Thursday 30 June 2016

IV Ketamine vs. Morphine for analgesia in the ED: an RCT

Here we go again...

This is another small study comparing ketamine to morphine conducted by investigators trying to validate their preconceived notions. The lead author has been encouraging the “opiate free ED” for years and now has his home grown “evidence” to back him up.

Perhaps they believe opiates are agents of evil and should be replaced by a drug related to PCP. Let’s have a look further at this evidence.

This was prospective, randomized, double-blind trial of very much a convenience sample of ED patients with acute pain rated >5 on a NRS. The intervention was a K-hole dose of 0.3mg/kg of ketamine vs. morphine at 0.1mg/kg.

The primary outcome was a reduction of pain at 30 minutes.

They had a whopping 45 patients in each group. Pain scores were very similar at baseline at about 8.5 on the NRS. They went down to approximately 4.0 at the 30 minute mark in both groups.

So ketamine is just as good as morphine for acute pain in the ED. Ring the bells!  

Not so fast.

Observer bias was very likely an issue due to lack of blinding. It is very easy to clinically tell the difference between the effects of ketamine vs. morphine. My guess is most of the K-hole group had nystagmus and were babbling away with the fairies. Whether conscious or not, these authors clearly wanted to prove their point.

It could also be argued that they were comparing ketamine to an inadequate straw-man dose of morphine. This opiate is meant to be titrated to effect. 0.1mg/kg is a good starting dose in most patients whereby about half will have adequate analgesia.

Side effects were of course more common in the ketamine group. Not surprising since previous studies have found rates of up to 80%. To be fair, this study demonstrated lower rates but had investigators not blinded to the study hypothesis.

So what are we to do?

Although not specifically investigated in this study, ketamine for analgesia in the ED is probably fine for patients that cannot get adequate doses of opiates or in those chronically habituated.

We should not be replacing a medication that is well established, well known, effective when titrated appropriately and has a perfectly good reversal agent. This is most certainly not with a drug that has questionable efficacy and has a worse side effect profile.


Motov S, Rockoff B, Cohen V, et al. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the Emergency Department: a randomized controlled trial. Ann Emerg Med 2015;66:222-229.

Wednesday 29 June 2016

I dare you to Idarucizumab for dabigatran reversal

The major concern over the new oral anticoagulants (NOAC’s) was the lack of a rapid reversal agent. With some pretty clever science comes what many have been waiting for.

This was a randomized double blind placebo controlled trial of 13,429 patients with severe haemorrhagic complications while on dabigatran (Pradaxa). They were randomized to reversal with idarucizumab (Praxbind) or matching placebo. The primary outcome was mortality at 30 days with secondary outcomes of safety and haemorrhage control.

Just kidding... Such a study would never be feasible and some might argue unethical.

Therefore, this was a small unblinded, uncontrolled interim analysis of a larger observational study. As expected, it was sponsored and mostly written by the drug company that stands to make handsome profits if they return positive results.

90 patients on dabigatran who had serious bleeding or required an urgent procedure were given idarucizumab. Most were found to have elevated thrombin or ecarin clotting times at baseline. Evidently, the study drug normalized the test results in 88 to 98% of the patients rather quickly.

So, it seemed to work.

(I’m not going to dwell on the study’s primary outcome measure of “maximum percentage reversal of the anticoagulant effect” as I believe this overstates the real efficacy of idarucizumab. Ok... it was 100% (95% CI 100 to 100). How close were they trying to make the goal post?)

Despite the profound limitations of this study, I will probably give this reversal agent in the rare event I have a suitable patient that meets indications. I think it makes sense.

It is a monoclonal antibody. Unlike activated clotting factors, it is probably safe and unlikely to cause thrombotic events. However we will need to look at phase IV post marketing experience to be sure.

Some quick comments.

This study led to the approval of idarucizumab by the FDA in October 2015 and TGA in June 2016. As of this writing, it is available in some centres in Australia under the Special Access Scheme until Boehringer Ingelheim can get the proper packaging that will satisfy TGA regulations. In a few months it should cost about $3000 a pop.  

Boehringer is probably loving the fact that they can now market dabigatran as having a rapid reversal agent. Cha-ching!

Not to be outdone, the other NOAC’s (rivaroxaban, apixaban) will probably have reversal agents come to market soon (andexonate alfa).

Oh... and the name “idarucizumab?”

