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).
- 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