“My name is Tom, and I don’t like muscle relaxants”
A soft murmur ripples around the group. A handful of heads nod sympathetically, whilst others turn to their neighbour, eyebrows dancing. Anaesthetists are well known for their particularities of practice, but this was still a surprising revelation. That’s a whole third of the sacred triad!
“I just think reversing them is a whole pile of…”
Not as bad as organophosphates
“So this new drug of yours completely reverses our neuromuscular blockers?”
“Well, it’s a bit more complicated than that. You see, we don’t actually reverse the drug itself”
“....okay, can you explain a bit more”. There is a slight sinking feeling somewhere in the stomach.
“Let me give you a bit of an analogy. So imagine that you’re Mr Acetylcholine, and you’re trying to get in your house. However, Mr Rocuronium is stopping you getting through your front door. Neostigmine is the equivalent of getting a load of your mates round to help encourage this obstructive aminosteroid out of your doorway”
“I see. And I assume that there are no problems with having too many of your ‘mates’ round fighting with some aminosteroid on your front lawn”.
“Well, they can cause a few issues with your heart rate, so we have to give it with another drug to try and reduce that. And if there isn’t any Mr Rocuronium there, then you mates will actually think they’re all invited in and cause a bit of property damage and obstruction of their own. And sometimes your mates might clear off a bit early, leaving you on your own, and then an irate Mr Rocuronium might drag you back out of your house again....”
Seeing more than a hint of hesitation our rep changes tact.
“It works a bit like organophosphates, although not as toxic, obviously.”
I’m not sure that I’d be bowled over by either his story-telling or his product.
We can contrast this to the next morning, as the purveyor of Sugammadex turns up for a sales pitch.
“So this new drug of completely yours completely reverses our neuromuscular blockers?”
“You mean it just completely removes the relaxants from the effect site?”
“And this works nearly instantly?”
Okay, I know it’s ‘just’ rocuronium and vecuronium, but the contrast is an absolute chasm. The mechanism of action makes a lot more sense and, as anyone who has used it can attest to, this is incredibly apparent clinically. It’s almost magical.
Cochrane step in
The Cochrane review followed the standard meta-analysis approach, casting their net wide to catch as many relevant RCTs as they could. They ended up with a total of 41 trials, 31 of which were suitable for meta-analysis. These primarily looked at rocuronium (with a few including vecuronium) and comparing sugammadex to neostigmine.
They specifically looked for the answers to 3 questions:
- Any difference between ‘normal’ reversal times (a TOF count of 2)?
- Any difference in ‘dense block’ reversal times (needing tetanic facilitation to get a count of 1-5)?
- Any difference in complication rates?
Firstly, how do neostigmine and sugammadex compare to each other when reversing a ‘normal’ degree of neuromuscular blockade? The researchers have defined this as the presence of at least 2 twitches on a train of four (TOF) count, admittedly pushing the boundaries a little bit on reversibility. The difference in time is pretty impressive though, with the mean sugammadex time over 10 minutes faster than neostigmine, reversing in just under 2 minutes compared with just under 13. The results were similarly pronounced when comparing rocuronium/sugammadex with cisatracurium/neostigmine (1.9 vs 9.0 minutes) or against vecuronium/neostigmine (2.7 vs 17.9 minutes), although these weren’t included in the meta-analysis. There was no apparent impact from the use of TIVA or volatile anaesthesia.
Secondly, what about the cases of ‘dense’ neuromuscular blockade, defined by the authors as a post tetanic count of 1-5. Here they compared the higher doses of 4mg/kg sugammadex with 0.07mg/kg neostigmine. The results here, as would probably be expected, are even more pronounced. The mean time to recovery (TOF > 0.9) was 2.9 minutes with sugammadex and 48.8 minutes in the neostigmine group. To be honest, I would have imagined most of that neostigmine effect is from rocuronium excretion after that amount of time. Whilst not part of their meta-analysis, the authors provide a narrative of some of the other studies exploring a time difference, and the trends are all the same, in many cases strikingly so.
