It’s just turned 8pm on Tuesday, and the room is about half full of the usual crowd. The smell of freshly brewed, specially sourced Peruvian coffee wafts over the circle of plastic chairs and their occupants, as gentle conversation about anaerobic thresholds is exchanged. The door shuts gently behind a lycra-clad latecomer - the breeze of its closing causing the ‘Anaesthetists Anonymous” banner on the adjacent wall to flutter gently. As the chair signals the start of the meeting, a young man (though not as young as he would like to still think) stands up to speak first.
“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…”
“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…”
We shall return to out hero later, but first there’s some blogging to be done. To provide you some context, this whole topic came into being with a debate about reversing a patient with sugammadex. I had been independently anaesthetising a patient with a collection of conditions that might make them slightly higher risk for postoperative respiratory complications. I felt well inclined to give this patient to best possible wake-up, and the clean reversal of rocuronium with sugammadex was one component of my simple yet elegant approach. To say that this idea caused a bit of controversy with one of my more senior colleagues is a slight understatement. The general theme of their observation was that there was no clinical difference between the two approaches, but that sugammadex was a huge amount of extra cash. This was one of those situations where my understanding of the evidence was such that I felt that this perspective was not actually factually true, but could not recall the literature well enough to compose an appropriate riposte. On reflection, I find that this is sometimes the case in anaesthesia, where I have had a good deal of teaching based on expert experience (as well as my own personal experience) and that this can carry as much weight in my memory as that from the literature. Some of this is incredibly valuable, whilst other bits may be tainted by layers of the many implicit biases that people naturally accrue. As such, I realised that this was a topic where my understanding of the evidence was not as good as I would have liked - time to delve a bit further.
Not as bad as organophosphates
Firstly, as a little thought experiment, let’s try and imagine a time before reversal agents were invented. We have our muscle relaxants, but there is clearly a problem from their prolonged effects. Now, assuming that we aren’t planning on using suxamethonium and mivacurium for every case, we can picture the scene of a drug rep making a pitch for their fancy new drug: neostigmine. Our, still slightly exasperated, hero returns for some dialogue.
“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?”
“Yes!”
“You mean it just completely removes the relaxants from the effect site?”
“Yes”
“And this works nearly instantly?”
“Yes”
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.
“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?”
“Yes!”
“You mean it just completely removes the relaxants from the effect site?”
“Yes”
“And this works nearly instantly?”
“Yes”
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
With this theoretical landscape now imaginatively well explored, we can turn our attention to a bit of actual science. As I began searching for a font of knowledge on this subject, you can imagine my delight when I found a Cochrane review looking at the very same question. And only a couple of years old too - marvellous! It would seem that we would soon have an answer to this question, so let’s dive 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:
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.
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.
Wrapping Up
So what do we think? To summarise my thoughts, this is a decent sized meta-analysis drawing on data from 41 studies that included 4206 participants. Despite some of the limitations, including the dubious value of looking at the ability of neostigmine to reverse a deep block, much of the quality is described as moderate. In short, sugammadex is just a better drug. It makes more pharmacological sense, anecdotally is just in a completely different class and now we have extensive evidence of a more practical and (more importantly) safer profile.
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.
Tom
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.
Tom
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/
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