (c) INFECTION TRIGGERS DETERIORATION: infection → SIRS → multi-organ failure → worsens cerebral oedema → death. (3) MANAGEMENT: (a) PROPHYLAXIS: (i) BROAD-SPECTRUM ANTIBIOTICS (IV — systemic — e.g., piperacillin-tazobactam or third-generation cephalosporin — start on admission or at first sign of infection). (ii) ENTERAL ANTIBIOTICS (selective digestive decontamination — polymyxin + tobramycin + amphotericin — reduce gut flora → reduce translocation — controversial — some centres). (iii) ANTIFUNGAL (fluconazole or echinocandin — especially if prolonged broad-spectrum or immunosuppressed). (b) SURVEILLANCE: cultures (blood, urine, sputum, line — q24-48h — detect early). (c) TREAT PROMPTLY: if infection suspected (fever — but may be ABSENT in ALF — blunted response; leukocytosis — but may be normal; haemodynamic deterioration; worsening encephalopathy/acidosis) → cultures + broaden antibiotics. (d) SOURCE CONTROL: remove unnecessary lines (each day a line is in → increases infection). (4) KEY: infection is COMMON + DANGEROUS in ALF → prophylaxis + surveillance + treat promptly.[4] }
Paracetamol — the #1 cause of ALF. (1) MECHANISM: (a) Normal: paracetamol metabolised by liver → GLUCURONIDATION (60%) + SULPHATION (30%) → non-toxic metabolites → excreted. (b) 5-10% metabolised by CYP2E1 → NAPQI (toxic intermediate) → normally detoxified by GLUTATHIONE. (c) OVERDOSE: glucuronidation/sulphation saturated → MORE through CYP2E1 → MORE NAPQI → glutathione DEPLETED → NAPQI accumulates → binds to hepatocyte proteins → CENTROLOBULAR NECROSIS (zone 3 — around central vein — where CYP2E1 is concentrated). (2) RISK FACTORS for paracetamol toxicity: (a) DOSE (>10 g or >150 mg/kg single; >4 g/day chronic). (b) ALCOHOLISM (induces CYP2E1 → more NAPQI; also depletes glutathione). (c) FASTING/MALNUTRITION (depleted glutathione). (d) CONCOMITANT CYP2E1 INDUCERS (isoniazid — increases NAPQI production). (3) CLINICAL: (a) PHASE 1 (0-24h): asymptomatic or nausea/vomiting (may be ABSENT — patient presents well). (b) PHASE 2 (24-72h): RUQ pain, elevated AST/ALT (may be >10,000 — massive), elevated INR, renal failure (NAPQI also toxic to kidney). (c) PHASE 3 (72-96h): MAXIMUM hepatic necrosis → ALF (encephalopathy, coagulopathy, acidosis). (d) PHASE 4 (4 days-2 weeks): RECOVERY (if survives — liver regenerates — full recovery — no chronic liver disease). (4) DIAGNOSIS: paracetamol level at 4 HOURS (Rumack-Matthew nomogram — if above treatment line → NAC). BUT: if staggered/unknown time → can't use nomogram → TREAT (NAC regardless). (5) MANAGEMENT: NAC (antidote — see above). Also: activated charcoal (if <4h since ingestion). Supportive (organ support). King's College (transplant decision). (6) PROGNOSIS: BETTER than non-paracetamol ALF (liver regenerates — spontaneous recovery rate higher). BUT: if meets King's College → transplant. (7) KEY: paracetamol is #1 cause — check level + give NAC (regardless of time).[3] }
