The Pre-brief
My older toddler loves asking me “why?” Why did the flower die after we picked it? Why is that person not wearing a helmet while biking? Why is there no gravity in space but there is gravity here?
It’s good to ask why and practice with a questioning attitude. Why do we do the things we do? Why do we give ketamine and propofol together instead of just giving one for procedural sedation? Is the combination better than monotherapy?
Introduction
“Ketofol” as it’s endearingly known, is the combination of ketamine and propofol, which are given together during procedural sedation. For good procedural sedation, it’s important to have a medication with rapid onset of action, duration of action long enough to sustain the procedure but short enough to allow for quick recovery, and minimal to no adverse effects. The patient should be adequately sedated and relieved of pain.
Propofol is a lipophilic anesthetic with sedative and amnestic properties. Amnesia from propofol lasts ~16 minutes in adults who have received a 1 mg/kg dose followed by 0.5 mg/kg until sedation is achieved. It’s been shown that patients exhibit a response to noxious stimuli during the procedure but do not recall it afterward, confirming the lack of analgesic effect. Propofol’s limiting factors include hypoxia, respiratory depression, apnea, and hypotension.
Ketamine is a phencyclidine derivative, which causes dissociation between the cortical and limbic systems through non-competitive NMDA antagonism. Patients experience analgesic and dissociative effects. They cannot perceive pain, nor the environment around them. One of the benefits of ketamine is that it does not cause respiratory depression unless given too quickly. Adverse effects include laryngeal spasms, increased airway secretions, and bronchodilation. Ketamine is also associated with an emergence phenomenon as it wears off; patients may experience vivid dreams or become acutely agitated. Advantages of ketamine include preservation of respiratory function and reduced respiratory side effects. This coupled with its ability to mute pain perception in theory could make it a nice complement to propofol.
Ketofol Concept and Preparation
Since propofol and ketamine make up for one another’s limitations, it makes sense that the combination could work synergistically. In addition, literature shows that using the two medications together allows for lower doses of each component to be used while still achieving good conscious sedation conditions.
Propofol and ketamine may be combined in a single syringe. The advantage to this is one syringe and one medication label. It is recommended to use the 10 mg/mL concentration of each medication to ensure that you get a 1:1 ratio with every milliliter administered. Also, while the two medications do look drastically different (propofol being white and ketamine clear) it does minimize the risk of “selection error” in which the administrator selects the wrong medication to administer. The disadvantage to the single syringe preparation strategy is that it does not allow for flexibility of administering only one agent. For example, perhaps you give the patient the initial bolus dose of Ketofol, but then decide to give only 10 mg of propofol without ketamine for a subsequent dose.
Ketofol vs Propofol
While there are plenty of articles published in the early 2000’s, the last big article was the 2016 POKER trial (summary of the trial below). Ultimately, the investigators concluded, “Ketofol and propofol resulted in a similar incidence of adverse respiratory events requiring the intervention of the sedating physician. Although propofol resulted in more hypotension, the clinical relevance of this is questionable, and both agents are associated with high levels of patient satisfaction.”
In that same year, Jalili and colleagues put together a meta-analysis of the evidence to determine the analgesic effects and side effects of ketofol vs propofol for procedural sedation (see below). They concluded that ketofol is an appropriate substitution for propofol and allows for use of lower doses of each component and lower risk of adverse effects.
In 2019, Ghojazadeh and colleagues published a meta-analysis showing similar findings. The authors concluded that there was a lower incidence of respiratory adverse effects in the ketofol group vs the propofol monotherapy group however more research is needed to compare efficacy.
Oh and colleagues evaluated ketofol against propofol during loop electrosurgical excision procedure (LEEP). Although this study was not conducted in ED patients specifically, the concept is the same and worth including in my evaluation.
Overall, the majority of literature leaves me with the notion that ketofol may not be as advantageous as we thought when compared to propofol monotherapy. Providers could use either option safely, knowing that one is not significantly better than the other. The study by Oh and colleagues is interesting because it suggests that a lower dose of ketamine may be used as part of a Ketofol regimen. A 1:1 (ketamine:propofol) may not be needed.
Ketofol vs Ketamine
There is a paucity of literature available assessing ketofol against ketamine monotherapy. In 2017 an article was published in the Journal of Emergency Medicine reviewing the findings of Weisz and colleagues when they evaluated adverse events between ketamine monotherapy and ketamine propofol combination therapy for procedural sedation in a pediatric emergency department and in 2019 a meta-analysis was published of the available evidence by Hu and colleagues.
Conclusion
Based on the above articles, ketamine monotherapy does not appear to be ideal, however, propofol monotherapy and ketamine/propofol are safe and effective. Ultimately, I’m not convinced that we need to be using ketofol. It’s not as advantageous as we thought, makes for an extra medication that needs to be drawn up with little added benefit, especially when it is possible to utilize propofol monotherapy with good outcomes.
What do you do in your hospital? Have you had experience using the combination vs monotherapy of one agent or the other? Comment below!
The DeBrief
- The ideal agent for procedural sedation should exhibit the rapid onset of action, duration of action long enough to sustain the procedure but short enough to allow for quick recovery, and minimal to no adverse effects.
- In theory, combining propofol with ketamine would be ideal since propofol provides amnestic and sedating properties, while ketamine provides analgesia and preservation of respiratory function. However, the literature has not been able to demonstrate a clear win for the combination compared to single-agent use.
- If using ketofol, lower doses of each component (e.g. 1 mg/kg ketamine and propofol in equal ratios or less) may be reasonable without compromising efficacy.
References
- Ferguson I, Bell A, Treston G, New L, Ding M, Holdgate A. Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine-The POKER Study: A Randomized Double-Blind Clinical Trial. Ann Emerg Med. 2016;68(5):574-582.e1. doi:10.1016/j.annemergmed.2016.05.024
- Jalili M, Bahreini M, Doosti-Irani A, Masoomi R, Arbab M, Mirfazaelian H. Ketamine-propofol combination (ketofol) vs propofol for procedural sedation and analgesia: systematic review and meta-analysis. Am J Emerg Med. 2016;34(3):558-569. doi:10.1016/j.ajem.2015.12.074
- Ghojazadeh M, Sanaie S, Paknezhad SP, Faghih SS, Soleimanpour H. Using Ketamine and Propofol for Procedural Sedation of Adults in the Emergency Department: A Systematic Review and Meta-Analysis. Adv Pharm Bull. 2019;9(1):5-11. doi:10.15171/apb.2019.002
- Oh C, Kim Y, Eom H, et al. Procedural Sedation Using a Propofol-Ketamine Combination (Ketofol) vs. Propofol Alone in the Loop Electrosurgical Excision Procedure (LEEP): A Randomized Controlled Trial. J Clin Med. 2019;8(7):943. Published 2019 Jun 28. doi:10.3390/jcm8070943\
- Weisz K, Bajaj L, Deakyne SJ, et al. Adverse Events During a Randomized Trial of Ketamine Versus Co-Administration of Ketamine and Propofol for Procedural Sedation in a Pediatric Emergency Department. J Emerg Med. 2017;53(1):1-9. doi:10.1016/j.jemermed.2017.03.024