Sometimes I wonder if the drug companies purposely make the generic names as confusing as possible so we resort to using the catchy trade names. Sure “Praxbind” is catchy. But so is “I dare you cizumab.” Since two vials are usually given, “I double dare you cizumab!”

Beat that Praxbind!


Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20.

How to get it wrong: Succinylcholine is associated with increased mortality when used for RSI in patients with severe traumatic brain injury

This is a fantastic study!

It is a fantastically bad study of how to perform research and come to wrong conclusions. It is so awful it makes one’s heart sink.

These authors performed a retrospect data-base review of patients who were intubated in their ED for traumatic brain injury. The main outcome was the difference in mortality when patients were intubated with either rocuronium or succinylcholine.

The results? No difference in mortality was found. Death occurred in 23% in each group.

Not satisfied with negative results, the authors conducted a post-hoc subgroup analysis and found that there was a difference in those with severe TBI. If you torture the data enough, it will talk.

Wooohooo... we can publish something!

They conclude, “in severely brain-injured patients undergoing RSI in the ED, succinlycholine was associated with increased mortality compared to rocurunium.”

This is totally nuts.

Regardless of the crazy analysis, all of the difference could easily be attributed to unmeasured confounding. This was not a randomized trial; therefore the patients given sux were very likely sicker.

Most experienced airway experts will tell you that they reach for sux when they want very rapid intubating conditions in sicker patients as compared to other neuromuscular blockers. Correcting for confounding (especially with a retrospective database) is far from an perfect science.

In the end, this is a small study with a high risk of bias that comes to unbelievable conclusions. Do we really believe a number needed to kill of 5 for succinylcholine in severe TBI!?!

There is so much I haven’t mentioned... the crazy power calculation, mixing association with causation, confusing subgroup analysis with stratification, neglecting the details of biological plausibility etc.

In 2005, John Ioannidis published his famous paper, “Why most published research findings are false.”

This study is a case in point. On so many levels, it is just wrong.

At best, it might raise a hypothesis for prospective testing. However, NOBODY should be changing their practice as a result of this paper.


Patanwala AE, Erstad BL, Roe DJ, et al. Succinylchoine is associated with increased mortality when used for rapid sequence intubation of severely brain injured patients in the Emergency Department. Pharmacotherapy. 2016;36(1):57-63.

(Special thanks to Dr Mark Reeves, FANZCA and Dr Ryan Radeski for providing me with some of their insights. However they take no responsibility for the terrible nature of this post.) 

Efficacy of nasal cannula oxygen as a preoxygenation adjunct in emergency airway management in healthy volunteers

Who would have figured that giving patients more oxygen during simulated emergency airway management results in better oxygenation?

Ok... I’m being overly cynical.

Some clinicians provide extra oxygen through nasal cannula in addition to either a nonrebreather (NRB) or bag-valve mask (BVM) prior to RSI. But does this really matter? Or is it just an extra step in an otherwise stressful situation that could be avoided?

This Australian study randomized 60 young healthy volunteers to either a NRB or BVM with or without a supplemental nasal cannula running at 10L/min. In addition, they also investigated whether the addition of a simulated mask leak changed the results.

The primary outcome was a comparison of end-tidal oxygen between the groups.


The addition of a nasal cannula to a NRB or BVM did not seem to do much unless there was a mask leak. The BVM achieved higher oxygenation than the NRB. (I don’t think the actual numbers are important, but if you are interested then click on the link to the abstract below.)

The major limitations of this study are obvious. 

Unless you are sadistic, healthy volunteers are not the patients we typical intubate in the ED. The primary outcome was a surrogate marker and not necessarily a meaningful patient oriented one. Looking at real morbidity would have required a much larger study of actual patients.

What should we take from this?

The addition of a nasal cannula might be beneficial (or not) when performing RSI in the ED. This is not great evidence and it probably doesn’t matter in the vast majority of patients. Sure, give it a try when you really want to maximize pre-oxygenation. Also make sure you have a good mask seal.

Pedantic adherence to a supplemental nasal cannula adjunct during RSI is probably silly. But depending on the situation it might make sense and probably won’t hurt.


Hayes-Bradley C, Lewis A, Burns B, et al. Efficacy of Nasal Cannula Oxygen as a Preoxygenation Adjunct in Emergency Airway Management. Ann Emerg Med. 2015; Dec 31 [ePub]