Ketofol: Combination Propofol and Ketamine

Despite their demonstrated efficacy as sedation and analgesics, propofol and ketamine can result in adverse events [1]. Propofol can lead to hypotension, respiratory depression, hypoventilation, and loss of airway reflexes [2]. Conversely, ketamine does not risk the compromise of a patient’s airway reflexes, but it can cause hypertension, emergence delirium, vomiting, and tachycardia [2]. Ketamine can also impede the central nervous system [1]. To avoid the complications associated with each medication, researchers developed ‘ketofol’ as a combination of propofol and ketamine [1].

At first glance, ketofol appeared to be an effective replacement for ketamine and propofol. In 1999, Friedberg conducted a large meta-analysis of 2,059 operations performed on 1,264 patients anesthetized using combination propofol and ketamine [3]. None of the patients reported hallucinations, uncontrolled pain, vomiting, and nausea, and all of them were satisfied with their anesthetic regimen [3]. The study concluded that ketofol is a safe and effective anesthetic [3]. More recently, Slavik and Zed retrospectively analyzed 23 studies, all of which were centered on the efficacy of propofol and ketamine in combination [1]. They concluded that there was not substantial literature to demonstrate that ketofol evades the adverse cardiovascular events associated with ketamine and propofol [1]. Furthermore, ketamine-propofol did not appear to provide better analgesia than propofol alone [1]. While these findings do not necessarily contradict Friedberg’s conclusion, they certainly demonstrate the need for more research on ketofol.

For anesthesia providers considering using ketofol during an operation, knowledge of the appropriate ratio to administer is essential. Several studies have compared different ratios among themselves, as well as to anesthetic monotherapies, such as propofol alone [4]. One such study drew a comparison between 2:1, 3:1, and 4:1 propofol-ketamine combinations; propofol alone; and a propofol-fentanyl combination [4]. All of the ketofol mixtures provided patients with effective analgesia [4]. However, the 3:1 and 4:1 mixtures led to especially quick recovery and discharge times [4]. Additionally, the 4:1 mixture was responsible for the lowest incidences of postoperative dizziness and respiratory depression among the propofol-ketamine mixtures [4]. While these are the results of only one experiment, they could help guide physicians toward the ideal ratio with which to create ketofol.

Despite its uncertain benefits, ketofol has already found meaningful application in hospital emergency departments (ED). Phillips et al. studied the efficacy of combination ketamine and propofol in an ED during brief procedures, such as fracture manipulation [5]. Of the 28 patients studied, none required intervention or underwent respiratory depression [5]. Compared to the propofol group, the ketofol group was closer to their target bispectral index monitoring score and experienced less hypotension [5]. Willman and Andolfatto also encountered promising results when analyzing the cases of 114 patients who received ketofol in an ED [6]. No patient experienced vomiting or hypotension, and 96.5% of patients did not require additional sedatives [6]. Together, these results suggest there may be cardiovascular benefits, among others, to the use of ketofol as a sedative.

Still, ketofol does not seem so promising in all contexts. One such context is pediatrics. A recent meta-analysis of 29 studies sought to determine the efficacy of ketofol in operations conducted on children [7]. Hayes et al. did identify reduction of some risks due to ketofol–including apnea, hypotension, and bradycardia [7]. Yet, they also found that ketofol may increase children’s risk of respiratory adverse events, hypertension, and tachycardia [7]. Another study did not find a significant difference in sedative quality between ketofol and ketamine, with adverse events occurring at comparable frequencies [2]. Whether these results are the symptoms of imperfect ratios, or indicative of a greater failure on the part of ketofol, warrants continued investigations into the mechanisms of combination propofol and ketamine.

References

[1] V. C. Slavik and P. J. Zed, “Combination Ketamine and Propofol for Procedural Sedation and Analgesia,” Pharmcotherapy, vol. 27, no. 11, p. 1588-1598, January 2012. [Online]. Available: https://doi.org/10.1592/phco.27.11.1588.

[2] Y. Hu, W. Xu, and F. Cao, “A meta-analysis of randomized controlled trials: combination of ketamine and propofol versus ketamine alone for procedural sedation and analgesia in children,” Internal and Emergency Medicine, vol. 14, p. 1159-1165, September 2019. [Online]. Available: https://doi.org/10.1007/s11739-019-02173-6. 

[3] B. L. Friedberg, “Propofol-ketamine technique: Dissociative anesthesia for office surgery (A 5-year review of 1264 cases),” Aesthetic Plastic Surgery, vol. 23, no. 1, p. 70-75, January-February 1999. [Online]. Available: https://doi.org/10.1007/s002669900245.

[4] S. Amornyotin, “Ketofol: A Combination of Ketamine and Propofol,” Journal of Anesthesia & Critical Care, vol. 1, no. 5, p. 1-3, January-February 1999. [Online]. Available: https://doi.org/10.15406/jaccoa.2014.01.00031.

[5] W. Phillips et al., “Propofol Versus Propofol/Ketamine for Brief Painful Procedures in the Emergency Department: Clinical and Bispectral Index Scale Comparison,” Journal of Pain & Palliative Care Pharmacotherapy, vol. 24, no. 4, p. 349-355, December 2010. [Online]. Available: https://doi.org/10.3109/15360288.2010.506503.

[6] E. V. Willman and G. Andolfatto, “A Prospective Evaluation of “Ketofol” (Ketamine/Propofol Combination) for Procedural Sedation and Analgesia in the Emergency Department,” Annals of Emergency Medicine, vol. 49, no. 1, p. 23-30, January 2007. [Online]. Available: https://doi.org/10.1016/j.annemergmed.2006.08.002.

[7] J. A. Hayes et al., “Safety and Efficacy of the Combination of Propofol and Ketamine for Procedural Sedation/Anesthesia in the Pediatric Population: A Systematic Review and Meta-analysis,” Anesthesia & Analgesia, vol. 132, no. 4, p. 979-992, April 2021. [Online]. Available: https://doi.org/10.1213/ANE.0000000000004967.