In this episode, I’ll discuss why I think ketamine and propofol don’t belong in the same syringe.
Ketamine and propofol are compatible in the same syringe, and several published studies have specifically stated that the two medications were placed in the same syringe.
But just because we can, doesn’t mean we should.
These two medications frequently given together for procedural sedation in the Emergency Department and elsewhere. This combination is sometimes called “ketofol”.
This combination has been studied for well over a decade, and there are now meta-analyses published on the topic in both adults and children for procedural sedation in the ED.
In this combination, propofol serves to provide sedation while ketamine serves to provide analgesia without increasing the respiratory depressant effects of propofol. An additional benefit of the combination is that the hypotension from propofol may be partially offset by the positive cardiovascular effects of ketamine.
Indeed, the previously described meta-analysis support that ketamine plus propofol results in fewer episodes of bradycardia and hypotension than propofol alone. Ketamine-related psychomimmetic side effects don’t appear to occur more frequently than in the propofol monotherapy group, or at least the difference is not statistically significant.
The ratio of ketamine to propofol varies widely with some studies using 1:1, some using 1:10, and several more at various points in between this range.
The problem I have with placing ketamine and propofol together in the same syringe comes when this practice is taken from a controlled study environment to a real-world setting.
The analgesic effects of ketamine may last up to 90 minutes, while the sedative effects of propofol will only last a few minutes. With two different durations of action in the same syringe, what happens when the procedure goes a bit longer than planned and more sedation is needed? The clinician is forced to give more ketamine even though all that was needed was propofol. Worse yet, if more analgesia is called for, the clinician needs to give it along with more propofol, raising the risk of respiratory compromise for no good reason.
While most of the time, a serious adverse event will not occur when a second dose of “ketofol” is given to provide more analgesia or more sedation, that’s not the point. The point is that the risk of adverse event is raised for a capricious reason that is easily avoidable by using 2 syringes. In my opinion, there is no need to take this risk and ketamine and propofol belong in two separate syringes, even when used together for procedural sedation.
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I always tell trainees to avoid combination drugs because inevitably you will give more of one drug than you intended or need to for the clinical effect that you are seeking
“Don’t belong” in the same syringe?
Your article began well, explaining how well the two drugs synergize for a powerful yet safe sedation. You then appropriately pointed to the very different half lives of the two drugs. This difference means that prolonged use of a constant ratio of drug quantities will eventually result in unwanted accumulation of ketamine. To avoid this, there a number of possible strategies. One can separately administer the two drugs, limiting the ketamine at some point, and continue with propofol alone. Or one could begin with a mixture in the first syringe (or two), then continue with propofol alone. Suggesting that the second practice “doesn’t belong” is needlessly restrictive. Giving propofol and ketamine together as a mixture works well so long as you keep in mind the total ketamine dose. I use one or the other strategy in different circumstances.
When I was in hospital, we used to make Kefzol (or Metrocef) a combo of metronidazole for anaerobes and Ancef for gram positives. In that case it made sense to combine; one dose, no titrating. I agree with your recommendation to never used a drug you have to repeat for titration with one that does not need to be repeated. However, my understanding is that the combo is used for first dose only, and after that they use propfol alone.
This article seems to be assuming that the drugs are being given as bolus dosing. In my experience, most people use ketofol as an infusion, which avoids the issue of large doses given toward the end of surgery.
I was the principal investigator of 2 studies that employed a mixture of propofol and remifentanil in a single syringe. Admittedly, the pharmacokinetics of remi is more similar to propofol than ketamine, but it doesn’t really matter over the time course of most procedural sedation. In the second study, I developed a control system designed to maintain the depth of sedation at a constant level by delivering a fixed bolus of the mixture at a specified time via a Graseby 3300 PCA pump. This worked because if your goal is a single endpoint (unresponsiveness to noxious stimuli) there will always be a point of the isobologram for the 2 drugs that will achieve this. Thus, the patient is moving, press the button. The notion that you can titrate sedatives to hemodynamic side effects is not particularly useful for a single agent; for mixtures it is meaningless.