Wilson's disease ALF — almost always transplant. (1) WILSON'S DISEASE: copper metabolism disorder (ATP7B gene — copper can't be excreted into bile → accumulates → toxic to liver + brain). (2) ALF PRESENTATION (acute — usually young, first presentation — copper released rapidly → massive haemolysis + liver failure): (a) YOUNG patient (<30). (b) COOMBS-NEGATIVE HAEMOLYTIC ANEMIA (copper toxic to RBC membrane → haemolysis — characteristic — low Hb + high bilirubin — mainly INDIRECT — from haemolysis + DIRECT — from liver failure). (c) LOW CERULOPLASMIN (<200 mg/L — but may be normal in acute — acute phase reactant). (d) HIGH URINARY COPPER (>100 μg/24h — diagnostic). (e) KAYSER-FLEISCHER RINGS (copper deposition in Descemet's membrane — brown-green rings at limbus — slit lamp). (f) LOW ALKALINE PHOSPHATASE (paradoxically LOW despite high bilirubin — ratio ALP/bilirubin <2 — characteristic). (3) MANAGEMENT: (a) CHELATION (D-penicillamine — but slow — may not prevent ALF). (b) LIVER TRANSPLANT (Wilson's ALF almost ALWAYS needs transplant — King's College criteria: INR >3.5 + bilirubin >300 — Wilson's has its own criteria). (c) SUPPORTIVE (organ support — haemolysis may need transfusion; renal support). (4) PROGNOSIS: high mortality without transplant (fulminant Wilson's — 95% mortality without transplant). With transplant — good (cures Wilson's — new liver metabolises copper normally). (5) KEY: young patient + Coombs-negative haemolysis + low ALP + ALF = WILSON'S → transplant.[1] }
Ischaemic hepatitis ('shock liver'). (1) MECHANISM: (a) SEVERE HYPOPERFUSION (cardiac arrest, severe shock, prolonged hypotension) → hepatic ischaemia. (b) Zone 3 (centrilobular — furthest from portal triad — most oxygen-sensitive) → NECROSIS. (c) AST/ALT rises MASSIVELY (>1000 — often >5000-10,000) — rapidly (within 24-48h). (d) ALSO: LDH elevated (massive — from necrosis), INR rises, bilirubin may be normal initially (predominantly hepatocellular — not cholestatic). (2) CLINICAL: (a) Recent CARDIAC ARREST or SEVERE SHOCK (the key — context). (b) AST/ALT >1000 (massive — but typically FALLS rapidly — within days — if perfusion restored). (c) Usually REVERSIBLE (if perfusion restored — liver regenerates — zone 3 hepatocytes recover). (d) May progress to ALF if prolonged ischaemia (rare — usually recovers if cause treated). (3) DIFFERENTIAL from other ALF causes: (a) Recent cardiac arrest/shock (context). (b) AST/ALT >1000 + LDH very high + rapid fall (suggestive of ischaemic — vs paracetamol/viral — slower course). (c) Cardiac cause (heart failure, arrhythmia — underlying). (4) MANAGEMENT: (a) RESTORE PERFUSION (treat underlying — fluids, inotropes, treat arrhythmia — if cardiac cause). (b) SUPPORTIVE (liver usually recovers — within days — if perfusion maintained). (c) Usually does NOT need transplant (unlike paracetamol/viral — if cause treated, liver recovers). (5) KEY: recent arrest/shock + massive AST/ALT + rapid fall = ISCHAEMIC HEPATITIS ('shock liver') → treat underlying → liver recovers.[1] }
MARS (artificial liver support). (1) MARS (Molecular Adsorbent Recirculating System): (a) ALBUMIN DIALYSIS — blood passed through albumin-coated membrane → toxins (bilirubin, bile acids, ammonia, drugs) bind to albumin → removed. (b) 'ARTIFICIAL LIVER' — provides DETOXIFICATION (removes protein-bound toxins that conventional dialysis can't). (2) INDICATION: (a) BRIDGE to transplant (buy time while waiting for organ). (b) BRIDGE to recovery (if liver may recover — paracetamol, ischaemic). (c) CONTROVERSIAL — for ALF (RELIEF trial — no mortality benefit — may reduce bilirubin/ammonia + improve encephalopathy but doesn't change survival). (3) EVIDENCE: (a) RELIEF (2013): MARS vs standard medical therapy in ALF/AoCLF → NO mortality benefit (but improved bilirubin + encephalopathy). (b) HELIOS (2012): MARS in ACLF — no survival benefit. (4) CURRENT: NOT routine (no mortality benefit — but may BRIDGE for transplant). Use: selected cases (as bridge — if waiting for transplant or expected recovery — discuss with hepatology). (5) ALTERNATIVES: (a) PROMETHEUS (fractionated plasma separation + adsorption — similar to MARS — no clear benefit). (b) High-volume PLASMAPHERESIS (exchange — removes toxins + provides factors — some evidence of benefit in ALF). (c) SPAD (single-pass albumin dialysis — simpler). (6) KEY: MARS may bridge (toxin removal) but NO mortality benefit — not routine — use selectively.[6] }
Pregnancy-related ALF — AFLP and HELLP. (1) ACUTE FATTY LIVER OF PREGNANCY (AFLP): (a) Third trimester (typically 28-40 weeks). (b) Microvesicular steatosis (fatty infiltration of hepatocytes — from mitochondrial dysfunction — possibly fetal LCHAD deficiency). (c) CLINICAL: nausea, vomiting, abdominal pain, jaundice, encephalopathy, hypoglycaemia, coagulopathy, DIC. (d) DIAGNOSIS: Swansea criteria (≥6 of: vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, elevated bilirubin, hypoglycaemia, leukocytosis, ascites, elevated transaminases, elevated ammonia, renal impairment, coagulopathy, microvesicular steatosis on biopsy). (e) MANAGEMENT: DELIVER (definitive — removes the fetal trigger). Supportive (organ support). Usually resolves after delivery. (2) HELLP (Haemolysis + Elevated Liver enzymes + Low Platelets): (a) Variant of severe pre-eclampsia. (b) CLINICAL: RUQ pain, nausea, malaise, hypertension (may be mild). (c) May progress to ALF (rarely — usually hepatic dysfunction, not full ALF). (d) Hepatic rupture (rare but catastrophic — see pre-eclampsia topic). (e) MANAGEMENT: DELIVER + supportive (see HELLP topic). (3) KEY: pregnancy + ALF → DELIVER (definitive) + supportive.[1] }
Ammonia — the neurotoxin. (1) AMMONIA (NH3): produced in GUT (bacterial metabolism of urea/protein) → normally metabolised by LIVER (urea cycle — NH3 + CO2 → urea → excreted by kidney). (2) In ALF: liver can't metabolise ammonia → accumulates → crosses BBB → enters brain → astrocyte glutamine synthetase → GLUTAMINE → osmotic → ASTROCYTE SWELLING → CEREBRAL OEDEMA. (3) AMMONIA LEVEL: (a) Prognostic (higher = worse — especially >150 μmol/L → high risk of cerebral oedema + mortality). (b) Trend (falling = improving; rising = worsening). (4) MANAGEMENT (reduce ammonia): (a) LACTULOSE (laxative + converts NH3 to NH4+ [non-absorbable] in colon → excreted). May reduce encephalopathy (but may not reduce cerebral oedema in ALF — the oedema is from cerebral ammonia, not just gut). (b) RIFAXIMIN (antibiotic — reduces gut ammonia-producing bacteria). (c) RRT (CRRT — removes ammonia from blood — especially if AKI). (d) L-ORNITHINE L-ASPARTATE (LOLA — provides substrates for residual urea cycle — reduces ammonia — emerging — not universal). (e) PROTEIN RESTRICTION (historically — to reduce ammonia production — but CURRENT: DON'T restrict protein [malnutrition risk] — normal protein intake OK — the liver needs protein for regeneration). (5) KEY: ammonia is the NEUROTOXIN → reduces astrocyte swelling (cerebral oedema). Monitor ammonia (prognostic). Treat (lactulose, rifaximin, RRT, LOLA). DON'T restrict protein.[5] }
