What is propofol infusion syndrome (PRIS)?

Propofol Infusion Syndrome (PRIS)

Propofol infusion syndrome is a rare but potentially fatal constellation of metabolic derangements and organ system failures characterized by severe metabolic acidosis, hyperkalemia, rhabdomyolysis, cardiac dysfunction with arrhythmias, hypotension requiring escalating vasopressors, and acute kidney injury, with mortality rates reaching up to 33%. 1, 2

Clinical Presentation

PRIS manifests with variable but recognizable features that demand immediate recognition:

Core metabolic features:

• Worsening metabolic acidosis (often the earliest warning sign)
• Hyperkalemia
• Hypertriglyceridemia and lipemia

Cardiovascular manifestations:

• Progressive hypotension despite increasing vasopressor requirements
• Cardiac arrhythmias (including bradycardia progressing to asystole)
• ECG changes including coved ST segment elevation (similar to Brugada syndrome pattern) 2
• Cardiac failure and contractility impairment

Organ system involvement:

• Rhabdomyolysis (more common in adults than children) 3
• Acute kidney injury
• Hepatomegaly (more frequent in pediatric cases) 3
• Liver dysfunction
• Fever (particularly in children) 3

1

Risk Factors and Dosing Thresholds

PRIS is classically associated with prolonged propofol infusions exceeding 70 μg/kg/min (approximately 4.2 mg/kg/hr) for more than 48 hours, but critically, it can occur with lower doses and shorter durations. 1, 2

Major risk factors include:

• Decreased oxygen delivery to tissues
• Serious neurological injury and/or sepsis
• High-dose vasoconstrictors, steroids, or inotropes
• Young age (particularly under 3 years)
• Critical illness with depleted carbohydrate stores
• Obesity
• Elevated serum catecholamines

1, 2, 4, 3

The syndrome has been documented even with low-dose infusions (as low as 1.3 mg/kg/hr) and during large-dose, short-term infusions for surgical anesthesia 1, 5. Recent evidence from a structured literature review of 168 cases found that in adults, mean propofol infusion rates >5 mg/kg/hr were independently associated with mortality 3.

Pathophysiology

The underlying mechanism involves mitochondrial dysfunction with disruption of the respiratory chain, leading to:

• Impaired fatty acid oxidation
• Inhibition of ATP synthesis resulting in cellular hypoxia
• Diversion of carbohydrate metabolism to fat substrates
• Accumulation of propofol metabolites
• Excess lipolysis generating free fatty acids that cannot undergo adequate beta-oxidation

1, 4, 6

This metabolic catastrophe particularly affects high-energy-demand organs (heart, skeletal muscle, kidneys, liver), explaining the multi-organ failure pattern.

Incidence and Mortality

The incidence of PRIS with propofol infusions is approximately 1% 1. However, mortality from PRIS is alarmingly high at up to 33% and may occur even after discontinuing the infusion 1. In the pediatric population specifically, mortality is independently associated with fever and hepatomegaly, while in adults it correlates with ECG changes, hypotension, hyperkalemia, traumatic brain injury, and mean infusion rates >5 mg/kg/hr 3.

Diagnostic Approach

The variable presentation, lack of diagnostic specificity, and infrequent occurrence make detection of this potentially life-threatening condition extremely difficult. 1

Monitor these parameters in all patients receiving propofol sedation:

• Serial arterial blood gases (watching for progressive metabolic acidosis)
• Serum creatine kinase (CK) and CK-MB
• Serum lactate levels
• Liver enzymes (AST/ALT)
• Lipase and amylase
• Serum potassium
• Triglyceride levels
• Urine myoglobin
• Continuous ECG monitoring for arrhythmias and ST segment changes

4, 5

Critical warning signs requiring immediate action:

• Increasing propofol dose requirements to maintain constant sedation level
• Onset of unexplained metabolic acidosis during propofol administration
• Progressive elevation in CK levels
• New cardiac arrhythmias or ECG changes
• Escalating vasopressor requirements

1, 2, 3

Management Algorithm

Early recognition and immediate discontinuation of propofol are critically important and represent the cornerstone of management. 1

Step 1: Immediate discontinuation

• Stop propofol infusion immediately upon suspicion
• Switch to alternative sedation (dexmedetomidine or benzodiazepines)
• Do NOT abruptly discontinue without transitioning to alternative sedation, as this causes rapid awakening with anxiety, agitation, and ventilator dyssynchrony 2

Step 2: Aggressive supportive care

• Hemodynamic support with vasopressors/inotropes as needed
• Correct metabolic acidosis with sodium bicarbonate
• Manage hyperkalemia aggressively (insulin/glucose, calcium, dialysis if severe)
• Maintain adequate oxygen delivery to tissues
• Provide renal replacement therapy if indicated

Step 3: Consider extracorporeal support

• In severe cases, continuous hemofiltration or hemodialysis may be beneficial 3
• Extracorporeal membrane oxygenation (ECMO) for refractory cardiovascular collapse

4, 7, 8, 5

Prevention Strategies

Limit propofol use in high-risk patients:

• Avoid doses >70 μg/kg/min (4.2 mg/kg/hr) when possible
• Minimize duration of infusion, particularly beyond 48 hours
• Consider alternative sedatives (dexmedetomidine) for prolonged ICU sedation
• Use lowest effective dose for sedation goals
• Implement daily sedation interruption protocols when feasible

Enhanced monitoring for at-risk patients:

• Patients with traumatic brain injury, sepsis, or critical neurological injury
• Those receiving high-dose catecholamines or steroids
• Pediatric patients, especially under 3 years
• Patients with depleted carbohydrate stores or receiving inadequate caloric intake

1, 2, 3

Special Populations

Pediatric considerations: PRIS was first described in children in the 1990s, and propofol is no longer recommended for long-term sedation in pediatric ICU patients due to this risk 3. The FDA label specifically warns about use in pediatric ICU sedation 2. However, recent data suggest that with careful monitoring and dose limitation, propofol can be used safely for shorter durations in select pediatric cases 9.

Adult ICU sedation: While propofol remains widely used for adult ICU sedation, clinicians must maintain vigilance. The 2013 Critical Care Medicine guidelines emphasize that propofol should only be administered by persons skilled in managing critically ill patients and trained in cardiovascular resuscitation and airway management 1.