Propofol Infusion Syndrome

Propofol infusion syndrome (PRIS) is a rare, often fatal complication of prolonged or high dose propofol infusion, marked by metabolic acidosis, rhabdomyolysis, hyperkalaemia, hypertriglyceridaemia, cardiac failure and arrhythmia, and renal failure.

Epidemiology. Incidence is about 1% in prolonged critical care sedation, with mortality over 30% in reported cases. It is typically associated with doses over 4 mg/kg/h for more than 48 hours, though cases occur at lower doses and with shorter exposure.

Risk factors. High dose and long duration, children, critical illness (especially head injury, sepsis and airway infection), concurrent catecholamines and corticosteroids, low carbohydrate intake, mitochondrial or fatty acid oxidation disorders and high fat load from lipid emulsion.

Pathophysiology.

Propofol impairs mitochondrial fatty acid oxidation and respiratory chain function (carnitine palmitoyltransferase inhibition and complex II disruption). Energy failure occurs in cardiac and skeletal muscle.

Fatty acid and lactate accumulation, rhabdomyolysis and cardiomyocyte injury follow. Catecholamines and steroids increase lipolysis and worsen the defect.

New metabolic (lactic) acidosis, rising creatine kinase, hyperkalaemia, dark urine, fever, hepatomegaly, hypertriglyceridaemia, bradycardia, widening QRS with a Brugada like ST elevation, ventricular arrhythmia, refractory cardiovascular collapse and acute kidney injury.

Red flags.

• Rising vasopressor requirement during propofol infusion.
• Brugada like ST elevation or new right bundle branch block.
• Lactate over 4 mmol/L unexplained.
• Creatine kinase over 5,000 units/L.
• Hyperkalaemia with acidosis.
• Bradyarrhythmia or asystole.

Clinical diagnosis based on exposure plus at least two of the following: unexplained metabolic acidosis, rhabdomyolysis, hyperkalaemia, hypertriglyceridaemia, cardiac failure or arrhythmia, renal failure.

Investigations. Blood gas and lactate, potassium, creatine kinase, creatinine, triglycerides, liver enzymes, myoglobin in urine, ECG and echocardiography. Exclude sepsis, ischaemia and other causes.

Differential diagnosis.

• Sepsis.
• Myocardial infarction.
• Malignant hyperthermia or neuroleptic malignant syndrome.
• Rhabdomyolysis of other cause.
• Mitochondrial disease.
• Adrenal insufficiency.
• Poisoning.

Stop propofol immediately and replace with another sedative.

• Midazolam: 0.02 to 0.1 mg/kg/h IV infusion, after bolus 1 to 2 mg if needed; continue as required, titrated to sedation score; maximum about 0.2 mg/kg/h; monitor respiratory depression, sedation depth and accumulation; reduce in older adults and in hepatic or renal impairment.
• Dexmedetomidine (alternative, no loading dose): 0.2 to 0.7 microgram/kg/h IV; titrated; maximum 1.4 microgram/kg/h; monitor heart rate and blood pressure; reduce in hepatic impairment and avoid in high grade heart block.

Supportive treatment.

• Correct acidosis and hyperkalaemia (calcium, insulin with glucose, bicarbonate) and maintain urine output for rhabdomyolysis.
• Provide carbohydrate calories (glucose 6 to 8 mg/kg/min), though evidence for benefit is limited. Reduce lipid load.
• Treat arrhythmia and use pacing or catecholamines as needed. Prolonged support may require extracorporeal membrane oxygenation.
• Early haemofiltration or haemodialysis for acidosis, hyperkalaemia and renal failure, with possible removal of propofol and metabolites.

Prevention. Keep propofol at 4 mg/kg/h or less, and avoid prolonged use beyond 48 hours. Monitor triglycerides every 48 to 72 hours and lactate and creatine kinase during infusion. Avoid in children for long term sedation. Reduce concurrent catecholamines and steroids where possible.

Monitoring. Daily or more frequent lactate, creatine kinase, potassium, triglycerides, blood gas, creatinine and ECG.

Referral and escalation. Critical care and nephrology early. Cardiology for conduction abnormality. Consider toxicology or metabolic advice if a mitochondrial disorder is suspected.

Special groups. Children are at highest risk, and long term propofol sedation is not advised. Patients with known mitochondrial disease should avoid prolonged propofol.