Another fine day in Virchester and another marvellous weekly Journal Club discussing Ketofol. I was unable to attend our traditional meeting (which ended a few minutes ago) as I was visiting my parents but I guess the beauty of #FOAMed is that you actually do not have to physically be there to participate.
Here is my humble contribution and I hope my colleagues will add their input in form of comments/tweets in order to fuel the debate.
What is the paper all about then?
So, we looked at a paper which was a systematic review and meta-analysis published in the American Journal of Emergency Medicine. The authors looked at the analgesic and side-effects of ketofol (a combo of ketamine and propofol either in the same syringe or not and in different ratios – see EMCrit here by Scott Weingart if you had not heard of this before). As always you can read the abstract below but you should also read the full paper if you can get access.
Are the objectives of the study clearly stated?
Yes. The intention was clearly stated: to review the existing literature and conduct a meta-analysis to compare the analgesic effects and also side-effects of ketofol in comparison to propofol for procedural sedation and analgesia.
Were the search methods comprehensive to locate all relevant papers?
Yes. All randomised clinical trials (RCTs) comparing both agents were retrieved regardless of the patient’s age, sex, location, publication year and language.
I would say this is pretty broad and it is cool as that is what you want in a systematic review and/or meta-analysis. This however comes with problems (see below).
Were all appropriate and relevant outcomes considered?
The primary outcomes considered were relevant to EM and ED-based procedural sedation and focused on the complications of sedation (basically they are looking to see which is safer). The complications they looked for are the ones you and I would be worried about in the ED when administering any kind of sedative: respiratory complications requiring interventions (the interventions are not defined in the paper – just oxygen and jaw thrust or intubation?), hypotension (not defined), bradycardia (idem), psychomimetic complications, muscle rigidity, nausea/vomiting. I think these are fair as they are the potential complications you would try to avoid or mitigate during procedural sedation regardless of the agent you would be using.
The secondary outcomes were patients’ and providers’ satisfaction, discharge time and patients’ recall. More soft points but still relevant to our practice.
Were explicit methods used to determine which studies to include?
The search terms were appropriate (ketofol, ketamine, propofol) and five large databases were searched to retrieve the RCTs. However, there is a question about how the searches were done and thus how explicit we can be about the way it was done. It may have been better to focus the search strategy around a more formalised three part question.
The papers’ methodological quality were assessed using the Jadad score, which in a nutshell judges the methodological quality of RCTs based on randomisation and blinding processes along with dropouts. A score of 3 or above deems the RCT to be of good quality.
Was heterogeneity of included papers studied?
Yes and this is important in any meta-analysis! There are some who argue that there is no such thing as a perfect meta-analysis as a degree of heterogeneity is always expected in the process of combining RCTs.
The authors used Cochrane Q and I2 to study and describe heterogeneity of the included RCTs. The overall heterogeneity of the trials was considered low to moderate (I2 scores of 0-66% for different complications which is probably OK for progressing forward to a meta-analysis).
1335 abstracts and titles were reviewed, of which 1281 were excluded based on title/abstract irrelevance or duplication. 54 studies were scrutinised, of which 18 were considered eligible and met inclusion criteria.
Pooled risk ratios (RR) were worked out in favour of ketofol with 95% confidence intervals (CI).
And here are some of the results presented by the authors
- for respiratory complications they found that ketofol had fewer complications (6% vs 11.5%). That’s an absolute risk reduction of 5.5% and so a number needed to treat of 18 – but the confidence intervals are wide with a p value of 0.001
- for hypotension ketofol again had fewer complications (2.3% vs 8.7%). That’s an absolute risk reduction (ARR) of 6.4% and so a number needed to treat of 16.65. Not as impressive and still with broad confidence intervals (p=0.04).
- For bradycardia ketofol had fewer problems (2.4% vs 6.4%). That’s an ARR of 4% and an NNT of 20 p=0.008.
- Psychomimetic, Nausea, vomiting and muscle rigidity did not reach statistical significance.
I have not detailed the rest of the results as I felt the above ones were the most relevant to our daily practice. As we always say, get the full paper out and read for yourself.
