Propofol

Contents

Overview

Propofol (2,6-diisopropylphenol) is the standard sedative agent for ICU sedation and induction of anaesthesia. Its rapid onset, short duration, and antiemetic properties make it highly versatile. However, it requires close monitoring; high doses and prolonged infusion carry the risk of propofol infusion syndrome, a rare but potentially fatal complication.

Pharmacology

Mechanism: Propofol is a positive allosteric modulator of GABA-A receptors. It enhances chloride conductance, hyperpolarising neurons and reducing excitability. It also inhibits NMDA receptors and sodium channels.

Formulation: Available as a 1% or 2% lipid emulsion in soybean oil and egg lecithin. Patients with soy or egg allergy should be assessed — true anaphylaxis to propofol is rare, and the allergy is not considered an absolute contraindication in most guidelines, but the relevant allergy history should inform the clinical decision.

Each millilitre of 1% propofol provides 1.1 kcal from its lipid vehicle. This must be accounted for in nutritional calculations during prolonged infusion.

Pharmacokinetics: Onset is rapid (30–60 seconds IV). The short duration of effect after a bolus dose is due to redistribution from the CNS to peripheral tissues. With prolonged infusion, peripheral compartments become saturated and the context-sensitive half-life increases significantly — recovery from sedation becomes progressively slower.

Metabolism is primarily hepatic, to inactive glucuronide and sulphate conjugates. Extrahepatic metabolism (in the lung and kidney) also occurs. Metabolites are renally excreted. No dose adjustment is required for renal or hepatic impairment, as metabolites are inactive, though clearance of the parent drug may be altered in severe hepatic failure.

Clinical Effects

CNS: Sedation, hypnosis, anxiolysis. Reduces cerebral metabolic rate and ICP, making it suitable in TBI. Anticonvulsant properties. No analgesic effect.

Cardiovascular: Vasodilation through inhibition of sympathetic tone and direct vascular smooth muscle relaxation. Reduces systemic vascular resistance. Mild negative inotropic effect. A bolus induction dose often causes significant hypotension, particularly in the hypovolaemic patient or those on vasopressors. Slower infusion rates and fluid optimisation reduce this risk.

Respiratory: Bolus doses cause apnoea. Reduces upper airway reflexes, facilitating intubation without neuromuscular blockade in some circumstances. In spontaneously breathing sedated patients, excessive propofol causes respiratory depression; careful dose titration is required.

Antiemetic: Subanaesthetic doses have an antiemetic effect, contributing to its use in TIVA (total intravenous anaesthesia).

Propofol Infusion Syndrome

Propofol infusion syndrome (PRIS) is a rare but potentially fatal complication of propofol infusion, predominantly described with high doses or prolonged administration.

Pathophysiology

PRIS results from impairment of mitochondrial respiratory chain function. Propofol inhibits complex I and IV of the electron transport chain, and uncouples oxidative phosphorylation. It also impairs fatty acid beta-oxidation. These effects lead to cellular energy failure, particularly in tissues with high metabolic demands such as cardiac and skeletal muscle.

Clinical Features

  • Metabolic acidosis (lactic or mixed)
  • Rhabdomyolysis (elevated CK, myoglobinaemia, myoglobinuria)
  • Hyperkalaemia
  • Acute kidney injury
  • Hypertriglyceridaemia
  • Cardiac dysfunction: arrhythmias (new right bundle branch block, ST changes, Brugada-pattern ECG), cardiac failure

A new unexplained metabolic acidosis in a patient receiving propofol should prompt immediate consideration of PRIS.

