What are the risks and management strategies for Propofol (propofol) infusion syndrome?

Propofol Infusion Syndrome: Risks and Management

Definition and Clinical Presentation

Propofol infusion syndrome (PRIS) is a rare but potentially lethal complication presenting with worsening metabolic acidosis, hypertriglyceridemia, hypotension requiring escalating vasopressors, cardiac arrhythmias, acute kidney injury, hyperkalemia, rhabdomyolysis, and liver dysfunction—with mortality rates reaching 33%. 1

The syndrome typically develops after prolonged propofol administration, though it can occur unpredictably even at lower doses. 1 The incidence is approximately 1-2.9% in critically ill patients receiving continuous propofol infusions. 1, 2

Risk Factors

Key risk factors include: 1, 3, 4

• Propofol dose >70 μg/kg/min (though PRIS has occurred at doses as low as 36.4 μg/kg/min) 1, 2
• Duration >48 hours of continuous infusion 1, 3
• Acute neurological illnesses or traumatic brain injury 4, 5
• Severe inflammatory conditions or sepsis 4
• Concomitant catecholamine infusions 1, 4
• Corticosteroid therapy 1, 4
• Young age (particularly <3 years in pediatrics) 6
• Carbohydrate depletion 3

Pathophysiology

PRIS results from impaired mitochondrial fatty acid beta-oxidation and disruption of the electron transport chain, leading to ATP depletion and cellular hypoxia. 6, 3 In critically ill patients with depleted carbohydrate stores, excess lipolysis generates free fatty acids that cannot undergo adequate oxidation, contributing to metabolic acidosis and organ dysfunction. 6 Propofol also blocks beta-adrenoreceptors and cardiac calcium channels, compounding cardiovascular collapse. 3

Prevention Strategies

The American College of Critical Care Medicine recommends maintaining propofol infusion rates <70 μg/kg/min (ideally 5-50 μg/kg/min) and avoiding prolonged infusions beyond 48 hours when possible. 1

Specific Prevention Measures:

• Limit propofol to 5-50 μg/kg/min and reassess daily whether continuation is necessary 1
• After 48 hours, transition to alternative sedation:
  • Dexmedetomidine: Load 1 μg/kg over 10 minutes, maintain 0.2-1.5 μg/kg/hr (monitor for bradycardia/hypotension) 1
  • Midazolam: Load 0.01-0.05 mg/kg, maintain 0.02-0.1 mg/kg/hr 1
  • Lorazepam: Load 0.02-0.04 mg/kg, maintain 0.01-0.1 mg/kg/hr (monitor for propylene glycol toxicity) 1
• Consider analgesic-first approach using low-dose fentanyl with minimal sedative 1

Monitoring Requirements:

Daily laboratory monitoring is crucial for early PRIS detection: 1

• Serum triglycerides (hypertriglyceridemia occurs in 100% of PRIS cases) 2
• Arterial blood gases (metabolic acidosis present in 78.9% of cases) 2
• Creatine kinase (rhabdomyolysis in 26.3% of cases) 2
• Renal and liver function tests 1
• ECG monitoring (T-wave inversions may precede circulatory collapse by 29 hours) 5
• Serum lactate 6

The FDA label emphasizes monitoring serum triglycerides during extended propofol use, with dose adjustment if fat clearance is inadequate. 7

Early Warning Signs

Unexplained metabolic acidosis should prompt immediate evaluation for PRIS. 1 Additional early signs include: 2, 5

• Progressive metabolic acidosis despite treatment
• ECG changes (T-wave inversions, bradycardia) 5
• Rising triglycerides
• Increasing vasopressor requirements
• Elevated creatine kinase

PRIS typically develops at a median of 125 hours post-propofol initiation at cumulative doses around 276.5 mg/kg. 2

Management of Established PRIS

Immediately discontinue propofol infusion upon suspicion of PRIS—this is the single most critical intervention. 1, 3

Supportive Care Algorithm:

1. Stop propofol immediately 1, 3
2. Switch to alternative sedation (dexmedetomidine or benzodiazepines) 1
3. Hemodynamic support:
   • Aggressive fluid resuscitation 7
   • Vasopressors/inotropes as needed 7
   • Consider extracorporeal membrane oxygenation (ECMO) in refractory cardiovascular collapse 3
4. Metabolic acidosis management:
   • Sodium bicarbonate administration 1
   • Renal replacement therapy for severe acidosis and acute kidney injury 1, 3
5. Monitor and treat complications:
   • Hyperkalemia management 3
   • Rhabdomyolysis treatment (aggressive hydration, monitor myoglobin) 6
   • Hemodialysis for renal failure 3

The FDA label confirms that propofol overdosage causes cardiorespiratory depression requiring artificial ventilation, fluid resuscitation, vasopressors, and anticholinergic agents. 7

Special Populations

In CYP2B6 poor metabolizers, reduce propofol infusion dose by 50% (to 25 μg/kg/min) to avoid excessive drug exposure. 8 These patients have prolonged propofol clearance and increased PRIS risk even at standard doses. 8

In elderly, debilitated, or ASA-PS III/IV patients, avoid rapid bolus administration and use lower maintenance rates. 7 The FDA specifically warns against rapid bolus dosing in these populations due to profound hypotension and cardiorespiratory depression risk. 7

Critical Pitfalls

• PRIS is easily missed because its manifestations overlap with common ICU complications 1, 2
• The syndrome can be fatal even at doses below traditional thresholds (cases reported at 36.4 μg/kg/min) 2
• Concomitant catecholamines and steroids dramatically increase PRIS risk in patients with neurological or inflammatory illnesses 4
• Abrupt propofol discontinuation causes rapid awakening with anxiety and ventilator resistance—maintain light sedation until 10-15 minutes before extubation 7
• Propofol has no analgesic properties—combine with opioids for painful procedures 8
• The lipid emulsion provides 1.1 kcal per mL—adjust concurrent lipid administration to prevent hyperlipidemia 7

Bottom Line for Clinical Practice

For sedation beyond 48 hours, transition from propofol to dexmedetomidine or midazolam-based regimens to prevent PRIS. 1 When propofol must be continued, maintain doses ≤50 μg/kg/min with daily laboratory monitoring including triglycerides, creatine kinase, lactate, and continuous ECG surveillance. 1, 5 Any unexplained metabolic acidosis, ECG changes, or rising vasopressor requirements mandate immediate propofol discontinuation. 1, 5