[Disclaimer: First of all, I would like to declare that I am severely biased as combining (but temporally separating!) ketamine and propofol for ED sedation as this has been my own practice for a couple of years now. I had high hopes in this paper as it touched on an area of my work I really enjoy delivering and teaching on: procedural sedation in the ED. It furthermore assessed the safety profile of an analgeso-sedative combo I am a big fan of. I think it’s important to declare this at the beginning of the discussion as our prior beliefs influence how we think and implement new evidence (Ed – if you want to know more see Simon’s smacc talk on exactly this).]
When I look at my own practice, I might not be using it as ketofol per se as described in this paper. I use an analgesic dose of ketamine IV a few minutes before I start the sedation with small increments of propofol until I achieve adequate level of sedation, that’s arguably not Ketofol at all (my colleagues who use ketofol mix the drugs as in this paper). I learned my separate method a few years back from my previous mentor (and I have kept it ever since). This is an important consideration as complications may be influenced by how the drugs are used and in this paper the trials have quite different doses and ways of administering the drugs. In Virchester we have found that patients have rather different reactions to sedative drugs and so most (Ed – if not all) of us titrate to effect, with our initial sedation bolus being somewhat lower than in these trials. Perhaps that is why we think that the overall complication rates in these studies is higher than we experience locally.
Overall, the paper appears to be well conducted and the literature search is adequate, and the papers have surprisingly little statistical heterogeneity in the RCTs retrieved by the authors.
There are concerns though.
Firstly, the procedures were of varying nature (and some not relevant to my ED practice like endoscopy, laparoscopy, biopsy etc.) and there were a variety of administered concomitant medications (oral hydroxyzine, IV lignocaine or even combination with spinal anaesthesia). I’m unsure how those patients are relevant to my practice in the ED. We are often sedating a group of patients who are already in pain which is very, very different to those in elective practice.
Secondly, the papers included a variety of ketamine-propofol doses and ratio (1:1 to 1:10). Colleagues have tailored their ratios in Virchester increasing the ketamine component for procedures that are likely to be very painful but only as far as 3:1, not as far as 10:1 as described in some source articles. Similarly there is a lack of standardisation around other aspects of sedation such as preoxygenation, fluids, fasting times etc. These could similarly influence the results.
Thirdly, the included patients belong to ASA scores ranging from I to III. We don’t perform sedation on ASA III patients in our ED (at least not intentionally!).
Fourthly, the differences above would in themselves suggest a clinical heterogeneity between the studies, which interestingly did not seem to be reflected in the statistical scores (see the I2 results in the paper). I think this is a really important point and reinforces the requirement for us all to read the papers from a clinical perspective and not just look at the numbers.
Lastly, I also had some doubt around internal validity as the presented included trials did not somehow add up. The authors analysed 18 trials but only 17 were presented in their table: the Negroo et al. (2011) paper seems to have disappeared during the process.
Oh, and perhaps now is the time to mention that there are no outcomes here on whether the sedation was successful! Whilst it’s really important to know about complications, I also want to know about success, both from the patient’s and the clinician’s perspectives. There are papers that do look at appropriate outcomes and the largest (Andolfatto) did look at clinically relevant outcomes – and let’s remember that they showed little or no clinically important difference.
I think this paper tried to address a very important and interesting question which is relevant to ED practice. However, it fails to address whether ketofol is better as a sedation agent in the ED.
The authors had concluded that their study supports the use of ketamine-propofol as an effective combination and substitution to propofol only based on the incidence of complications. Despite their presented stats that seem to support this statement, I am not sure this conclusion is justified for our ED practice due to the complexity inherent to heterogeneity as discussed above. Also, the lack of data on whether the sedation was effective for clinicians or patients means that there are still some unanswered questions in this debate. There are of course many other options for sedation in the ED and the correct agent rather depends on what you are trying to achieve. We’ve discussed this concept of balanced sedation at St.Emlyn’s before.
It’s important that we formulate our own opinions based on what we have read followed by a critical appraisal so…what do you think?
@baombejp on Twitter
(Thank you to Laura Howard for choosing this interesting paper to discuss)