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The Milk of Amnesia: Propofol



Ah, the “Milk of Amnesia,” that famous dairy product-looking medication that got the best of Michael Jackson 🙄 (We’ve all heard it). Or, maybe I’m assuming you all heard that in medic class too… and I’m wrong. 😏



Propofol is in the spotlight in this blog. We will be discussing several things Propofol.


Propofol became commercially available (FDA approved in the US) in the 1980s and is a highly lipid-soluble, short-acting general anesthetic often marketed as Diprivan that results in anesthetic effects (decreased level of consciousness) and amnesia [10]. It is used intravenously and has a very rapid onset and recovery making it a desirable medication, depending on the clinical scenario. Propofol is also on the World Health Organization's List of Essential Medicines since 2016 [3]. Aside from its use in the operating room for induction and maintenance of anesthesia, this agent is used as a sedative in mechanically ventilated patients. Propofol also has been used "off-label" for post-operative nausea and vomiting and to treat refractory status epilepticus.


Mechanism of Action


Jake Good (fellow FOAMfrat educator) mentions in his blog about ETOMIDATE that we all often hear or speak of “GABA” in medic class. But we don’t know much more about it other than, “there are medications that produce anesthesia and work on the GABA receptors.” And while I can’t say that’s true for everyone, I definitely agree with him. I have heard it myself and I know many others in the same boat. 😬 🛶


GABA stands for: Gamma Amino-Butyric Acid and its receptors are the primary/chief inhibitory receptors of the central nervous system (CNS) [2,4]. The CNS has a red light (GABA receptor) and a green light (NMDA receptor). Both, are functionally active at the same time and balance each other out, much like the sympathetic and parasympathetic nervous systems. That balance spends more time at the red light when we give a medication that affects the GABA receptor, more specifically the GABA-A receptor [4].



GABA-A receptors are ion channels that are activated by GABA, the major inhibitory neurotransmitter in the central nervous system. These receptors assemble from five protein subunits (alpha 1 & 2, beta 1 & 2, and gamma) with an integral pore that is permeable to chloride and bicarbonate ions. Intravenous anesthetics like propofol, etomidate, thiopental, and midazolam all act as positive allosteric modulators at GABA-A receptors, causing a loss of consciousness [3]. The response to these medications causes the channels to be activated for longer durations, resulting in an influx and increase in chloride ions leading to hyperpolarization of the cell membrane, making it harder for the action potential to fire [1].


Propofol enhances GABA activity at the GABA-A receptor site in the CNS, floods the cells with chloride ions causing hyperpolarization, decreasing the resting membrane potential, leaving the cells unable to depolarize. Once the cell is flooded with chloride and unable to depolarize, we see the clinical effects of the medication; unconsciousness/anesthetic effect.


Like me, you may be asking yourself what the 💩 is a positive allosteric modulator? allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, are medications like Propofol. Positive types of these modulators increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (increased affinity) and increasing its ability to activate the receptor (increased efficacy).


Chloride influx into CNS cells is what causes the inhibitory effect of these receptors. Remember, depolarization of neuronal cells is caused by a rapid influx of cations (namely sodium) into the cells. Sodium is a positively charged ion and increases the membrane potential of the cell past the threshold to elicit depolarization (aka an action potential). So, when a highly negative anion, like chloride, enters the cell, it keeps that membrane potential very low and therefore doesn’t allow the cell to depolarize — rather, it maintains a very low resting membrane potential [4].



Indications

Propofol is an IV anesthetic used for procedural sedation, during monitored anesthesia care, or as an induction agent for general anesthesia.


Its clinical use as we see it in the ER, pre-hospital, and critical care environment is geared towards:

  • Procedural sedation

  • Induction for rapids sequence induction

  • Continued sedation for the intubated, mechanically ventilated patient

  • Refractory status epilepticus (off-label use)


Contraindications

  • Hypersensitivity

  • Hypotension; or caution in use


Dose

Propofol can be used for both induction for RSI and continued sedation of the mechanically ventilated patient, making it a multipurpose tool in your tackle box

  • 1 to 2 mg/kg bolus for induction [10]

  • 5 to 200 mcg/kg/min for continued sedation

  • Widely varying recommendations; follow your local protocol or guidelines

** From the FDA medications package insert **

Advantages/Benefits

  • Rapid onset (15 to 45 seconds) [6]

  • Rapid recovery (5 to 10 minutes) [6]

  • Provides amnesia

  • Bronchodilator properties [12]

  • Anticonvulsant

  • Off-label use for status epilepticus


Adverse Effects & Considerations

  • Pain at the injection site (most common adverse reaction).

  • Decreased by administering IV lidocaine before a bolus (usually through protocol or medical direction).

  • Hypotension

  • Primarily due to venous and arterial dilation

  • Serum triglyceride and lipase rise during infusion

  • ECG changes such as QT prolongation have been seen (although reported as rare)

  • Provides no analgesia

  • Dose-dependent cardiovascular and respiratory depression [3]




Egg or Soybean Allergies???

Propofol is prepared in a lipid emulsion which gives it the characteristic milky white appearance and age ole name, “milk of amnesia.” The formula contains soybean oil, glycerol, egg lecithin, and a small number of preservatives [1].


Patients who are allergic generally react to ovalbumin and not lecithin, so propofol is not contraindicated in patients with an egg allergy [6].


