A multi-center RCT was released yesterday comparing rocuronium versus succinylcholine. It’s a thoroughly uninformative study, so at first I wasn’t planning to write about it. But then I realized that the study, in its very myopia, is a good illustration of our problem with rare catastrophic complications.
warmup: heparin infusions and rare catastrophic complications
A heparin infusion will occasionally cause one of the following two rare catastrophic complications:
- Intracranial hemorrhage
- Heparin-induced thrombocytopenia leading to death or limb loss
Now, let’s imagine two different scenarios.
- Scenario #1: A rare catastrophic complication from heparin occurs in one patient out of every 2,000 (0.05%).
- Scenario #2: A rare catastrophic complication from heparin occurs in 5% of patients.
In Scenario #2, it would rapidly become obvious that heparin was causing big problems. Actions would be taken to reduce the harm.
In fact, there is high-quality data that heparin infusions are often riskier than alternative therapies. In thromboembolic disease, low molecular-weight heparin causes a lower rate of hemorrhage than do heparin infusions. Likewise, in NSTEMI, fondaparinux was proven to reduce the risk of major bleeding and mortality.1 So, there are proven approaches for mitigating the risk of heparin. In Scenario #2, these avenues would be explored and the use of heparin would be reduced.
But now let’s imagine Scenario #1, where catastrophic complications occur, but at a very low rate. At this rate, a medium-sized hospital might experience a serious complication from heparin perhaps every five years. A single provider might never experience more than one complication.
What happens in Scenario #1? Probably nothing. The complications occur very infrequently. They run under the radar. They get written off as a fluke or freak event. There is no practice improvement. Everyone is busy, so it’s not worth it to re-design the system in order to prevent an adverse event that might happen once or twice in a decade.
This is an illustration of rare catastrophic complications and how they often persist in modern medicine. If Delta Airlines crashed one plane out of every 2,000 flights, that would be international news and the airline would undoubtedly fix the underlying problem. However, if a heparin infusion causes an intracranial hemorrhage in one patient out of every 2000, our tendency is to shake our heads and keep moving. There are more patients to see.
succinylcholine vs. rocuronium & rare catastrophic complications
Here is the classic Rubin Strayer video on Rocuronium versus Succinylcholine. It’s from 2013 but still very much on point, illustrating just how little progress we’ve made with this issue:
The key difference between rocuronium and succinylcholine is that succinylcholine can cause a handful of rare catastrophic complications:
- Hyperkalemia causing cardiac arrest.
- Malignant hyperthermia.
- Masseter spasm preventing intubation.
- Bradycardia causing cardiac arrest.
- Emergence of paralysis before intubation (in an unanticipated difficult airway) leading to clinically significant harm (e.g. anoxia or arrest). For example, succinylcholine can convert a challenging airway into a real disaster if paralysis wears off and the patient starts vomiting during laryngoscopy.
Succinylcholine is a great drug ~99% of the time. So any individual provider may run into trouble with succinylcholine only very rarely (perhaps once every 3-5 years, for a non-anesthesiologist who isn’t intubating constantly).
This is a classic example of rare catastrophic complications – bad things happen with succinylcholine, but they occur so infrequently that they run under the radar. When bad things do happen, we don't want to dwell on them – so there is a natural tendency to sweep them under the rug.
The truly fascinating aspect of this situation is that there’s an extremely easy and simple approach to eliminating these complications with succinylcholine: switching to rocuronium. Rocuronium doesn’t cause rare catastrophic complications.
So that’s the frustrating paradox of rare catastrophic complications – horrific things happen, but they happen very rarely. It would be possible to eliminate these complications, but we don’t.
fresh JAMA paper comparing rocuronium versus succinylcholine
This brings us to the new JAMA RCT comparing rocuronium versus succinylcholine.2 The paper compares succinylcholine versus rocuronium in 1226 patients, using first-pass success rate as as primary endpoint:
Both rocuronium and succinylcholine are excellent paralytics, which will work well the vast majority of the time. So there’s really no reason to expect the first-pass success rate to be different. And, of course, it wasn’t.
Does this mean that rocuronium is non-non-inferior to succinylcholine? Of course not. The issue of rare catastrophic complications persists. It’s impossible to resolve this issue with a RCT, because these are very infrequent events. For an RCT to have sufficient power to detect rare catastrophic complications from succinylcholine, it would require an insanely large sample size.
This paper doesn’t advance our understanding of rocuronium vs. succinylcholine. If anything, it illustrates how flawed our thinking about these drugs is. As long as we focus on common events (like first-pass success), we will continue to overlook rare catastrophic complications.
- Rare catastrophic complications are severe events which occur very infrequently (e.g. <<1%).
- Due to the rarity of these events (e.g. occurring perhaps once every 3-5 years), they attract little attention. Although rare catastrophic complications are often preventable, they tend to run under the radar.
- Succinylcholine causes a few rare catastrophic complications (e.g. hyperkalemic cardiac arrest, malignant hyperthermia). Since these complications occur very infrequently, there is little impetus to change the system of care.
