Acute Liver Failure — CritCare.in

📘 1 · Washington Manual of Critical Care, 4th Ed

Washington Manual Summary

"Acute liver failure is defined as the development of hepatic encephalopathy and coagulopathy in a patient without pre-existing liver disease. The most common cause in the United States is acetaminophen toxicity. Liver transplantation remains the definitive therapy, and early referral to a transplant center is critical."

Washington Manual of Critical Care, 4th Ed. Wolters Kluwer 2023. Chapter: Acute Liver Failure.

Clinical Synopsis

Definition: Abrupt hepatic dysfunction (without prior liver disease) + coagulopathy (INR ≥1.5) + hepatic encephalopathy — occurring within 26 weeks of first symptoms
Cause in India: Hepatitis E (most common in pregnant women), hepatitis B, drug-induced (anti-TB drugs, NSAIDs, herbal/ayurvedic medicines), ischaemic hepatitis
Hyperacute ALF: Encephalopathy within 7 days of jaundice (paracetamol, hepatitis A/E) — better prognosis. Subacute: 4–26 weeks — worst prognosis
Mortality without transplant: up to 80%; with transplant: 33% (Marino, p.658)
Key: Early referral to liver transplant centre as soon as Grade II encephalopathy develops

📗 2 · Marino's The ICU Book, 5th Edition (2025)

Marino Physiology — Ammonia, Cerebral Oedema & Inflammation

🔬 How acute liver failure reaches cerebral oedema

TriggerAcute liver injury — paracetamol · viral · ischaemic · drug → massive hepatocyte necrosis

Loss of hepatic synthetic, metabolic & clearance functions

Ammonia clearance (urea cycle) fails → arterial ammonia >150 μmol/Lcrosses BBB → astrocyte glutamine → osmotic cytotoxic oedema

↓ Clotting-factor synthesis + SIRScoagulopathy; vasodilatation, ↓ SVR (septic-like)

Raised ICP + multi-organ involvement (AKI, circulatory failure)

Pathological stateCerebral herniation and/or multi-organ failure

"The management of patients with liver failure is a particular challenge because of the numerous life-supporting functions that are lost when the liver fails. These include: (a) the production of about 20,000 proteins, including all the coagulation factors and transport proteins in blood, (b) the metabolism of innumerable endogenous and exogenous substances, and (c) the removal of microbes that breach the mucosal barrier in the GI tract."

Marino PL. The ICU Book, 5th Ed. Ch.39: Liver Failure. Wolters Kluwer; 2025. p.658

📗 Marino Ch.39, p.662 — Ammonia and Cerebral Oedema

Ammonia (byproduct of protein degradation, mainly in bowel) is normally cleared by the liver via the urea cycle. In ALF, this clearance fails → ammonia accumulates in blood → crosses the BBB → taken up by astrocytes → converted to glutamine.

Glutamine accumulation creates an osmotic force that draws water into astrocytes → "cytotoxic" cerebral oedema → raised ICP → herniation.

Clinical threshold: Arterial ammonia >150 μmol/L = high risk of cerebral oedema (Marino, p.663). Normal <60 μmol/L.

📗 Marino Ch.39, p.661 — Haemodynamics in ALF

The haemodynamic instability in ALF resembles septic shock: vasodilation + ↓ SVR + relative hypovolaemia (from hypoalbuminaemia). Management: volume resuscitation (albumin preferred when serum albumin <3 g/dL) + vasopressors (noradrenaline) as needed.

Important: Avoid Ringer's Lactate in ALF — Marino specifically notes it is not advised because it promotes hyponatraemia, which will exacerbate cerebral oedema in hepatic encephalopathy.

📗 Marino Ch.39, p.664 — CVVH Superior to Lactulose for Severe HE

"CVVH is considered superior to lactulose or rifaximin for patients with ALF and hepatic encephalopathy, and should be considered in the following situations: (a) persistent oliguria, (b) plasma ammonia level >150 μmol/L, and (c) evidence of cerebral oedema, regardless of the serum creatinine. CVVH should be started as soon as possible, as its effectiveness is time-dependent."

📋 3 · Guidelines & Evidence

Key Guidelines — ALF Management

NAC for Acetaminophen ALF

N-Acetylcysteine (NAC): IV regimen: 150 mg/kg in 200 ml D5W over 1h → 50 mg/kg over 4h → 100 mg/kg over 16h. Give within 8h for maximum benefit; still give up to 24h. NAC has also been used empirically in non-acetaminophen ALF (some evidence of benefit). Mechanism: replenishes glutathione (the principal intracellular antioxidant).

