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:
Name Neostigmine Sugammadex Class Acetylcholinesterase inhibitor Selective binding agent Chemistry Quaternary ammonium compound γ-cyclodextrin Routes of administration IV or oral IV only Absorption Poor absorption; minimal oral bioavailability (less than 5%) Minimal oral bioavailability (<4%) because of degradation by digestive enzymes Solubility pKa=12.0; good water solubility, minimal lipid solubility pKa= 2.82; reasonable water solubility Distribution VOD=0.12 L/kg; 15-25% protein-bound VOD=0.16-0.20 L/kg; minimally protein-bound Target receptor Acetylcholinesterase Rocuronium molecules are the drug target Metabolism Slowly hydrolysed by acetylcholinesterase and also by non-specific plasma esterases Not really metabolised Elimination About 70% is eliminated in the urine unchanged Cleared renally (which means any nondepolarising agent captured by this molecule will also be cleared renally Time course of action Half-life ~70 minutes, duration of action 20-30 minutes Elimination half-life is about 2 hours; onset of effect is within about 3 minutes Mechanism of action By binding to acetylcholinesterase, neostigmine acts as a competing substrate, replacing acetylcholine and decreasing acetylcholinesterase activity. The dugs is metabolised much more slowly than acetylcholine, which means the enzyme is blocked for a sustained period. The cyclodextrin is a funnel-shaped molecule with a lipophilic core that binds the steroid ring of aminosteroid agents and traps them, preventing them from having any further activity on the neuromuscular junction. Clinical effects Reversal of neuromuscular junction blockade (by nondepolarising agents). Also, in high doses, can cause depolarising neuromuscular blockade on its own. A ceiling effect reduces its efficacy as a NMJ blocker reversal agent. Has many cholinergic side effects, including salivation, bronchorrhoea, bradycardia, lacrimation, urinary incontinence and diarrhoea Reversal of nondepolarising blockade due to rocuronium, vecuronium, and to a lesser extent pancuronium. Also: may (rarely) cause bradycardia, QT prolongation, and anaphylaxis Single best reference for further information Calvey et al (1979) Bom (2009)
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:
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.
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|
Diplopia, difficulty tracking moving objects
Reduced ability to clench teeth (i.e. chew the tube)
Maximum inspiratory flow rate is markedly impaired
Grip strength is about 50-75% of normal.
Sustained eye opening, tongue protrusion
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
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.
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.
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:
Disadvantages of neostigmine, however, are many:
So, if neostigmine is so terrible, what is the alternative like?
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:
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:
|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,
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)
Advantages of sugammadex, however, are: