What is the mechanism, diagnosis, and treatment of propofol (2,6-diisopropylphenol) infusion syndrome?

From the Guidelines

Propofol infusion syndrome (PRIS) is a rare but potentially life-threatening complication that requires immediate discontinuation of propofol and supportive management, as it is associated with high mortality rates of up to 33% 1. The mechanism of PRIS involves impaired mitochondrial function, where propofol inhibits fatty acid oxidation and the electron transport chain, leading to energy production failure and cellular damage 1. Some key points about PRIS include:

• It is usually associated with prolonged administration of high propofol doses (> 70 μg/kg/min), but it may also occur with low-dose infusions 1
• The incidence of PRIS with propofol infusions is approximately 1% 1
• Mortality from PRIS is high and may occur even after discontinuing the infusion 1
• The variable presentation, lack of diagnostic specificity, and infrequent occurrence of PRIS make detection of this potentially life-threatening condition difficult 1 Diagnosis of PRIS requires clinical suspicion in patients receiving propofol infusions who develop unexplained:
• Metabolic acidosis
• Hypertriglyceridemia
• Hypotension with increasing vasopressor requirements
• Arrhythmias
• Acute kidney injury
• Hyperkalemia
• Rhabdomyolysis
• Liver dysfunction Treatment of PRIS is primarily supportive and includes immediate discontinuation of propofol, as this is critically important for patient outcomes 1. Additional management strategies include:
• Hemodynamic support with fluids and vasopressors
• Correction of metabolic abnormalities
• In severe cases, hemodialysis or extracorporeal membrane oxygenation may be necessary Prevention of PRIS is crucial and involves:
• Limiting propofol infusion rates
• Avoiding prolonged use beyond 48 hours when possible
• Daily monitoring of patients at high risk for PRIS
• Considering alternative sedatives for patients requiring long-term sedation 1

From the FDA Drug Label

Use of propofol injectable emulsion for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes and/or cardiac failure The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (greater than 5 mg/kg/h for greater than 48h)

The mechanism of Propofol Infusion Syndrome is not fully understood, but it is thought to be related to the metabolic effects of propofol, particularly with high-dose and prolonged infusions. The diagnosis of Propofol Infusion Syndrome is based on the presence of severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes, and/or cardiac failure in patients receiving propofol infusions. The treatment of Propofol Infusion Syndrome involves discontinuing the propofol infusion and providing supportive care, including management of metabolic acidosis, hyperkalemia, and cardiac failure, as well as renal replacement therapy if necessary 2.

• Key risk factors for the development of Propofol Infusion Syndrome include:
  • Decreased oxygen delivery to tissues
  • Serious neurological injury and/or sepsis
  • High dosages of vasoconstrictors, steroids, inotropes, and/or prolonged, high-dose infusions of propofol (greater than 5 mg/kg/h for greater than 48h)

From the Research

Mechanism of Propofol Infusion Syndrome

• The primary pathophysiology behind Propofol-Related Infusion Syndrome (PRIS) is the disruption of the mitochondrial respiratory chain, causing inhibition of adenosine triphosphate (ATP) synthesis and cellular hypoxia 3.
• Excess lipolysis of adipose tissue occurs, especially in critically ill patients, generating excess free fatty acids (FFAs) that cannot undergo adequate beta-oxidation, contributing to the clinical pathology of PRIS 3.
• The pathophysiology of PRIS also includes impairment of mitochondrial beta-oxidation of fatty acids, disruption of the electron transport chain, and blockage of beta-adrenoreceptors and cardiac calcium channels 4.

Diagnosis of Propofol Infusion Syndrome

• The disease commonly presents as an otherwise unexplained high anion gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and cardiac dysfunction 4.
• Clinicians must observe the patient's electrocardiogram (ECG), serum creatine kinase, lipase, amylase, lactate, liver enzymes, and myoglobin levels in urine under propofol sedation 3.
• Common laboratory and instrumental findings in PRIS include myoglobinuria, downsloping ST-segment elevation, an increase in plasma creatine kinase, troponin I, potassium, creatinine, azotaemia, malonylcarnitine, and C5-acylcarnitine 5.

Treatment of Propofol Infusion Syndrome

• Management of overt PRIS requires immediate discontinuation of propofol infusion and supportive management, including hemodialysis, hemodynamic support, and extracorporeal membrane oxygenation in refractory cases 4.
• If PRIS is suspected, propofol must be stopped immediately, and cardiocirculatory stabilization and correction of metabolic acidosis initiated 5.
• A prospective screening protocol, including daily serum creatine phosphokinase (CPK) and lactate draws, can be effective in preventing PRIS, with propofol stopped for a positive screen defined as an increase in CPK to greater than 5000 IU/L or lactate greater than 4 mmol/L 6.