Lovato, Luis M. MD
You might be right to think you already know everything you need to know about procedural sedation in the ED, but the editors responsible for the May issue of the Annals of Emergency Medicine might beg to differ. With no less than nine separate articles on the topic — three original studies, two editorials, a journal club guide, a clinical practice guideline, a policy revision, and a news update — the topic seems to be raging hotter than a manic shroomer with emergence hallucinosis.
The latest craze making headlines in the sedation literature is ketofol, a combination of ketamine and propofol, each given at a dose less than when administered alone. The combination is intriguing, according to the article by Shah et al, because the two agents have potentially synergistic properties. Theoretically, the intrinsic antiemetic and anxiolytic effects of propofol could reduce emergence nausea and agitation from ketamine. And perhaps ketamine, with its propensity toward cardiovascular stimulation and preserved respiratory reflexes, could minimize the hypotension and respiratory depression associated with propofol. Ketofol proponents also argue that recovery is quicker and the potential for untoward side effects is smaller because each agent is given at less than full dose.
In the study by Shah et al, children 2 to 17 requiring procedural sedation for orthopedic injuries were randomized to receive either a combination of intravenous ketofol — ketamine (0.5 mg/kg) and propofol (0.5 mg/kg) — or ketamine alone (1.0 mg/kg) along with a white, fat emulsion placebo. A repeat dose of each regimen was given every two minutes until adequate sedation was achieved. The primary study outcome was total sedation time, with median total sedation time reported to be three minutes shorter with ketofol (13 minutes) than with ketamine alone (16 min). (–3 min; 95% CI, –5 min to –2 min.)
In another study by David and Shipp, children and adults requiring procedural sedation for a variety of indications were randomized to receive pretreatment first with intravenous ketamine (0.5 mg/kg) or placebo, followed immediately by propofol (1.0 mg/kg). Repeated half-doses of propofol (0.5 mg/kg) were given as needed to maintain sedation. The primary outcome was respiratory depression, which was similar in both groups: ketofol (22%) vs. propofol alone (28%). (6%; 95% CI, 6% to 18%.)
Both studies prominently mention greater satisfaction scores with ketofol than with each control group.
A Blinded, Randomized Controlled Trial to Evaluate Ketamine/Propofol versus Ketamine Alone for Procedural Sedation in Children
Shah A, et al
Ann Emerg Med
Randomized Controlled Trial of Ketamine/Propofol versus Propofol Alone for Emergency Department Procedural Sedation
David H, Shipp J
Ann Emerg Med
Let's examine these studies more closely before jumping on the ketofol bandwagon.
Although the primary outcome in the Shah study was statistically significant, one might question the overall clinical significance of recovering from procedural sedation three minutes faster. This potential benefit becomes even more questionable if one considers another equally important factor: sedation onset. When ketamine alone was given at a dose of 1.0 mg/kg, 53 of 69 patients (77%) achieved adequate sedation after a single bolus. In stark contrast, 35 of 67 patients (52%) who received ketofol required two or more doses to achieve adequate sedation, and six (9%) required five doses or more! This raises the possibility that total procedure time may actually be longer, despite total sedation time being shorter, with ketofol if the physician must wait for repeated doses of ketofol to take effect.
One should also consider whether the ketamine-alone control group was inherently placed at a disadvantage by being underdosed. According to the most recent clinical practice guideline, the minimum dose of ketamine required to reliably achieve a dissociative state in children is 1.5 mg/kg IV. (Ann Emerg Med 2011;57;449.)
Some secondary outcomes — higher patient, nurse, and provider satisfaction scores — in the ketofol group were called statistically significant over the ketamine-alone group. But one must keep in mind that this study was specifically designed and powered to measure only its primary outcome. Secondary outcomes should always be considered secondary for good reason, even when the results appear to be statistically significant. Unfortunately, secondary outcomes often get primary outcome billing when they find their way into an abstract's conclusion.
Using a similar argument, the only firm conclusion one should take from the study by David and Shipp is that ketofol and propofol are equally safe in respiratory depression. Again, satisfaction scores, a secondary outcome, are mentioned prominently in the abstract's conclusion, despite the fact that they are secondary. As the authors point out, the secondary outcomes become even less convincing when one considers the potential effects of unblinding, the unintuitive lack of correlation between sedation depth and sedation satisfaction, and the use of a nonvalidated pain scale.
If ketofol is indeed the future of procedural sedation, it still lays a long way ahead of us. As these two articles highlight, very basic questions remain unanswered. What dose of each agent should one use? In what order should they be administered? And, perhaps most importantly, why use ketofol when much better established alternatives are available? On the other hand, if factors like single-agent, rapid onset, reliability, and an established track record are important in choosing a sedation regimen today, ask yourself this: Is ketofol really one step forward or two steps back?
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