Friday, 30 January 2015

An RCT comparing intranasal fentanyl vs. ketamine… please stab me with a pitchfork

Sometimes you look at a study and think, “oh why…” But clearly the study authors of the PICHFORK trial and the editors of the Annals of Emergency Medicine think differently.

This was a double blind RCT comparing 1.5mcg of intranasal fentanyl to 1mg/kg of intranasal ketamine in children with limb injuries. The primary outcome was reduction in pain at 30 minutes.

With only 73 patients for analysis, there was no surprise that there was no statistical difference found in pain reduction. Obviously the possibility for a type II error is huge (i.e. not finding a difference when one was really present).

80% of the ketamine group had some adverse events that the authors conclude were minor. Who would have thought that something related to angel dust might cause some problems.

Those of us that have been using intranasal fentanyl know that it works very well and has been a game changer for paediatric analgesia. 1.5mcg/kg is at best a low starting dose and is usually repeated at 10 minutes. I personally usually give 2-3mcg/kg to start with depending on the situation.

By the way, the authors make a big point about the limitations of fentanyl in its 50mcg/ml concentration. But my ED has been using the 300mcg/ml concentration for years. It is made in Australia and widely available. (Oron Laboratories Pty Ltd, 25-29 Delawney St, Balcatta WA 6021 Australia)

My conclusion? This was an underpowered study that could only ever find large differences between the two treatment groups. Ketamine was compared to an inadequate or “straw-man” dose of fentanyl. Therefore there was no surprise that this study could not find any differences. It would be really disappointing if people are duped in to thinking this study is proof as to the effectiveness of intransal ketamine and subject children to undertreated pain and side effects. 

Ketamine certainly has its rightful place in Emergency Medicine. It is an absolutely fantastic drug for procedural sedation and for induction of RSI or DSI. But for primary analgesia, please use something that we know is safe, effective with minimal side effects. Stick with fentanyl.



Covering

Graudins A, Meek R, Egerton-Warburton D, et al. The PICHFORK (Pain in Children Fentanyl or Ketamine) Trial: A Randomized Controlled Trial Comparing Intranasal Ketamine and Fentanyl for the Relief of Moderate to Severe Pain in Children with Limb Injuries. Ann Emerg Med. 2014  Nov 18. pii: S0196-0644(14)01363-8. doi: 10.1016/j.annemergmed.2014.09.024. [Epub ahead of print]


Is Epinephrine (Adrenalin) During Cardiac Arrest Associated with Worse Outcomes?

Answer: yes of course.

But does it cause worse outcomes? Who knows- and this study does not help us find the answer.

This was registry review over a 12 year period at a single centre in Paris designated as a “cardiac arrest receiving hospital.” They looked at non-traumatic out of hospital cardiac arrest with ROSC. They compared the group that got adrenalin to those that didn't. The primary outcome measure was favourable neurologic outcome at discharge from hospital.

As you could guess, the cohort that got adrenalin was sicker in every possible way. They were less likely to be witnessed arrests, less bystander CPR and less likely to have initial shockable rhythms. By their very nature, they were more prolonged arrests.

Therefore it should come as no surprise that the adrenalin group did much worse. Only 17% of the adrenalin group had a good outcome vs. 63% that did not get adrenalin. Of course the authors recognized this bias and performed all kinds of adjustments, regression analysis, propensity modelling and bootstrapping. When was the last time you bootstrapped?

Given the study design, these adjustments are all very appropriate. But it should be emphasized that a lot of assumptions go in to this analysis and it is far from perfect.

After adjustments, the authors conclude that the use of adrenalin was negatively associated with favourable neurological outcome. They were careful not to address causation and rightfully suggest further study.

Should this study change our practice? No.

This was not an RCT and can really only raise a hypothesis for further study. I think a properly powered RCT would certainly be feasible. But the late Ian Jacobs tried this in Australia and ran in to a huge political & “ethical” roadblock. Nevertheless, this is more evidence that suggests that adrenalin may cause more harm than benefit.  I hope we will find a definitive study one day.

Covering:

Dumas F, Bougouin W, Geri G, et al. Is Epinephrine During Cardiac Arrest Associated with Worse Outcomes in Resuscitated Patients. J Am Coll Cardiol 2014;64:2360-2367.


Delayed Sequence Intubation: We did it, we liked it and thought it was cool


Congratulations to Dr Scott Weingart for putting his money where his mouth is and publishing something that is genuinely challenging to study.

How would we ideally design a study to look at the efficacy of DSI? Would we do a large blinded randomized trial comparing DSI to standard rapid sequence intubation with a primary outcome of mortality? Such a study would be near impossible to conduct as it would be totally unfeasible to recruit such large numbers and couldn't be blinded. Therefore we do the best we can.

This study was not an RCT but rather a prospective observational study in a convenience sample of patients in whom DSI was thought to be indicated. They were all given ketamine to facilitate oxygenation before intubation. The primary outcome was improvement in the oxygen saturations during DSI.

In general, it looks like DSI works. Saturations increased from about 90% up to 99% just prior to intubation. There were even two patients with asthma where intubation was avoided.

Critics might argue that this was not a trial, had a convenience sample with small numbers and used a non-patient oriented outcome measure. But good luck finding better evidence! Three large hospitals were only able to recruit a total of 62 patients over a year and a half. It would probably take me two hundred years to recruit enough patients at my hospital to conduct a properly powered RCT looking at small changes in patient oriented outcomes.

I think this is enough evidence to change practice. I doubt we will ever get better data. It seems to work and is probably safer than standard RSI in suitable patients. Yes, this study is far from hard science but I think it is a game changer. Thanks Scott.



Covering:

Weingart SD, Trueger NS, Wong N, et al. Delayed Sequence Intubation: A Prospective Observational Study. Ann Emerg Med 2014 Oct 23. pii: S0196-0644(14)01365-1. doi: 10.1016/j.annemergmed.2014.09.025. [Epub ahead of print]