Having said this, I don’t use ketofol for a number of reasons. The first is that it forces me to handle a controlled substance when I otherwise wouldn’t. The second is that it forces me to label syringes legibly. The third is that ketamine is too variable in its effects to be able to titrate in an unconscious patient. Of course, the third reason is hypothetical and not nearly as compelling as the first two.
You can start off with a propofol-ketamine syringe and then switch to propofol only later in the case. Easy. Also, there’s not much harm in having extra analgesia after the case is over.
I routinely mix propofol and ketamine in the same syringe for a continuous infusion for total knee arthroplasty under regional (spinal plus Motor-sparing femoral nerve block) anesthesia. This provides excellent sedation for the patient with prompt wake up at the end of the procedure. I use a ratio of 10 mg of propofol to 1 mg of ketamine and set the infusion at 60-70 mcg/kg/min of propofol.
If more than 500mg of propofol is required, my subsequent syringes are prepared without ketamine.
Initial bolus is usually 40-50 mg propofol plus 30 mg ketamine.
Simply limit your total ketamine dose to 50 for ED procedures and less that 100 for outpatient surgery. If you have a pre-determined limit on ketamine then they are fine in the same syringe.
I completely agree. I have used this combination since the mid 1990’s, when I published an article on its use in full face resurfacing with the CO2 laser. I have tried many different techniques and the “advantage” of mixing any two drugs in one syringe is outweighed by the inability to titrate either drug individually. Other than the novelty of trying to come up with a “perfect anesthesia in a syringe” (which I find to not exist), there is no advantage.
Sorry, I totally disagree. I have given 50mg Ketamine in 500mg Propofol to literally 1000s of patients with none the problems you describe. After the first syringe of Ketafol , I will use on Propofol alone, really never need more Ketamine, Substituting dexmedetomidine as needed in bolus doses. I use this non narcotic combo in all surgery scenarios, not just sedation cases.
I agree completely with this. I regularly use ketamine and propofol together, but I do not mix it for exactly this reason.
I think his logic is. . . . . . . think about the individual pharmacology of each agent you’re using, tailor your drug use according to this pharmacology & patient need, to optimize benefits and potentially reduce risk.
I.e., be thoughtful, specific and deliberate in tailoring your anesthetic.
While I agree that 2 syringes are Ideal, and in the setting you refer to Procedural Sedation in the ED it seems appropriate, I would like to state that Ketafol, and PFK are mixtures I learned as CRNA in the Military where space, weight, time and other factors make this an Ideal mixture in the many Austere environments we find ourselves. So in your controlled practice setting I can understand your position and don’t disagree with your rational, however as a broad statement that they don’t belong in the same syringe I have to disagree when in knowledgeable and practiced hands for different situations from whence the combination was born out of necessity.
I disagree. I’ve used ketamine with propofol numerous times for total knees and hips when the spinal has worn off or in deep sedation procedures. Where I put 20mg into a 200mg propofol syringe. Usually run it at 50mc/kg/min. Once I’ve reached 50mg ketamine then straight propofol. The issue I have with this article is the authors rationale for why not to use it. I’m assuming most practitioners are using thought before giving any anesthetic. I don’t think it is wrong to do it one way or the other. I don’t think there was good rationale given why not to do it.
Everyone from the anesthesia department, please disregard this entire read. Good Lord folks I’ve been using so called “ketofol” for an eon now and I never am “forced” to give more ketamine than I want…. Like …: ever! You know your surgical time, you know your therapeutic goal and you take into account emergence and time to discharge from the PACU. You stop the infusion that contains the ketamine and use straight prop from there until the end. Since when has ANY providers hands been “tied” to giving what’s in a syringe? Thanks for labeling the contents of this syringe and opinion piece….