King's College Criteria — Transplant Referral

Paracetamol ALF: pH <7.30 after resuscitation — OR — ALL 3: INR >6.5 + Creatinine >300 μmol/L + Grade III–IV encephalopathy.
Non-paracetamol ALF: INR >6.5 alone — OR — ANY 3 of: Age <10 or >40, aetiology (non-A non-B, DILI, Wilson's), jaundice-to-encephalopathy >7 days, INR >3.5, Bilirubin >300 μmol/L.

Hepatic Encephalopathy Grading

Grade I: personality change, mood disturbance | Grade II: asterixis, lethargy, disoriented to time | Grade III: stuporous but responsive, disoriented to place | Grade IV: coma. Grade II: ICU admission. Grade III–IV: intubate for airway protection.

Coagulopathy in ALF — Do NOT Correct Prophylactically

ALF causes balanced deficiency of both pro- and anti-coagulant factors. INR overestimates bleeding risk. DO NOT give FFP or vitamin K to "correct" INR unless: active bleeding or invasive procedure planned. Use TEG/ROTEM to guide transfusion. Platelet transfusion only if <10,000 or invasive procedure.

💊 4 · Drug Doses

Drug Reference in ALF

Drug	Indication	Dose	Notes
N-Acetylcysteine	Acetaminophen ALF (and empirical in non-Paracetamol)	IV: 150 mg/kg/1h → 50 mg/kg/4h → 100 mg/kg/16h	Within 8h = maximum benefit; up to 24h still effective
Lactulose	Hepatic encephalopathy — reduce ammonia	30 ml TDS to QDS PO/NGT; titrate to 2–3 soft stools/day	Metabolised by colonic bacteria → ↓ pH → ↓ ammonia absorption
Rifaximin	Chronic HE prevention + adjunct to lactulose	550 mg BD PO/NGT	Non-absorbed antibiotic; reduces ammonia-producing bacteria
Mannitol 20%	Cerebral oedema/ICP spikes	0.5–1 g/kg IV over 15–20 min	Target osmolality <320 mOsm/kg; check UO — need adequate diuresis
Hypertonic Saline 3%	Target hypernatraemia to prevent cerebral oedema	Infuse to maintain Na 145–150 mEq/L	↑ Plasma osmolality → opposes osmotic cerebral oedema
Noradrenaline	Haemodynamic instability (vasodilatory)	0.05–1 mcg/kg/min IV	Albumin 5% preferred resuscitation fluid if albumin <3 g/dL (Marino p.661)
Pantoprazole	Stress ulcer prophylaxis	40 mg IV OD	All ALF patients on ICU

🗺 5 · Clinical Flowchart

ALF Management Algorithm

Recognition & Early Referral

ALF = hepatic encephalopathy + coagulopathy (INR ≥1.5) without prior liver disease. ICU admission for Grade II or higher. Refer to transplant centre EARLY — as soon as Grade II encephalopathy. Do not wait for King's College criteria.

Specific Antidote (if paracetamol)

N-Acetylcysteine IV within 8h ideally; still give up to 24h. For non-paracetamol: consider empirical NAC. Check drug history carefully — anti-TB drugs, herbal medicines, NSAIDs common in India.

Haemodynamics

Target MAP ≥65 mmHg. Volume: albumin 5% if albumin <3 g/dL (Marino); avoid Ringer's Lactate (worsens hyponatraemia → worsens cerebral oedema). Vasopressors: noradrenaline if needed. Avoid overload.

Hepatic Encephalopathy & Ammonia

Lactulose + rifaximin (reduce ammonia). Check arterial ammonia — if >150 μmol/L: high risk cerebral oedema → CVVH (Marino p.664 — superior to lactulose in severe HE). Head of bed 30°. Avoid sedatives; use fentanyl if needed.

Cerebral Oedema Prevention

Maintain Na 145–150 mEq/L (hypertonic saline infusion). ICP monitoring if Grade IV. Mannitol 0.5–1 g/kg for acute ICP spikes. Avoid: hypo-osmolar fluids, fever, seizures, hypoglycaemia (all worsen cerebral oedema).

AKI Management

CVVH preferred over IHD (haemodynamic instability). Indication: AKI + ammonia >150 OR cerebral oedema OR oliguria (regardless of creatinine — Marino p.664). Citrate anticoagulation; avoid heparin (bleeding risk). NAC may help by improving hepatic perfusion to kidneys.