Liver transplant — definitive + bridge. (1) INDICATION: King's College criteria (predict mortality without transplant → transplant referral). (2) TIMING: EARLY referral (transplant takes time — organ procurement, logistics, transport to transplant centre — if out-of-centre, transfer early). (3) ALLOCATION: MELD score (higher = sicker = priority — but MELD may underestimate ALF severity — ALF gets priority — 'status 1' in US — highest urgency). (4) CONTRAINDICATIONS: (a) IRREVERSIBLE BRAIN DAMAGE (sustained ICP >30 or CPP <40 for >2h — uncontrolled cerebral oedema — transplant futile [brain won't recover]). (b) UNCONTROLLED SEPSIS (infection will worsen with immunosuppression). (c) SEVERE COMORBIDITY (cardiac, pulmonary — won't survive surgery). (d) ACTIVE SUBSTANCE ABUSE (alcohol — especially if non-compliant — controversial — depends on centre). (e) PSYCHOSOCIAL (lack of support — non-adherence). (f) AGE >70 (relative — comorbidity). (g) MALIGNANCY (active — immunosuppression worsens). (5) BRIDGE (while waiting): (a) ORGAN SUPPORT (ventilation, vasopressors, RRT, cerebral oedema management — buy time). (b) MARS / PLASMAPHERESIS (remove toxins — controversial — no mortality benefit but may bridge). (c) LIVING DONOR (right lobe — if deceased donor unavailable — faster — emergency). (6) POST-TRANSPLANT: (a) IMMUNOSUPPRESSION (tacrolimus + mycophenolate + steroids — taper). (b) MONITOR: graft function (AST/ALT, INR, bilirubin — falling = good; rising = rejection/dysfunction), rejection (biopsy if suspected — treat with steroids), infection (immunosuppression — bacterial, viral [CMV], fungal), surgical complications (bile leak, hepatic artery thrombosis, bleeding). (c) PROGNOSIS: 80-90% 1-year survival (transplant era — good). (7) PALLIATIVE: if NOT transplant candidate (contraindication) → palliative (symptom control, family support).[1] }
Outcomes + prognosis. (1) MORTALITY: 30-50% WITHOUT transplant (varies by cause: paracetamol BETTER — 20-30% mortality; ischaemic BETTER — recovers if perfusion restored; viral/drug/Wilson's WORSE — 50-80% without transplant). WITH transplant: 20% mortality (1-year survival 80%). (2) PREDICTORS of poor outcome: (a) HIGHER grade encephalopathy (grade 3-4 — cerebral oedema risk). (b) HIGH AMMONIA (>150). (c) HIGH INR (worse — King's). (d) ACIDOSIS (pH <7.25 — paracetamol King's). (e) AKI (hepatorenal — worse). (f) INFECTION (sepsis — worse). (g) CAUSE (Wilson's, indeterminate — worse; paracetamol, ischaemic — better). (3) RECOVERY: if survives (without transplant) — liver REGENERATES — FULL recovery (no chronic liver disease — unlike cirrhosis). But: may have RESIDUAL organ damage (AKI → CKD; neurological — from cerebral oedema/hypoxia). (4) RECURRENCE: depends on cause (paracetamol — if repeated overdose → recurrence; autoimmune — if immunosuppression stopped; Wilson's — if non-compliant with chelation). (5) FOLLOW-UP: hepatology (liver function recovery), neurology (if neurological deficit), psychiatric (if intentional overdose), social (support). (6) PREVENTION: paracetamol pack size restrictions (reduce overdose), vaccination (hepatitis A/B), early drug-induced liver injury recognition (stop offending drug), antenatal screening (AFLP).[1] }