Finally, the authors look at perhaps the most important question: the complication rates. Whilst I do have some interest in speed, it is the relative incompleteness of reversal that is the most concerning aspect of neostigmine. A full 28 trials looked at the difference of adverse effects, described here as a composite, giving a risk ratio of 0.60 (0.49-0.74) for sugammadex compared to neostigmine (a NNT of only 8). Despite this being a composite, the breakdown showed lower rates of bradycardia, PONV, desaturation, and need for supplementary oxygen post op. The most important finding, in relation to my specific concerns, was the increased rate of postoperative residual paralysis in the neostigmine group. Sugammadex had a RR of 0.40 (0.28-0.57) with a NNT of 13 in this regard. The authors had defined this as a composite of features including inability to perform 5s head lift, desaturation, respiratory distress/depression, and generalised muscle weakness. Some of the trials even described objective perseverance of MNJ blockade based on the TOF count on admission to the recovery area, a TOF ratio of <0.9 being determined as persistent blockade. One study found a rate of 43.4% of neostigmine patients (compared to 0% with sugammadex) and another quoted 60.5% (compared to 4%). Neostigmine fans will be pleased to know that there was no significant increase in ‘severe’ adverse drug reactions identified; although advocating for a drug based on its lack of MI-inducing properties is not a particularly glowing recommendation. The incidence of hypersensitivity reactions to sugammadex (well described elsewhere) is certainly something to keep an eye on, but there was no evidence of it on display here.
Regarding neostigmine then, should we really be hanging on to a drug with, to quote Cochrane, “an indirect mechanism of action, limited and unpredictable efficacy, and undesirable autonomic responses”? The question is therefore now one of cost rather than of clinical difference. This is a legitimate argument to have, but I worry it is occasionally mixed up with the clinical one, confusing the conversation. This is especially open to a lack of perspective when we actually look at these costs. Currently, the BNF states the cost of a 200mg vial of sugammadex as £60 each, compared to just over £1 for the standard neostigmine/glycopyrrolate mix. I concede that that is a bit of a difference, but the fraction of the over care costs is pretty small. The Cochrane authors conceded that it was beyond the scope of their review to explore the cost effectiveness of sugammadex, and with its patent coming to an end in 2021, I think the landscape of this will soon change anyway. An extra £60 quid makes it reasonable to use neostigmine for those straightforward cases who are pretty much fully reversed anyway. However, I will be less generous to any protestations about persevering with this relic when there is the risk of adverse effects from any whiff of residual paralysis, either through patient factors, or a fair degree of persisting block at the end of the op. If I was a patient, I would very strongly not wish to be still partially paralysed for the sake of £60. God knows how often that much money is wasted on a significantly less important outcome. The tantalising hints that there may actually be cost benefits associated with this (or at least cost neutrality) will have to be explore another time.
Thank you for reading, and please leave any comments or other useful references below. I’ll pin my colours to the mast now and summarise as such: sugammadex is the future of NMB reversal. It is clearly better, and when it goes off patent a move to universal use will bring the economy of scale into play, further bringing costs down. We will look back at our current practice in much the same way as we look back to a time before the universality of propofol, and think “how did we manage?”. Neostigmine is currently making its last stand. I will not miss it.
Links & References
- Hristovska, A-M. et al. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Review. 2017(8). https://www.ncbi.nlm.nih.gov/pubmed/28806470
- Kopman, A. Brull, S. Low-dose sugammadex reversal: there is no such thing as a free lunch. Anaesthesiology. 2013. 119:10-12. https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1918298
- Anaesthesia UK. Bridion. 2019. https://www.frca.co.uk/article.aspx?articleid=101366#
- Savic, L. et al. Sugammadex: the sting in the tail. BJA. 2018. 121(4): 694-7. https://bjanaesthesia.org/article/S0007-0912(18)30588-9/fulltext
- British National Formulary. https://bnf.nice.org.uk/