We’re always a little cautious (scared) about entering any sort of emergency airway debate on social media as opinions are usually strongly held, and evidence is often of the lighter variety. One of the more controversial questions is in the use of first choice paralytics for ED RSI. In the past we used suxamethonium for its rapid action, but it does have rather a lot of side effects which have led to be being described locally as a ‘dirty’ drug.
Rocuronium on the other hand has fewer side effects, but does not have the long tradition of use in anaesthesia and takes slightly longer to work.
So what’s best? Does it matter? What do we mean by best anyway? And is this really an important question anyway considering the debates that fly back and forth on twitter and in journals? On the BestBets site there are articles from 2011 that describes little difference,1 although there is a more recent review on the Cochrane site that favours Suxamethonium for intubating conditions,2 although several studies have used a lower dose of rocuronium which may not work well in emergency patients (we advocate 1.2mg/Kg as in this study, but others use as little as 0.6mg/Kg). In fact there are many other papers out there on this topic, but the debate continues about doses, outcomes and significance. Right up front I’ll say that I pretty much always use Rocuronium these days, with the occasional caveat as described below, although some of my colleagues still routinely use Suxamethonium (and it still works!).
This week we have a paper in JAMA3 that hopes to answer the question of whether they are equivalent in practice. As always please follow the links to the full paper and read it yourself before making any decisions on your practice3.
What kind of paper is this?
It’s an RCT which is the appropriate design to look for difference in performance of two interventions as in this study. RCTs are great for this, but we must remember that they are not good at looking for rare complications as you generally need vast numbers of patients to do this. That’s relevant here because some of the proposed differences between the drugs, such as rates of anaphylaxis and malignant hyperthermia are so rare that they could not be picked up in a study of this size.
Patients were block randomised in this study to take account of the large number of recruiting centres.
Tell me about the patients.
This is a nationwide French study in the prehospital environment. Adult patients requiring prehospital RSI were included. An impressive 1248 patients were included. Inclusion was based on the need for intubation in the opinion of the prehospital doctor on scene. Cardiac arrest patients were not included. Typical exclusions were known allergies, muscle disease and pregnancy. This leaves a fairly heterogeneous group of conditions, ages and pathologies which pragmatically reflects our work here in Virchester. Although this was a prehospital study its findings should be relevant to the resus room.
The most common reason for intubation was coma due to neurological disease or poisoning. Fewer than 10% of patients were trauma patients.
What did they do.
Patients were randomised to either 1mg/Kg of suxamethonium or 1.2mg/Kg of rocuronium. Two induction agents were recommended, either etomidate or ketamine, although additional agents could be used at the physicians discretion. Clinicians were not blinded to the drug used and since we see fasciculations in the majority of patients receiving suxamethonium it’s probably not possible to do so.
Patients were intubated using a Mac 3 or 4 blade with direct laryngoscopy. If that failed they followed their local failed airway algorithm.
What about the outcomes?
This is an important question in any anaesthesia based trial, as there are many potentially important outcomes. Laryngoscopy view, intubation success, time, mortality, complications and more could be considered important, but arguably in a trial specifically looking at the intubating conditions their chosen outcome, that of first pass success, seems reasonable.
Importantly this was a non-inferiority trial.4 It is designed to tell us whether one of these drugs is notably inferior to the other. This changes the stats and the sample size calculations, as opposed to a trial where we might be attempting to find a true difference between the two drugs. The authors chose a non-inferiority margin of 7%, in NNT terms that’s about 1 in 14 patients. So if the difference was one additional success (on average) for every 15 patients then the authors would consider that non-inferior. This is not the same as saying the two drugs are no different, just that they don’t differ by as much as a pre-set amount (in this case 7%).
Tell me the results.
The main outcome, that of first pass success showed a difference of 4.8% favouring suxamethonium. However, this did not reach the inferiority threshold of the trial and therefore the authors conclusion is that the two drugs have not been shown to be inferior to each other. Confidence intervals were wide at -9% to infinity.
The primary outcome of first pass success was 74.6% in the rocuronium group vs. 79.4% in the suxamethonium group.
In terms of the secondary outcomes there was little difference between the two drugs.
So they are the same then?
Well not quite. The difference of 4.8% is quite large and interestingly if this was a superiority study (which it is not) then that would be statistically significant (Chi Squared 3.986, p=0.0459). So the authors are not saying that they are the same, but rather that they have not demonstrated inferiority at the preset limit of 7%. I still have concerns that this is quite a large difference for such an important procedure. However, this is mitigated by the fact that the overall failure rates were close 1.8% for roc vs. 0.7% for sux. Supporters of sux may well look to the overall difference and the failure rates as evidence to maintain their practice.