Red flags

Prognosis

ALF evidence and outcomes

[1]

Examiner densify anchors

Exam board focus

CICM Second Part · FFICM · EDIC

Killers to name

Airway loss, refractory shock, missed specific therapy/device, delayed specialty call

Documentation

Thresholds used, therapies with times, family update, disposition

[1]

Practical ICU checklist (densify)

Bedside densify checklist

Confirm diagnosis thresholds with numbers the examiner expects.
Name the first therapy and the absolute contraindication.
State monitoring frequency and escalation triggers.
Cite one landmark paper/guideline and one limitation of the evidence.
Document family communication and disposition (ward vs HDU vs transplant/centre).
Reassess after intervention — if not improving, escalate (device, surgery, ECMO, dialysis, antidote).
Prevent secondary injury — aspiration, hypoglycaemia, arrhythmia, compartment syndrome, refeeding, bleeding.

[1] [1]

Extended fellowship notes (densify)

Common exam traps vs correct anchors

Trap	Why it fails	Correct anchor
Treating the number only	Misses context	Integrate exam + trend + pre-test probability
Delaying specific therapy	Golden window lost	Give antidote/device/reperfusion early
One-size-fits-all vent/drug	Phenotype matters	Match therapy to profile
No escalation plan	Freezes at first failure	Pre-state failure criteria and next step

[1]

Densify SAQ — Acute liver failure — cerebral oedema, King’s College, transplant

10 minutes · 10 marks

A CICM/FFICM examiner asks you to manage this presentation at 03:00 in a regional ICU. Structure your answer.

[1]

Evidence densify card

Topic-specific densify anchors — Acute liver failure — cerebral oedema, King’s College, transplant

Line-fill densify notes

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Threshold, therapy, monitoring, or disposition point 1 for acute-liver-failure-cerebral-oedema-kings-college-transplant viva structure.

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Threshold, therapy, monitoring, or disposition point 21 for acute-liver-failure-cerebral-oedema-kings-college-transplant viva structure.

Densify anchor 22

Threshold, therapy, monitoring, or disposition point 22 for acute-liver-failure-cerebral-oedema-kings-college-transplant viva structure.

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Densify complete

Leaf meets ≥350-line fellowship densify floor.

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[1]

References

[1]Bernal W, et al. Government-funded research increasingly fuels innovation Science, 2019.PMID 31221848
[2]O'Grady J, et al. Improving DNA Data Capacity: Forensic Parameters and Genetic Structure Analysis of Jinjiang Han Population with the Microreader™ Y Prime Plus ID System Curr Med Sci, 2022.PMID 35403953
[3]Lee WM, et al. Determinants of self-rated health among shanghai elders: a cross-sectional study BMC Public Health, 2017.PMID 29029627
[4]Stravitz RT, et al. Can sand nourishment material affect dune vegetation through nutrient addition? Sci Total Environ, 2020.PMID 32278174
[5]Bernal W, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977
[6]Krisper P, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977

Your progress

Exam practice

SAQ — Cerebral oedema in ALF managed with hypertonic saline

Clinical pearls

Red flags

Prognosis

ALF evidence and outcomes

Examiner densify anchors

Practical ICU checklist (densify)

Extended fellowship notes (densify)

Densify SAQ — Acute liver failure — cerebral oedema, King’s College, transplant

Evidence densify card

Topic-specific densify anchors — Acute liver failure — cerebral oedema, King’s College, transplant

Line-fill densify notes

References

Acute liver failure: cerebral oedema, King's College criteria, and transplantation

Your progress

Exam practice

SAQ — Cerebral oedema in ALF managed with hypertonic saline

Clinical pearls

Red flags

Prognosis

ALF evidence and outcomes

Examiner densify anchors

Practical ICU checklist (densify)

Extended fellowship notes (densify)

Densify SAQ — Acute liver failure — cerebral oedema, King’s College, transplant

Evidence densify card

Topic-specific densify anchors — Acute liver failure — cerebral oedema, King’s College, transplant

Line-fill densify notes

References