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Propofol infusion syndrome

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"propofol infusion syndrome"[MeSH Terms]

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"propofol infusion syndrome" pathophysiology management

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PMID: 36407194

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Propofol Infusion Syndrome (PRIS)

Definition

Propofol infusion syndrome is a rare but potentially fatal complication of propofol administration, most commonly associated with high doses or prolonged infusions in critically ill patients. It was first described in children and subsequently recognized in critically ill adults.

Risk Factors / Predisposing Conditions

Dose threshold: Infusions at 4 mg/kg/h (67 mcg/kg/min) or more for 48 hours or longer carry the highest risk, though cases have been reported with lower doses administered for as little as 3 hours.
Patient factors:
  • Young age (particularly children under 3 years)
  • Critical illness (sepsis, severe brain injury, trauma)
  • Elevated serum catecholamines (endogenous or exogenous)
  • Corticosteroid therapy
  • Obesity
  • Depleted carbohydrate stores
  • Elevated serum lipids
Genetic predisposition:
  • Disorders impairing fatty acid metabolism, especially medium-chain acyl-CoA (MCAD) deficiency
  • Low carbohydrate supply (energy substrate switches to fat, overwhelming impaired oxidation pathways)

Pathophysiology

The primary mechanism is disruption of the mitochondrial respiratory chain, leading to:
  1. Inhibition of ATP synthesis - propofol impairs Complex I and Complex II/III of the electron transport chain, blocking oxidative phosphorylation
  2. Cellular hypoxia - inadequate ATP production despite adequate oxygen delivery
  3. Excess free fatty acid (FFA) accumulation - in critically ill patients, the primary energy substrate shifts from carbohydrates to lipids; the resulting excess FFAs cannot undergo adequate beta-oxidation, and accumulate as toxic intermediates
  4. Impaired carnitine transport - long-chain fatty acids cannot enter the mitochondria, further impairing oxidation
  5. Hepatic lipid dysregulation - possibly worsened by hypoxia or glucose depletion, contributing to lipemia and hepatic dysfunction
The result is a cascade of muscle injury and release of intracellular toxic contents.

Clinical Features

PRIS presents with a constellation of findings, anchored by:
Cardinal feature:
  • Acute refractory bradycardia progressing to asystole
Plus one or more of:
SystemManifestation
MetabolicMetabolic acidosis (base deficit >10 mmol/L), lactic acidosis
MuscleRhabdomyolysis, skeletal myopathy
RenalAcute renal failure (myoglobinuria)
CardiacNew-onset cardiomyopathy, acute cardiac failure
HepaticHepatomegaly, hepatic dysfunction, fatty liver
ElectrolytesHyperkalemia
LipidsHypertriglyceridemia, lipemia
ECGConduction abnormalities, right bundle branch block pattern, ST changes
Early warning signs:
  • Rising triglycerides - often the first indicator of impending PRIS
  • Unexplained metabolic (lactic) acidosis
  • Unexplained tachycardia or new ECG changes

Monitoring

Patients on prolonged propofol infusions should have regular monitoring of:
  • Triglycerides (rising lipemia is an early sign)
  • Serum creatine kinase (CK)
  • Lactate
  • Liver enzymes (AST, ALT)
  • Urine myoglobin
  • ECG
  • Serum electrolytes (potassium)
  • Blood gases (for metabolic acidosis)

Management

Immediate:
  1. Stop propofol infusion - this is the single most critical step; early recognition and discontinuation is the key determinant of prognosis
  2. Switch to an alternative sedative agent (dexmedetomidine, midazolam, ketamine)
Supportive care:
  • Hemodynamic support - vasopressors/inotropes for cardiovascular collapse; ECMO has been used in refractory cardiac failure
  • Renal replacement therapy - for acute renal failure and to clear myoglobin; aggressive IV fluid resuscitation to prevent tubular injury
  • Dextrose infusion - correct carbohydrate deficit; provide glucose as energy substrate to bypass impaired fatty acid oxidation
  • Treat hyperkalemia - calcium gluconate, insulin-dextrose, sodium bicarbonate
  • Cardiac pacing - for refractory bradycardia/heart block
  • Lipid emulsion therapy - has been reported in case series as a potential antidote (20% intralipid), though evidence is limited

Prevention

  • Limit propofol to <4 mg/kg/h in adults when prolonged infusion is anticipated
  • Avoid propofol as a primary sedative for prolonged ICU sedation in children (not approved for pediatric ICU sedation in many countries)
  • Routinely monitor triglycerides
  • Target light sedation whenever possible; use daily sedation interruption protocols
  • Consider alternative agents (dexmedetomidine, midazolam) for prolonged sedation requirements
  • Ensure adequate carbohydrate supply during propofol infusion

Epidemiology & Prognosis

  • Incidence is estimated at up to 1% in critically ill adults receiving prolonged infusions
  • Mortality is high (reported >50% in established cases) when not recognized early
  • Outcome depends entirely on how quickly propofol is stopped and supportive care initiated
Sources:
  • Miller's Anesthesia, 10e - Chapter 21 (Propofol pharmacology and PRIS clinical features)
  • Miller's Anesthesia, 10e - Chapter 36 (ICU sedation and PRIS in critical care)
  • The Essentials of Forensic Medicine and Toxicology, 36e (Propofol toxicology)
  • Singh & Anjankar, Cureus 2022 - recent clinical review (PMID: 36407194)
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