Pharmacology of neuromuscular blocking drug antagonism

This chapter addresses Section L2(ii) from the 2017 CICM Primary Syllabus, which expects the exam candidates to have an "understanding of the antagonism of neuromuscular blocking drugs".   That the college examiners have valued this section's level of expected understanding (L2) lower than the one for "understanding of the pharmacology of neuromuscular blocking drugs" (L1) reflects the fact that most of the time intensivists have the luxury of leaving their patients intubated, and do not need to worry about reversing their paralysis. However, most critical care trainees worldwide (even those who end up working mainly in emergency departments and intensive care units) will at some stage be forced to do an anaesthetic rotation, and this topic will take on a real-life relevance. At this stage that appears to be the only relevance it has, because CICM have not included NMJ blockade reversal in their written papers, and the time-poor exam candidate can safely skim over this topic, reserving their attention for higher-yield subjects.

Preempting an SAQ on this subject:

The need for rapid reversal of neuromuscular blockade

It would hardly burden the reader's imagination to invent a scene where the immediate return of voluntary skeletal muscle power is a desirable and potentially life-preserving step.  There are several possible reasons to suddenly really want your neuromuscular junctions back:

• To permit the return of spontaneous breathing and airway muscle tone where the airway was unexpectedly difficult, and could not be secured
• To restore respiratory muscle power and prevent respiratory failure following extubation of a recently NMJ-blocked patient
• To allow the early return of muscle power following a short procedure that required neuromuscular junction blockade, eg. elective surgery - the crude commercial realities of the elective operating theatre production line is that you need to start the next case soon after you have finished the last, otherwise the economy may collapse.

There are two main ways to achieve all of these goals. One would be the use of a short-acting agent such as mivacurium or suxamethonium, and indeed the rapid offset of effect remains the most important (perhaps the sole?) argument for the continued use of such agents. The other approach is to use some kind of pharmacological antagonist to reverse the effects of residual neuromuscular blockade, once blockade is no longer desired.

Features of residual neuromuscular junction blockade

Neuromuscular block is obviously something of a continuum and ranges from a profound flaccid paralysis to a barely detectable fade on TOF testing. So how much block is too much? From the functional perspective of clinical utility, one would have to agree that the best definitions would have to be those that use repeatable objective measurements of muscle power and relate them to some kind of respiratory complications. TOF (train of four) is that objective measurement, and empirically it has been established that a TOF ratio of less than 0.9 (i.e. where the last twitch is at least 90% of the amplitude of the first ) is the boundary of satisfactory respiratory and airway reflex function (Murphy, 2006). Historically, anaesthetists had accepted a TOF  ratio of 0.7 or more, but this turned out to be entirely unsatisfactory. For one, the patients feel terrible. When Kopman et al (1997) partially paralysed some courageous volunteers down to a TOF ratio of ~ 0.7, all reported extremely unpleasant symptoms. "None considered themselves remotely "street ready" at this time", complained the authors, making that point presumably because the prevailing bed management practice of the time would have had these elective surgical patients turfed out on to the street as soon as they achieved a TOF ratio of 0.7 or more. 

What features can you expect if your neuromuscular junctions are progressively becoming more and more disabled? From Kopman et al, as well as other references, this table can be constructed to document the decline in muscle strength with progressively deepening block:

Train of four ratio	Clinical features, symptoms, physical findings
0.90	Diplopia, difficulty tracking moving objects
0.85	Reduced ability to clench teeth (i.e. chew the tube)
0.80	Maximum inspiratory flow rate is markedly impaired
0.70	Grip strength is about 50-75% of normal.  Sustained eye opening, tongue protrusion
0.60	Sustained head lift for 5 seconds is no longer possible. Vital capacity is down to 15-20ml/kg; which is apparently "clinically acceptable" (Ali et al, 1975). Maximum inspiratory pressure is still around 20-25 cm H2O , but not for sustained periods
0.40	The threshold for where an observer can reliably detect and describe fade in TOF (Viby-Mogensen et al, 1985)

In short, whether or not you consider a vital capacity of 15-20ml/kg to be appropriate (it's not), the conclusion one reaches after reading this is that anything short of near-total reversal is inadequate, and would place vulnerable patients at risk. 

So: how do we reverse nondeolarising neuromuscular junction block? There are two main ways. One is to send more acetylcholine to compete with the blocker, overwhelming the competitive antagonist and restoring neuromuscular transmission. The other would be to bind the blocker in a way that permanently disables or removes it, freeing the receptors to function normally. Both need to be discussed, but the latter is more relevant clinically, and will increase in prominence over the coming decades, whereas the former will sink into obscurity.

