Propofol

Propofol is an intravenous alkylphenol hypnotic with rapid onset, rapid recovery and antiemetic effect. It is the most widely used intravenous induction and sedation agent. It lowers blood pressure, depresses ventilation, and has no analgesic action. Prolonged high-dose infusion carries the risk of propofol infusion syndrome.

Class. Intravenous general anaesthetic (alkylphenol).

Mechanism. Positive modulation of GABA-A receptor chloride currents, with inhibition of sodium channels and glutamate (NMDA) effects.

Pharmacokinetics. Onset 30 to 60 seconds (one arm-brain circulation time). Duration 5 to 10 minutes after a single bolus because of redistribution. Protein binding about 98%. Large volume of distribution. Elimination half-life 4 to 7 hours, but context-sensitive half-time is short (about 10 minutes after infusions of 2 hours, rising to about 40 minutes after 8 hours). Hepatic glucuronidation with extrahepatic clearance (lung, kidney); inactive metabolites excreted in urine.

Formulation. 1% (10 mg/mL) or 2% (20 mg/mL) lipid emulsion containing soya oil, egg lecithin and glycerol; it supplies 1.1 kcal/mL and supports bacterial growth.

Indications are induction and maintenance of general anaesthesia (including total intravenous anaesthesia), sedation for procedures, and sedation of ventilated patients in intensive care.

Adults, induction

• Healthy adults under 55 years: 1.5 to 2.5 mg/kg intravenously, titrated at 20 to 40 mg every 10 seconds until loss of consciousness.
• Older adults, ASA 3 and 4, hypovolaemia: 1 to 1.5 mg/kg or less, titrated slowly.
• Use lean body weight for induction in obesity.
• Co-induction with an opioid or benzodiazepine reduces the dose by 20 to 40%.

Adults, maintenance

• Total intravenous anaesthesia: 4 to 12 mg/kg/hour (average 6 to 10 mg/kg/hour initially, then reduced to 4 to 6 mg/kg/hour), by manual infusion or target-controlled infusion with a validated model (effect-site target typically 2 to 6 micrograms/mL, lower in older adults).
• As part of balanced anaesthesia with volatile or nitrous oxide: 2 to 4 mg/kg/hour.
• Use total body weight for maintenance infusions unless the device model requires otherwise.

Sedation

• Procedural: 0.5 to 1 mg/kg intravenously, then 10 to 20 mg increments every few minutes as needed. Needs a clinician trained in airway management.
• Intensive care (adult): start 5 micrograms/kg/minute (0.3 mg/kg/hour) for at least 5 minutes, then increase by 5 to 10 micrograms/kg/minute every 5 to 10 minutes to a maintenance range of 5 to 50 micrograms/kg/minute (0.3 to 3 mg/kg/hour). Maximum 4 mg/kg/hour (67 micrograms/kg/minute) for sedation.
• Limit prolonged high-dose infusion to under 48 hours where possible.

Antiemetic. 10 to 20 mg intravenously; infusion 1 mg/kg/hour in resistant postoperative nausea.

Children

• Induction (1 month to 16 years): 2.5 to 4 mg/kg intravenously (higher in younger children).
• Maintenance: 9 to 15 mg/kg/hour.
• Sedation of ventilated children in intensive care: contraindicated at 16 years and under (propofol infusion syndrome).
• Not advised under 1 month for anaesthesia in most labels.

Contraindications. Hypersensitivity to propofol, soya, peanut or any component; sedation of ventilated patients aged 16 years or younger; unsupervised sedation; absence of airway equipment and trained staff.

Boxed-warning-level risks. Propofol infusion syndrome (metabolic acidosis, rhabdomyolysis, hyperkalaemia, cardiac failure, hepatomegaly, renal failure, raised triglycerides) with high doses (over 4 mg/kg/hour) for more than 48 hours; apnoea and airway obstruction; profound hypotension in hypovolaemia, older adults or with opioids.

Adverse effects. Common: pain on injection, hypotension, apnoea, reduced cardiac output, bradycardia, involuntary movements, hiccups. Serious: propofol infusion syndrome, anaphylaxis, bacterial contamination of opened vials, pancreatitis and hypertriglyceridaemia with long infusion, pulmonary oedema, seizure-like movements.

Interactions. Opioids, benzodiazepines, alpha-2 agonists and volatile agents add sedation and hypotension. Fentanyl-class opioids increase risk of bradycardia and asystole. Drugs that lower blood pressure add hypotension. Beta blockers add bradycardia.

Common prescribing errors. Giving a full induction dose to a frail or hypovolaemic patient; using for ICU sedation in children; leaving a vial or syringe open beyond 6 hours (12 hours for the infusion line); confusing 1% and 2% concentrations; failing to account for lipid calories in long infusions.

Special groups

• Pregnancy: used for induction at caesarean section; neonatal depression with high doses. Avoid prolonged infusion.
• Breastfeeding: compatible; no need to interrupt after single use.
• Older adults: reduce induction dose by 30 to 50% and slow the rate.
• Kidney impairment: no adjustment.
• Liver impairment: no adjustment for single doses; reduce rates in severe disease.
• Regional: confirm concentration on the label and prepare fresh syringes for each patient; infections linked to multi-use vials are well described.

Formulations. 1% and 2% emulsion in vials, ampoules, prefilled syringes and bags.

Administration. Shake before use. Give through a large vein with free-flowing fluid to reduce pain; pre-treatment with 20 to 40 mg lidocaine mixed with the dose, or injected beforehand with a tourniquet, reduces pain. Dilute only with 5% glucose, to no less than 2 mg/mL, if dilution is required. Use within 6 hours of opening a vial and within 12 hours for infusion lines and containers.

Baseline. Airway assessment, allergy history (soya, peanut, egg), cardiovascular status, volume status, weight and current sedatives.

Monitoring. Continuous electrocardiogram, oxygen saturation, capnography and blood pressure. Depth of anaesthesia or sedation by clinical signs or processed electroencephalogram (target index 40 to 60 for general anaesthesia). In long infusions, check triglycerides, creatine kinase, lactate and acid-base status daily.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Reduce or stop for hypotension, bradycardia, apnoea, or unexplained acidosis, rising lactate, rhabdomyolysis or arrhythmia (stop the infusion and treat propofol infusion syndrome).

Referral and escalation. Propofol infusion syndrome needs immediate cessation, intensive care, and possible renal replacement therapy or extracorporeal support. Anaphylaxis needs intramuscular adrenaline. Persistent hypotension needs vasopressor and fluid.