With that being said, some of the inserts accompanying the medication say that propofol should not be given to those with reported allergies to eggs, egg products, soy, or soy products. Allergic reactions occur secondary to exposure to specific proteins from both egg and soy sources and not the fats that make up the propofol emulsion. The oils used to manufacture propofol are unlikely to contain quantities of proteins significant enough to produce an allergic cross-reaction. Clinical judgment should be exercised.[1]


Don't Get Dirty with Propofol

Propofol has a high contamination risk. Despite the addition of antimicrobials, propofol preparations support rapid bacterial growth due to the lipid emulsion containing egg lecithin, glycerol, and soybean oil.


Minimize this risk by using an aseptic technique during preparation and avoiding multi-dosing from a single vial. Propofol should also be discarded six hours after opening. [2]


Utilization of propofol in the prehospital environment does not at all lend to this issue. Also, use an aseptic technique, always.


Propofol Related Infusion Syndrome (PRIS)

Although not usually something we would encounter in the pre-hospital setting, this is a rare but serious side effect of prolonged propofol infusions with a high mortality rate [8].


Characterized by a myriad of symptoms including dysrhythmia (bradycardia or tachycardia), widening of the QRS complex, heart failure, hypotension, asystole, lipemia, and hypertriglyceridemia, metabolic acidosis, and/or rhabdomyolysis or myoglobinuria with acute kidney injury and hyperkalemia [8].


Occurs at doses of >4 mg/kg/hr for more than 2 days, but has been seen with lower doses and in some cases between 1 and 4 days [8].


Ketofol

The combination of Ketamine and Propofol (“Ketofol”) was developed for procedural sedation and is used by some clinicians for induction during RSI. The purported benefit of this combination is to obtain the benefits of each drug (analgesic effects of ketamine) while minimizing the potential harms (hypotensive effects of propofol) [7].


Ketofol and propofol, in comparison, produced a similar incidence of adverse respiratory events during procedural sedation. Although propofol alone did result in more hypotension than Ketofol, the clinical relevance was still questionable. [9]



BOOM! 💥

Jared Patterson, CCP-C, FP-C, One Rad Dude



Killin' It Since 1989

Twitter: @OneRadMedic

Instagram: OneRadMedic








References:


1. Folino TB, Muco E, Safadi AO, et al. Propofol. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430884/


2. King, MD, A. (2020). General Anesthesia: Intravenous Induction Agents. Retrieved 26 December 2021, from https://www.uptodate.com/contents/general-anesthesia-intravenous-induction-agents?search=propofol--drug--information&source=search_result&selectedTitle=3~148&usage_type=default&display_rank=2#H2269447


3. Bernd Antkowiak & Gerhard Rammes (2019): GABA(A) receptor-targeted drug

development - New perspectives in perioperative anesthesia, Expert Opinion on Drug Discovery,

DOI: 10.1080/17460441.2019.1599356


4. Pharmacology NOT Taught in Medic School - Etomidate Edition; Jake Good - FOAMfrat (2021). https://www.foamfratblog.com/post/pharmacology-not-taught-in-medic-school-etomidate-edition


5. King, MD, A. (2020). General Anesthesia: Intravenous Induction Agents. Retrieved 26 December 2021, from https://www.uptodate.com/contents/general-anesthesia-intravenous-induction-agents?search=propofol--drug--information&source=search_result&selectedTitle=3~148&usage_type=default&display_rank=2#H2269447


6.Brown, C. A., Sakles, J. C., & Mick, N. W. (2018). The Walls manual of emergency airway management. Philadelphia: Wolters Kluwer.


7. Caro, D. (2021). Induction Agents for Rapid Sequence Intubation in Adults Outside the Operating Room. Retrieved 17 December 2021, from https://www.uptodate.com/contents/induction-agents-for-rapid-sequence-intubation-in-adults-outside-the-operating-room?search=RSI&topicRef=270&source=see_link#H14


8. Propofol: Drug Information. Retrieved 26 December 2021, from https://www.uptodate.com/contents/propofol-drug-information?search=propofol--drug--information&topicRef=94533&source=see_link#F214549


9. Ferguson I et al. Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine – The POKER Study: A Randomized Double-Blind Clinical Trial. Ann Emerg Med 2016 [Epub Ahead of Print] PMID: 27460905


10. Pollack, A., McEvoy, M., Rabrich, J., & Murphy, M. (April 3, 2017). Critical Care Transport (2nd ed.). Jones & Bartlett Learning.


11. Eames WO, Rooke GA, Wu RS, Bishop MJ. Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance after tracheal intubation. Anesthesiology. 1996 Jun;84(6):1307-11. doi: 10.1097/00000542-199606000-00005. PMID: 8669670.


12. Marik PE. Propofol: therapeutic indications and side-effects. Curr Pharm Des. 2004;10(29):3639-49. doi: 10.2174/1381612043382846. PMID: 15579060.


13. Corrado, Michael J. PharmD; Kovacevic, Mary P. PharmD, BCCCP, BCPS; Dube, Kevin M. PharmD, BCCCP, BCPS; Lupi, Kenneth E. PharmD, BCCCP, BCPS; Szumita, Paul M PharmD, FCCM, FASHP, BCCCP, BCPS; DeGrado, Jeremy R. PharmD, BCCCP, BCPS The Incidence of Propofol-Induced Hypertriglyceridemia and Identification of Associated Risk Factors, Critical Care Explorations: December 2020 - Volume 2 - Issue 12 - p e0282

doi: 10.1097/CCE.0000000000000282


14. Analgesia and Sedation. Retrieved 5 January 2022, from https://www.openanesthesia.org/analgesia_and_sedation/











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