Reversal agents

The two main groups are acetylcholinesterase inhibitors, of which the most representative is neostigmine, and cyclodextrin binders, of which the only available option is sugammadex.

Neostigmine

The pharmacology of acetylcholinesterase inhibitors is discussed in more detail elsewhere. Of all the 'stigmines, neostigmine is the most convenient for this role, whereas physostigimine has the embarrassing tendency to penetrate the blood-brain barrier and pyridostigmine is mainly available for oral administration. Edrophonium is another less-known alternative. It is unlikely that CICM, or any other exam-writing body, would ever ask their exam candidates to compare between these acetylcholinesterase inhibitors, as this activity would not stimulate any relevant deeper learning. However, it is likely (and probably beneficial) to be able to compare the advantages and disadvantages of neostigmine to the advantages and disadvantages of its competitor, sugammadex. 

Advantages of neostigmine as a reversal agent include:

• Cost (it is cheap)
• Self-perpetuating familiarity (neostigmine is known, because it is asked about in all the exams, and it is asked about in the exams because it is so well known)
• Short duration of action (thus, one only needs to put up with the side effects for a short period of time)

Disadvantages of neostigmine, however, are many:

• The onset of maximum effect takes about 8-9 minutes.
• It is renally cleared, making it treacherous in renal failure patients
• The duration of action is shorter than many long-acting agents (eg. pancuronium), which means there is the possibility of "re-curarisation", where some residual block develops again after a period of apparently normal neuromuscular function
• It is not useful unless the block has already started to resolve (at least two twitches of the TOF is recommended by many authors). That is because the affinity of the nondepolarising blockers for the receptor is very high, so truly preposterous amounts of acetylcholine are required to out-compete them. This means neostigmine will not be able to reverse a big dose of recently administered rocuronium, for example.
• If you did decide to give an excessive dose, when the nondepolarising blocker wears off, the neostigmine can itself produce depolarising block by excessive acetylcholine release
• The cholinergic side effects can be prohibitive, and require co-administration of anticholinergic drugs like atropine or glycopyrrolate

So, if neostigmine is so terrible, what is the alternative like?

Sugammadex

This substance is a lot more interesting than some old quaternary ammonium compound. Sugammadex is a γ-cyclodextrin, which is modification of a linear dextrin (carbohydrate polymer, specifically polymerised dextrose), which means it obviously has minimal oral bioavailability, being basically a starch, and therefore defenceless in the face of all those potato-ready digestive enzymes you've spent the last few million years developing. This thing is a carefully designed funnell-shaped molecule the cleverness of which is well explained by Bom (2009).  In short:

• Sugammadex is a cyclical molecule with a hydrophilic outside and a lipophilic inside
• The lipophilic central cavity can binds the steroidal structure at the core of the aminosteroid NMJ blockers
• The hydrophilic outer groups will then hold the positively charged nitrogen atom of  rocuronium in position

Thus, only rocuronium and vecuronium have any affinity for sugammadex, and for the others (eg. mivacurium, cisatracurium) sugammadex will have no effect. Vecuronium has about three times less affinity for this "soluble receptor" than rocuronium does, and pancuronium is a long shot, requiring much larger doses. Speaking of doses, that sounds like something you should be able to know and quote:

Sugammadex Doses to Reverse Different Agents

Rocuronium 1.2mg/kg	16mg/kg sugammadex
Rocuronium 0.6mg/kg	4mg/kg sugammadex
Partial residual rocuronium paralysis	2mg/kg sugammadex
Partial residual vecuronium paralysis	4mg/kg, and takes longer
Partial residual pancuronium paralysis	No established dose-response relationship; probably something like 4-6mg/kg

To wit: for a 70kg patient,

• 16mg/kg is 1120mg, or eleven 100mg ampoules
• 4mg/kg is 280mg, or three 100mg ampoules

And so on. Those "acute omg" reversal doses are clearly rather high, which might stimulate the attentive reader to ask: what might be the undesired effects of giving this drug in such a high dose? Which brings us to:

Disadvantages of sugammadex (mostly from Lee et al, 2019)

• It may cause hypersensitivity reactions
• Adverse effects reported with its use are rare, and may be idiosyncratic. These include severe bradycardia, QT interval prolongation, coagulopathy, 
• The reversal with aminosteroids is unequal among aminosteroids, and in particular pancuronium may not be very susceptible. Theoretically, in the future, an aminosteroid agent may become available that is completely immune to the effects of sugammadex
• The non-aminosteroid agents are completely unaffected by this agent
• Cost. This drug remains out of reach for many health services in the developing world.

Advantages of sugammadex, however, are: 

• Rapid onset
• Relatively free from adverse effects
• Able to reverse even high doses of rocuronium
• Half-life is longer than the half-life of basically all NMJ blockers that it would act on