Episode 44 – Propofol, White Lightning

Why can propofol cause Propofol-Related Infusion Syndrome?

On this episode of the podcast, we discussed the Propofol-Related Infusion Syndrome (PRIS). Propofol is a very common medication in the intensive care unit (ICU). It is a sedative-hypnotic medication with many advantages compared with other continuous sedative infusions. In particular, it has both quick a onset and offset of action. Because it inhibits GABA signaling, propofol is also used in the treatment of alcohol withdrawal. It’s been called “milk of amnesia” due it its amnestic properties and milky-white color. 

Many clinicians reflexively order monitoring labs including CK but don’t necessarily understand why they’re doing so.

Propofol was developed and first used clinically in the 1970s. In the 1980s and 1990s, reports started to emerge of pediatric patients who had received high dose, extended propofol infusions and then developed a curious constellation of symptoms: rhabdomyolysis with frank muscle necrosis, bradyarrythmias, cardiovascular collapse, lactic acidosis, and multiorgan system failure. And it just seemed clearly linked to propofol infusion. Adults could be affected too but kids appeared to be more susceptible. 

The initial insult seems to be muscle necrosis, which typically involves skeletal muscle but also cardiac muscle as well. These different types of muscular necrosis lead to rhabdomyolysis, cardiac dysfunction, and multisystem organ failure. But it all seems to start with some going wrong in the muscle. It’s important to note that this seems to be a dose-dependent phenomenon – higher doses with longer infusion times are key to being at risk for PRIS.

The question then comes: why muscle? One important clue came from a study performed in rats, published in the journal Biochemical Pharmacology in 1991. The researchers studied isolated rat liver mitochondria. They found that when these rat mitochondria were exposed to high doses of propofol, their production of ATP dropped dramatically. They essentially stopped producing ATP.

To ascertain whether propofol was the cause a study in Critical Care Medicine from 2000 exposed isolated guinea pig hearts to varying doses of propofol. The researchers found that higher doses of led to a steep drop in oxygen utilization, which is a proxy for mitochondrial function and ATP production. Their actual experiment looked at what happened to the oxygen saturation of myoglobin molecules with propofol exposure, and they found a dose response curve where high concentrations of propofol led to higher myoglobin saturations. If more myoglobin was able to get saturated with oxygen, this implied that oxygen didn’t get utilized by the mitochondria of these guinea pig hearts, which itself implied that the mitochondria had been poisoned by propofol. 

One potential mechanism for this observation is that propofol can block the function of co-enzyme Q, which is an important electron carrier in the electron transport chain. This would inhibit the function of the electron transport chain and decrease ATP production. 

An important clue to another purported mechanism for propofol mitochondrial toxicity is that patients with PRIS have actually been found to have elevated serum levels of specific types of free fatty acids (FFAs). These include the long chain free fatty acid C5-acylcarnitine and the short chain free fatty acid malonylcarnitine.

FFAs mobilize from fat tissue and then undergo oxidization by mitochondria. This oxidation generates ATP via the electron transport chain. They’re are an important source of ATP for tissues, particularly muscle which churn through a lot of ATP. This is particularly true during critical illness where free fatty acids actually become a primary fuel source for the body in a catabolic state.

It appears that propofol inhibits the ability of mitochondria to utilize free fatty acids as oxidative fuel. Patients with PRIS have elevated levels of both long and short chain free fatty acids. This is significant because each type of fatty acid has its own mechanism of entering mitochondria to be used as oxidative fuel. Long-chain FFAs require conjugation to carnitine in order to cross the mitochondrial membrane. They then undergo oxidation, get converted to acetyl coa, and then get utilized for ATP production as a part of the Krebs cycle.

Short-chain FFAs, on the other hand, can cross the mitochondrial membrane without conjugation. They just go straight into oxidation and conversion to acetyl-CoA, prior to being used for ATP production. 

The fact that both short and long chain FFAs are increased in PRIS suggests that propofol can inhibit both FFA conjugation and oxidation, as another mechanism of mitochondrial toxicity.

In fundamental way PRIS is a problem of inadequate fuel supply for increased metabolic demand. Critical illness is a massively stressful state for the body and if tissues like muscles don’t have adequate fuel for their metabolism they’re not going to thrive. And that’s exactly what is seen with the muscular necrosis leading to PRIS.

Take Home Points

  1. Propofol-related infusion syndrome (PRIS) is characterized by skeletal and cardiac muscular necrosis, which leads to the clinical syndrome
  2. Blockade of free fatty acid utilization in mitochondria by propofol causes decreased ATP production. Blockade of co-enzyme Q function in the electron transport chain likely also plays a role
  3. This essentially is a mismatch between metabolic energy supply and demand during critical illness that leads to muscle necrosis, but it is entirely preventable with appropriate dose limits, proper CK monitoring, and cessation of the drug when early signs of muscle injury arise


Click here to obtain AMA PRA Category 1 Credits™ (1.00 hours), Non-Physician Attendance (1.00 hours), or ABIM MOC Part 2 (1.00 hours).

Listen to the episode


Credits & Citation

◾️Episode written by Avi Cooper
◾️Show notes written by Tony Breu and Avi Cooper
◾️Audio edited by Clair Morgan of nodderly.com

Cooper AZ, Abrams HR, Breu AC. Propofol, White Lightning. The Curious Clinicians Podcast. March 2, 2022

Image credit: https://www.latimes.com/opinion/la-ol-propofol-colonoscopies-doctors-mailbag-20131022-story.html

Published by Tony Breu

Tony Breu, MD is an internist/hospitalist who loves asking ‘why’?

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