- A large randomized controlled trial will invariably overlook rare catastrophic complications (mathematically, it’s nearly impossible to build a large enough RCT to evaluate this problem).
references
- 1.Mehta S, Granger C, Eikelboom J, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol. 2007;50(18):1742-1751. doi:10.1016/j.jacc.2007.07.042
- 2.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
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And on the other hand, rocuronium really does have problems. It takes longer to act. Substantially longer. In my experience the time to adequate paralysis is probably double that of succinylcholine. Yes, you can try to make them look equivalent with underpowered studies that wait until one minute to compare, by which time they are indeed pretty close, and yet even with that roc doesn’t quite make it (see the Cochrane review) but the reality on the ground is that a minute can be a long time and succinylcholine really is faster. As well, the clearance of roc can be… Read more »
1) if dosed adequately there’s no meaningful difference in time to onset.
2) prolonged paralysis is nearly always a benefit, not a drawback. Very, very, very rarely prolonged paralysis is an issue and you can give sugammadex but that’s incredibly infrequent. It’s much more frequent that ongoing paralysis is a benefit (allows patient to settle down on ventilator, etc)
3) if you’re not sedating patients adequately thats a problem, but don’t blame that on the roc.
I agree with Jordan there is a significant difference in time to onset. I do RSI with roc every day (frequently with doses higher than 1.2mg/kg) so I’m comfortable with it and like it. I infrequently use succ, but I still believe succ leads to faster intubating conditions. One thing that helps is that the fasciculations are an easy visual indicator of paralysis that you don’t get with roc. You can be putting the mask down, grabbing blade, and beginning blade insertion all while fasciculations are occurring. With roc, you’re just waiting a vague amount of time. Occasionally if you’re… Read more »
Inadequate sedation is a real problem and there are signals to suggest that time to sedation (not necessarily adequate sedation, just the sedation itself) is longer with roc (https://www.ncbi.nlm.nih.gov/pubmed/25797938). In an ideal setting, appropriate sedation would be high on the list of staff to accomplish post-intubation, but the real world experience suggests that without typical signs of motor agitation, sedation protocols are not aggressively pursued. The use of CPOT and RASS scores for sedation are thrown out the window when using rocuronium, leading to 3 scenarios 1) oversedation as you snow the patient in hopes of adequate sedation 2) inadequate… Read more »
Roc does indeed take longer, though certainly not double the time. High-dose roc takes about 60 sec; sux ~45 sec. If you are intubating at 30 sec with sux, then you are intubating without full paralysis. Both of these drugs require waiting an arbritary amount of time–it is the only way to guarantee full paralysis. If you are really concerned about those 15 sec, give the roc first and wait 15 sec before pushing your induction–we have discussed this on the blog already. I agree with Josh, those 15 sec are meaningless. I still use Sux when I want an… Read more »
this is exciting. reminds me of the playground in Brooklyn, and someone starts shouting, ” Fight!! Fight!!”. i always ran the other way, especially if i was the one fighting, i’m not a cardiac anesthesiologist, nor an MD/P.HD. i did spend two years in hershey where Jordan is from. i’ just a simple ER doc in a rural hospital. isn’t here in EMCRIT that i heard a pod “Roc ROCKS, and Sux SUCKS” , or was that elsewhere. that has a fuller , more colorful , discussion . ah, found it: it was Anand Swaminathan, emDOCS, dec 1, 2014 that… Read more »
Josh, your statement that “rocuronium doesn’t cause rare catastrophic complications” is demonstrably wrong. Suxamethonium, rocuronium, and all other neuromuscular blockers have their own unique rare complications, which require a good understanding of the pharmacology of the drug being chosen. Rocuronium in particular has a much higher incidence of anaphylaxis than other non-depolarising NMBAs [so for elective surgery we are now predominantly using vecuronium and avoiding rocuronium unless a very rapid onset is required and sux is contraindicated]. A rapid bolus of high dose rocuronium also causes tachycardia which can create its own set of subsequent complications (eg coronary ischaemia). The… Read more »
(1) Drug allergy: NAP6 found that anaphylaxis was more common following *sux* than roc (https://www.nationalauditprojects.org.uk/downloads/NAP6%20Chapter%2016%20-%20Neuromuscular%20blocking%20agents%20and%20reversal%20agents.pdf). Roc-induced anaphylaxis might be more to be more common in Australia due to cross-reactions with pholcodine (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168376/). So roc-induced anaphylaxis may be a substantive concern in Australia, but this doesn’t seem to be a real problem in the US or UK. Thanks for mentioning this, I should have addressed it in the body of the post. (2) The concept that critically ill patients in respiratory failure can wake up from sux and be fine is mythological and leads to awful decisions regarding airway management. If… Read more »
Thanks, Josh. Comments: (1) NAP6 (and all the NAPs) were self reported cohort studies in the UK which provide very important information but not any sort of definitive epidemiology. Yes, sux can also cause anaphylaxis. My comment was that rocuronium has a much higher incidence of anaphylaxis than other non-depolarising NMBAs [sux is depolarising] which I acknowledge has geographic variability and probably pharmacogenetic variability but certainly locally (with good epidemiological data available) the most frequent causes of anaesthetic anaphylaxis are rocuronium specifically, and first generation cephalosporins. (2) I wasn’t saying critically ill patient with respiratory failure ‘wake up fine’, I… Read more »