The Pre-brief
- Propofol has become one of the most commonly used sedatives in critical care and anesthesia worldwide.
- Propofol is a GABAA receptor agonist, NMDA receptor antagonist, and diminishes calcium influx via slow calcium ion channels causing global CNS depression resulting in sedative, anxiolytic, and anticonvulsant properties.
- Propofol has an ideal pharmacokinetic profile with a 30-second onset of action and duration of action 3-10 minutes, but this may be prolonged with extended use (e.g. 10 days)
- Propofol infusion syndrome (PRIS) is a rare and potentially fatal condition that was first reported in children in 1990. It is characterized by profound metabolic acidosis and bradycardia which may ultimately lead to cardiac arrest.
- While PRIS in adults has generally been seen with long-term (>48 hour) and high-dose (>4-5 mg/kg/h or ~67 mcg/kg/min) propofol use, more recent cases are described in older patients receiving infusions within recommended dose limits.
Pathophysiology
While glucose is generally the major source of energy to the brain, cardiac system, and skeletal muscles, there is a shift toward the use of free fatty acids during times of stress in the setting of elevated epinephrine and cortisol levels. Elevated stress hormones increase lipase activity in the adipose tissue which promotes the degradation of triglycerides into glycerol and free fatty acids. Liver cells then use glycerol as a source for glucose, but the free fatty acids undergo beta-oxidation in the mitochondria (Krebs cycle). The final products of the Krebs cycle include ketone bodies which may be used as an energy source as well as H+ and NADH which then enter the mitochondrial transport chain to produce ATP.
The pathophysiology of PRIS has not fully elucidated, but the current theory includes propofol inhibition of intracellular energy production by 1) inhibition of the transportation of long-chain fatty acids into the cell and 2) inhibitory effects on the mitochondrial respiratory chain.
Since propofol is formulated in a lipid emulsion, the solvent, as well as the drug itself, contribute to hyperlipidemia and hypertriglyceridemia. The accumulation of free fatty acids promotes cardiac arrhythmias. Additionally, propofol blocks calcium channels which can lead to decreased cardiac contractility. Other “priming” factors that may contribute to the development of PRIS include critical illness, neurological injury, decreased carbohydrate stores, advanced stress, vasopressor administration, and use of glucocorticoids.
Clinical features of PRI
PRIS should be considered when there is unexplained metabolic acidosis, ECG changes, and rhabdomyolysis.
Clinical Features of PRIS | |
Cardiac | Cardiac failure, pulmonary edema, QRS widening, bradycardia, ventricular tachycardia or ventricular fibrillation, asystole |
Respiratory | Hypoxia |
Vascular | Hypotension |
Renal | Acute kidney injury |
Musculoskeletal | Rhabdomyolysis |
Metabolism and nutrition | High anion gap metabolic acidosis, hyperkalemia, hyperlipidemia, hyperthermia |
Hepatobiliary | Hepatomegaly, elevated LFTs |
In a recent analysis of published case reports (124 adult, 44 pediatric), Hemphill and colleagues systematically described the range and frequency of clinical features, organ dysfunction, and predictors of mortality in PRIS. Overall, mortality was 48% in adults with PRIS, and it affected patients with a broad range of body habitus, mean body weight 70 kg (IQR 66-192 kg). The median mean-infusion rate of propofol in adults was 5.1 mg/kg/h and the median cumulative dose was 380 mg/kg.
No single clinical feature was common to all reported cases in either children or adults, but the most common feature in adults was metabolic acidosis (80%) followed by ECG changes (63%)
Univariate analysis demonstrated that fever, hyperkalemia (but not rhabdomyolysis), hypotension, ECG changes, traumatic brain injury, mean infusion rate >5 mg/kg/h, duration of infusion >48 h, and cumulative dose >240 mg/kg were associated with an increased risk of mortality in adults. Multivariate analysis showed that ECG changes, hypotension, hyperkalemia, traumatic brain injury, and mean propofol infusion rate >5 mg/kg/h are associated with an increased mortality.
Although there was no relationship between patient weight or BMI and the development of PRIS, pharmacokinetic studies have suggested that propofol dosing should be calculated based on ideal body weight. The difference in ideal vs. actual body weight may not be clinically significant for many patients but could be substantial in obese patients. ICU order sets for sedation may not routinely utilize ideal body weight for dosing calculations. Careful attention to the selected dosing weight should be made for obese patients requiring deep sedation with propofol.
Management of PRIS
There are no established treatment guidelines for PRIS, but successful treatment depends on rapid recognition of the disease process. Clinicians should have a heightened awareness of the clinical features associated with PRIS and be ready to suggest appropriate management including prompt discontinuation of propofol. Alternative sedation with either dexmedetomidine or benzodiazepines should be utilized as tolerated.
There is no antidote for propofol, but dextrose infusion may have some benefit due to the mitochondrial injury in PRIS. Emergent, supportive care should focus on mitigating ECG changes, hyperkalemia, hypotension, and fever. Standard treatments for arrhythmia should be utilized. Correction of acidosis including the use of continuous hemofiltration should be considered to prevent the development of arrhythmia and improve response to vasopressors. Some case reports have shown venoarterial extracorporeal membrane oxygenation (VA-ECMO) effective in aiding cardiac recovery.
The Debrief
- Propofol infusion syndrome (PRIS) is a rare and potentially fatal condition caused by shifts in intracellular energy production.
- Clinical features including fever, hyperkalemia, hypotension, ECG changes, traumatic brain injury, mean infusion rate >5 mg/kg/h, duration of infusion >48 hours, and cumulative dose >240 mg/kg are associated with increased mortality in PRIS.
- Propofol should be dosed using ideal body weight in obese patients to minimize the risk for developing PRIS.
References
- Mirrakhimov AE, Voore P, Halytskyy O, et al. Propofol infusion syndrome in adults: a clinical update. Crit Care Res Pract. 2015; 2015: 260385.
- Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 2019; 122(4):448-459.
- Diedrich DA, Brown DR. Analytic reviews: propofol infusion syndrome in the ICU. J Intensive Care Med. 2011; 26:59-72
