SGEM#114: Ketofol – Does It Take Two to Make a Procedure Go Right?

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Date: March 25th, 2015

Guest Skeptic: Dr. Steve Carroll. Steve is an Emergency Medicine Physician and EM Core Faculty with the US Army at San Antonio Military Medical Center in San Antonio, Texas. He also does an awesome podcast called EM Basic that is your “boot camp guide to emergency medicine”. EM Basic reviews common EM topics at the level of a medical student or intern.

Case: A 40-year-old male comes to the Emergency Department with a dislocated shoulder while playing football. He’s a weekend warrior and has never had any shoulder dislocations in the past. It took him about an hour to get the Emergency Department. After some pain control, you try the Cunningham and scapular manipulation to get the shoulder back in but they are not working. You decide that he needs procedural sedation. One of your residents asks you “I’ve heard about ketofol thing, can we try it in this patient?”

Background: Ketofol’s use has been rising in popularity in the EM and pediatric EM community. Ketofol refers to a combination of ketamine (which we talked about using in a sub dissociative dose for pain control recently) and propofol. It is often mixed in the same syringe but people some choose to give it separately. The theory is that the two medications can make a procedure go right by canceling out the bad effects of the other.

Propofol tends to cause hypotension and sometimes apnea whereas ketamine usually raises the blood pressure and doesn’t affect the respiratory drive. On the flip side, ketamine tends to cause vomiting when emerging from its effects whereas propofol has some antiemetic properties.

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Clinical Question: How does propofol compare to ketofol mixed at 1:1 ratio compared to ketofol mixed at 4:1 (propofol to ketamine) for adults requiring procedural sedation in the Emergency Department?

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Reference: Miner et al. Randomized, Double-Blinded, Clinical Trial of Propofol, 1:1 Propofol/Ketamine, and 4:1 Propofol/Ketamine for Deep Procedural Sedation in the Emergency Department. Annals of Emerg Med 2014

• Population: Adults 18 and over presenting to the ED requiring procedural sedation for a painful ED procedure
• Intervention: Propofol/ketamine at 1:1 ratio or 4:1 ratio
• Comparison: Propofol alone
• Outcome:
  • Primary Outcome: Number and proportion of subjects experiencing airway or respiratory adverse events leading to an intervention.
  • Secondary Outcomes: Lowest oxygen saturation during the procedure, success of the procedure, recovery agitation, patient’s pain scale, memory of the procedure by the patient, and patient satisfaction with the procedure

Authors’ Conclusions: “We found a similar frequency of airway and respiratory adverse events leading to intervention between propofol alone and either 1:1 or 4:1 ketofol.”

Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the ED. Yes
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Yes– 24/7 enrollments with trained research assistants
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Unsure?- syringes all looked the same, prepared ahead of time
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes
11. The treatment effect was large enough and precise enough to be clinically significant. Unsure

Key Results:

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There was no statistically significant difference in the number and proportion of subjects experiencing airway or respiratory adverse events leading to an intervention.

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• Primary Outcome: Propofol 32% vs. 1:1 Ketofol 22% vs. 4:1 Ketofol 33%

• Secondary Outcomes: were similar between the three groups. The only exception was that there was more recovery agitation in the ketofol 1:1 group and the ketofol 4:1 group compared to propofol alone. This is to be expected since ketamine is known to cause recovery agitation, however the clinical significance of this is uncertain. The authors didn’t mention whether any patient had recovery agitation that was significant enough to require treatment or that the patient remembered after the procedure

1. Composite Endpoint: While composite endpoints make the target bigger and easier to hit, each component may not be of equal importance to the patient. They had six components in their composite outcome: hypoxia, central apnea, subclinical respiratory depression, complete airway obstruction, laryngospasm and aspiration. There were zero events for half (three) of the components for any of the interventions. The most common adverse component was subclinical respiratory depression 51/271 (19%). How important is this event
2. Surrogate Endpoints: They used definitions from previous studies. However, these do not represent patient oriented outcomes. The authors did recognize this as a limitation to their study.
3. Un-blinding: They did a good job in attempting to blind the physicians to the group allocation by having the syringes look identical. Despite the strategy physicians were able to guess group allocation more than chance. They guessed the 1:1 group 58% of the time. This could have un-blinded the study and introduced some bias. Bias being defined as moving the results away from the truth.
4. Power Calculation: The anticipated ~30% adverse composite outcome. When you look at their results they were pretty close with an observed range from a low of 19% in the 1:1 group to a high of 32% in the 4:1 group. However, they set their sample size on a 20% difference in their primary outcome. Why did they pick such a large number? There was a 10% difference between propofol vs. 1:1 ratio and 11% difference between the 1:1 ration vs. 4:1 ratio. If the sample size were larger would there be a regression to the mean or would this difference hold up. If the later, the NNT would be 10 favoring the 1:1 ratio.
5. Patient Oriented Outcomes: The composite adverse outcomes may not have been that important to the patients. Especially when the intervention to address the problems were; providing supplemental oxygen, bagging the patient, repositioning during the procedure and stimulating the patient to induce ventilation. No patient in any of the three groups needed an airway adjunct. An important patient oriented secondary was satisfaction with the procedure. More patients were satisfied with propofol alone (85%) compared to 1:1 ratio (71%). The study was not powered to make any conclusions on secondary outcomes but the results could generate a hypothesis for a future study.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The conclusion seemed a little misleading. A more accurate conclusion would be there was not a greater than 20% difference in composite outcome (respiratory and airway adverse events) between propofol alone vs. either 1:1 propofol/ketamine ratio or 4:1 ratio.

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SGEM Bottom Line: Ketofol in a 1:1 or 4:1 ratio does not appear to have a greater than 20% benefit (less adverse respiratory/airway events) compared to propofol alone.

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Case Resolution: You and the resident both take a look at this article and decide to proceed with just propofol for the sedation since it will require less nursing time and less potential for medication errors in mixing as compared to propofol. As always, you do a good pre-procedure assessment of the airway as well as doing a good history and physical. You get all of your airway equipment to the bedside, check your equipment and size it appropriately. You also have the RSI kit at the bedside just in case. The patient receives the propofol and you successfully reduce the patient’s shoulder on the first attempt without any respiratory issues.

Clinically Application: I am generally going to use IV opioids for pain control followed by propofol for procedural sedations.

What Do I Tell My Patient? We are going to use propofol to sedate you to help put your shoulder back in. Propofol is a very safe drug that we have a lot of experience using in our Emergency Department. Side effects are rare and may include having to breathe for you with a mask or put a tube down your throat but we will watch you closely and be prepared for any possible problem ahead of time.

Keener Kontest: Last weeks winner was Andrew Hamilton an Ortho Technician at Collingwood General and Marine Hospital. He knew that Dr. Alexander Hamilton (possible relative) was the Scottish surgeon published a paper in 1816 on Camp Fever demonstrating the importance of allocation bias or randomization.

Listen to the podcast for this weeks gunner/keener question. If you know the answer send an email to thesgem@gmail.com with “keener” or “gunner” in the subject line. The first correct response will win a cool skeptical prize.

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Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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