⚠️ 6 · Common Mistakes

Common Mistakes in ALF

❌ Mistake 1 — Giving FFP to Correct INR Prophylactically

ALF causes balanced coagulopathy — both pro- and anti-coagulant factors are deficient. INR is unreliable. Giving FFP "normalises" the INR but worsens fluid overload and doesn't prevent bleeding. Use TEG/ROTEM; transfuse only for active bleeding or planned procedures.

❌ Mistake 2 — Using Ringer's Lactate as Resuscitation Fluid

Marino (Ch.39, p.661): RL is not advised in ALF because it promotes hyponatraemia, which exacerbates cerebral oedema. Use 0.9% NaCl or albumin 5% (especially if serum albumin <3 g/dL).

❌ Mistake 3 — Delayed Transplant Referral

Do NOT wait until King's College criteria are met to refer. Refer to transplant centre as soon as Grade II encephalopathy develops. Mortality without transplant is 80%. Every hour of delay = worse outcomes.

❌ Mistake 4 — Not Starting CVVH Early Enough

Marino (p.664): CVVH should be started as soon as possible in ALF with severe encephalopathy — its effectiveness is time-dependent. Don't wait for creatinine to rise. Indications: oliguria, ammonia >150, or cerebral oedema regardless of creatinine.

❌ Mistake 5 — Sedating with Benzodiazepines

Benzodiazepines worsen hepatic encephalopathy and have prolonged action due to impaired hepatic metabolism. Use fentanyl for analgesia/sedation (minimal hepatic metabolism). Propofol in low doses acceptable if haemodynamically stable.

🎓 7 · Exam Pearls

Exam Pearls

Q: Marino's pathophysiology of cerebral oedema in ALF?
Liver failure → ↑ ammonia → crosses BBB → astrocytes convert to glutamine → glutamine creates osmotic force → draws water into astrocytes → "cytotoxic" cerebral oedema (Marino Ch.39, p.662). Target arterial ammonia <150 μmol/L. CVVH is superior to lactulose in clearing ammonia.

Q: Marino's key point on fluid choice in ALF?
Avoid Ringer's Lactate (promotes hyponatraemia → worsens cerebral oedema). Use 0.9% NaCl or albumin 5% (preferred if albumin <3 g/dL). Maintain Na 145–150 mEq/L with hypertonic saline to prevent cerebral oedema (Marino Ch.39, p.661).

Q: King's College Criteria for transplant in paracetamol ALF?
pH <7.30 after resuscitation (alone sufficient) — OR — ALL 3: INR >6.5 + Creatinine >300 μmol/L + Grade III–IV encephalopathy. Any one criterion met = refer for liver transplant. Don't wait for all three.

Q: Why NOT correct INR with FFP in ALF?
ALF causes balanced loss of pro- and anti-coagulant factors. INR overestimates true bleeding risk (measured by TEG/ROTEM = often near-normal clot formation). FFP worsens fluid overload and portal hypertension. Transfuse only for active bleeding or planned invasive procedure.

Q: Most common cause of ALF in India?
Hepatitis E virus (particularly in pregnant women — very high mortality, up to 20%). Also: hepatitis B reactivation, anti-TB drug hepatotoxicity, ayurvedic/herbal medicines. Paracetamol toxicity is less common in India vs Western countries.

📚 8 · References

References

Marino PL. Marino's The ICU Book, 5th edition. Chapter 39: Liver Failure (pp.658–688). Philadelphia, PA: Wolters Kluwer; 2025.
O'Grady JG, Alexander GJM, Hayllar KM, Williams R. Early Indicators of Prognosis in Fulminant Hepatic Failure (King's College Criteria). Gastroenterology. 1989;97(2):439–445.
Stravitz RT, Lee WM. Acute Liver Failure. Lancet. 2019;394(10201):869–881.
Shalimar, Acharya SK. Management in Acute Liver Failure. J Clin Exp Hepatol. 2015;5(Suppl 1):S104–S115.
Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study. Hepatology. 2005;42(6):1364–1372.
Washington Manual of Critical Care, 4th Ed. Kollef MH, Witt CA (eds). Wolters Kluwer; 2023.
Oh TE (ed). Oh's Intensive Care Manual, 8th edition. Chapter 39: Acute Liver Failure. Elsevier; 2018.