Cerebral Oedema in Acute Liver Failure

Cerebral oedema in acute liver failure is brain swelling with raised intracranial pressure caused by hyperammonaemia and loss of osmotic regulation, in patients with acute liver failure (coagulopathy with INR of 1.5 or more and hepatic encephalopathy in the absence of pre-existing cirrhosis). It can cause herniation and death.

Epidemiology. It occurs in up to 30 to 50% of patients with grade 3 to 4 encephalopathy and fewer than 10% with milder grades. The frequency has fallen in recent years with earlier treatment.

Risk factors. Hyperacute presentation (such as paracetamol overdose), arterial ammonia over 150 to 200 micromol/L, rapid onset of grade 3 to 4 encephalopathy, vasopressor requirement, renal failure and infection.

Pathophysiology. Ammonia is converted to glutamine in astrocytes, which draws water into the cell (osmotic swelling) and causes mitochondrial dysfunction. Loss of cerebral autoregulation, systemic inflammation, hyponatraemia and increased cerebral blood flow add to swelling.

Presentation is worsening encephalopathy (confusion to coma), agitation, hypertension with bradycardia, pupillary abnormalities, decerebrate posturing, seizures and loss of reflexes in herniation. Clinical signs of raised pressure are unreliable.

Red flags.

• Grade 3 to 4 encephalopathy with arterial ammonia over 150 micromol/L.
• Pupillary asymmetry or poor reaction, hypertension with bradycardia.
• Myoclonus, seizures and decerebrate posturing.

CT head to exclude haemorrhage (limited sensitivity for oedema), intracranial pressure monitoring in selected patients at high risk (grade 3 to 4 encephalopathy, listing for transplant), transcranial Doppler, optic nerve sheath ultrasound, and EEG. Measure arterial ammonia, glucose, sodium, osmolality, lactate, INR, creatinine, arterial gas and cultures. Treatment goals are intracranial pressure under 20 to 25 mmHg and cerebral perfusion pressure at least 60 mmHg.

Differential diagnosis. Intracranial haemorrhage, nonconvulsive status, sedative effect, hypoglycaemia, sepsis, hyponatraemia and metabolic encephalopathy.

General. Treat in a transplant capable intensive care unit. Raise the head to 30 degrees with the neck neutral, avoid stimulation and hypotension, correct hypoglycaemia, hypoxia and hypercapnia, and treat fever.

Airway and sedation. Intubate for grade 3 to 4 encephalopathy. Use propofol 1 to 4 mg/kg/h with fentanyl, with minimal use of long acting sedatives.

Sodium and osmolar therapy.

• Target sodium 145 to 155 mmol/L with 3% sodium chloride infusion (continuous, 5 to 30 mL/h) or boluses of 150 to 250 mL over 15 to 20 minutes (23.4% sodium chloride 30 mL over 10 to 20 minutes via a central line for herniation). Keep serum osmolality under 320 mOsm/kg.
• Mannitol 20% 0.5 to 1 g/kg IV over 15 to 20 minutes for acute intracranial pressure rise or signs of herniation, if osmolality is under 320 mOsm/kg and renal function permits (avoid in anuria unless renal replacement is available).

Hyperventilation. Brief hyperventilation to PaCO2 of 4.0 to 4.5 kPa (30 to 35 mmHg) as a bridge for impending herniation, not for long term use.

Ammonia lowering. Continuous renal replacement therapy (high dose, 35 to 40 mL/kg/h) when arterial ammonia is over 150 micromol/L or if there is renal failure or intracranial hypertension. Lactulose is not of benefit in acute liver failure.

Temperature. Avoid fever, and keep temperature at 34 to 36 °C if intracranial pressure remains high. Aggressive hypothermia is not required.

Refractory intracranial hypertension. Indomethacin 0.5 mg/kg IV has been used, thiopental 3 to 5 mg/kg IV bolus then 1 to 3 mg/kg/h with EEG monitoring and haemodynamic support, and emergency liver transplantation.

Specific treatment for the cause. N-acetylcysteine for paracetamol injury: 150 mg/kg IV over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours. For non-paracetamol acute liver failure, 150 mg/kg over 1 hour then 12.5 mg/kg/h for 4 hours then 6.25 mg/kg/h for up to 67 hours. Antiviral therapy for hepatitis B (entecavir 0.5 mg daily), aciclovir 10 mg/kg IV every 8 hours for herpes simplex, and delivery for acute fatty liver of pregnancy.

Seizures. Levetiracetam 60 mg/kg IV (maximum 4500 mg) or phenytoin. Prophylactic anticonvulsants are not advised.

Coagulopathy. Do not correct INR unless bleeding or before intracranial pressure monitor placement (balance bleeding risk). Give vitamin K 10 mg IV once.

Monitoring. Intracranial pressure, cerebral perfusion pressure, pupils, sodium every 4 to 6 hours, ammonia, glucose hourly and EEG.

Referral and escalation. Contact a liver transplant centre early. Urgent listing is considered for grade 3 to 4 encephalopathy, rising lactate, renal failure or high ammonia.

Special groups. In paracetamol overdose, treat with N-acetylcysteine without waiting for levels in late presentation. In pregnancy, urgent delivery for acute fatty liver and HELLP syndrome. In children, intracranial pressure targets are lower, and weight based dosing applies.