Similarly the long action of rocuronium is seen as a problem by some, largely in relation to sedation and awareness. Personally I think that’s a failure of a sedation plan post intubation rather than a pharmacokinetics issue. In Virchester we usually use a combination of Propofol and Remifentanyl post induction. I will admit to still using Thio/sux in some of my status epilepticus patients in the ED.
The first pass success rate may be on the low side, perhaps because patients do not seem to have been optimised for intubation. In Virchester we routinely position, use bougies etc. to obtain as high a first pass rate as possible, It’s not clear that this was done here.
Most importantly, and eloquently explained on the EMCRIT blog5 is the fact that studies like this can never assess rare complications. We know that rocuronium and suxamethonium are paralytic drugs that work, and so finding little or no difference between them should be no real surprise. For me it’s more about the potential risks associated with each drug. We know that suxamethonium has many adverse features, some of which are potentially fatal to our patients. Rocuronium simply does not have much in the way of complications. At one time it was thought to cause more anaphylaxis, but the recent NAP6 study disputes this6.
Global health perspective
From a global health perspective there are two key points. The first is quite straight forward: rocuronium is not included on the WHO essential drug list. Although it might be available in some settings (such as South Africa where Tim below practices), it is unlikely to be available in the majority of low- and middle-income settings.
The second point is that low- and middle-income countries lack critical care beds. The vast majority of low- and middle-income countries lack any published data on critical care capacity. The World Bank’s dataset does not specifically describe critical care bed capacity, and hospital beds per 1000 patient data are between 5 and 15 years out of date.
Additionally, most critical care units in low- and middle-income countries are located in large city referral hospitals. This essentially means that a prehospital service is required to connect critically ill patients to critical care beds. And yet formalised prehospital services are lacking or largely inadequate in the majority of these settings.
Mould-Millman found that only one in five surveyed African countries had government-financed prehospital systems; only one in four had a toll-free, public-access telephone number. Basic emergency medical technicians and Basic Life Support-equipped ambulances made up 84% of services.
I guess you can see where I’m going with this. Intubating a patient (whether using rocuronium or suxamethonium) in these settings is but a small part of an unpredictable patient journey – often resulting in a dead end due to highly variable resource restrictions.
Sadly as healthcare is not free in many low- and middle-income settings, a high-stakes-uncertain-benefit decision to intubate is often not perceived as appropriate practice. Charmaine Cunningham wrote an excellent blog about this paradox, which is well worth a read (even if you are UK-based).
When considering intubation in low- and middle-income settings, it is imperative to first have a clear understanding of the scope of the critical care service that underpins the local system. When appropriate to use, suxamethonium will remain the unquestionable primary choice in these settings.
The bottom line
This study fails to find a difference between rocuronium and suxamethonium. However, the decision as to which to use is complicated by more than just first pass success rates and there are clearly clinicians out there who still favour one over the other. On balance, the lower complication rate of rocuronium places it as first choice in Virchester ED.
- 1.Herbstritt A. Is rocuronium as effective as succinylcholine at facilitating laryngoscopy during rapid sequence intubation? BestBets. https://bestbets.org/bets/bet.php?id=2280. Published 2011. Accessed 2019.
- 2.Tran DT, Newton EK, Mount VA, Lee JS, Wells GA, Perry JJ. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database of Systematic Reviews. October 2015. doi:10.1002/14651858.cd002788.pub3
- 3.Guihard B, Chollet-Xémard C, Lakhnati P, et al. Effect of Rocuronium vs Succinylcholine on Endotracheal Intubation Success Rate Among Patients Undergoing Out-of-Hospital Rapid Sequence Intubation. JAMA. December 2019:2303. doi:10.1001/jama.2019.18254
- 4.Lesaffre E. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis. 2008;66(2):150-154. https://www.ncbi.nlm.nih.gov/pubmed/18537788.
- 5.Farkas J. Rare and Catastrophic complications. EMCRIT. https://emcrit.org/pulmcrit/rare-catastrophic-complications/. Published 2019. Accessed 2019.
- 6.Cook T. NAP 6. National Airway Project. https://www.nationalauditprojects.org.uk/NAP6home. Published 2019. Accessed 2019.