Risk Factors

  • High infusion rates (>4 mg/kg/hour)
  • Prolonged infusion (>48 hours)
  • High-fat, low-carbohydrate intake (carbohydrate depletion reduces alternative metabolic substrate availability)
  • Catecholamine infusions
  • Corticosteroids
  • Severe physiological stress
  • Children (historically more susceptible — propofol is not licensed for ICU sedation in children under 16)

Management

Stop propofol immediately and switch to an alternative sedative (such as midazolam or dexmedetomidine). Provide supportive care: manage acidosis, treat arrhythmias, and provide renal replacement therapy if required. Haemodialysis may help clear propofol. Venoarterial ECMO has been used as rescue therapy in refractory cardiac failure. PRIS-related mortality is high once cardiac failure develops.

Practical Considerations

  • Maximum recommended dose: 4 mg/kg/hour for ICU sedation in adults. Do not exceed this without close monitoring.
  • Giving sets: Change every 12 hours to reduce infection risk from the lipid vehicle.
  • Triglycerides: Monitor in patients receiving high doses or prolonged infusions. Elevated triglycerides may indicate impaired lipid metabolism and early PRIS.
  • Nutritional calculation: Subtract propofol calories from the target nutritional intake to avoid overfeeding.
  • Alcohol content: Some formulations contain ethanol as a preservative — relevant in patients with alcohol-related conditions.
  • Pain on injection: Common with peripheral administration; use a large vein or add lignocaine 1% (0.1 mg/kg) prior to injection.

Viva Questions

What is propofol infusion syndrome? How does it present and how is it managed?

Propofol infusion syndrome is a rare complication of propofol infusion, characterised by mitochondrial dysfunction causing multi-organ failure. It is most commonly associated with high infusion rates (above 4 mg/kg/hour), prolonged use, and additional risk factors including catecholamine infusions, corticosteroids, and carbohydrate depletion. Clinically it presents with a new metabolic acidosis (often lactic), rhabdomyolysis, elevated creatine kinase, hyperkalaemia, hypertriglyceridaemia, and cardiac dysfunction including arrhythmias (right bundle branch block, Brugada-pattern changes) and myocardial failure. The mechanism is inhibition of the mitochondrial electron transport chain and impaired fatty acid oxidation, leading to cellular energy failure. Management requires immediate cessation of propofol and conversion to an alternative sedative. Further care is supportive: correction of acidosis, management of arrhythmias, renal replacement therapy for AKI or to correct metabolic derangements, and in refractory cardiac failure, venoarterial ECMO. Mortality is high once significant cardiac dysfunction develops, so early recognition is critical.

What are the haemodynamic effects of propofol and how do you mitigate them?

Propofol causes vasodilation through sympathetic inhibition and direct vascular smooth muscle relaxation, reducing systemic vascular resistance. It also has a mild negative inotropic effect. Together these produce a fall in blood pressure that can be significant with bolus induction doses, particularly in hypovolaemic or elderly patients, or those already receiving vasopressors. To mitigate these effects, induction doses should be titrated incrementally rather than given as a large bolus, and the patient should be adequately fluid resuscitated beforehand. Using a lower induction dose, combining with a small dose of vasopressor if haemodynamically at risk, and having emergency vasopressor support readily available are all appropriate strategies. During ICU sedation, propofol is usually titrated as a continuous infusion at low rates, where the haemodynamic impact is less pronounced. In haemodynamically unstable patients, ketamine may be a more appropriate induction agent.

How does propofol's pharmacokinetics change with prolonged infusion?

After a single bolus, propofol has a short duration of effect because the drug rapidly redistributes from the CNS into peripheral (adipose and muscle) compartments, lowering plasma and brain concentrations quickly. With a prolonged infusion, peripheral compartments become saturated and can no longer act as a sink for drug redistribution. The context-sensitive half-time therefore increases substantially with duration of infusion. In practice, patients who have received propofol for 24–48 hours or longer may take much longer to wake up after stopping the infusion than would be predicted from the drug's short half-life in single-dose use. Accumulation in obese patients is also greater due to a larger volume of distribution. Clinicians should anticipate this when planning sedation holds or wake-up assessments in patients who have received propofol for more than a day.