Monitoring of neuromuscular blockade

This chapter addresses Section L3(i) from the 2017 CICM Primary Syllabus, which expects the exam candidates to "describe the monitoring of neuromuscular blockade". 

It does not seem to have been accessed by the examiners for any First Part exam SAQs, but is fair game, considering it is in the textbooks and the syllabus document. Moreover, the exam candidates are reminded that CICM often borrows SAQs from the ANZCA primary exam, where nightmares such as this are lurking:

"Describe the terms train-of-four stimulation and double burst
stimulation with respect to the peripheral nerve stimulator. Describe their
advantages and disadvantages when used to evaluate non-depolarising
neuromuscular blockade."

In short, though the time-poor candidate could reasonably skip this section and move on to higher-scoring topics, they would be doing so while casting an uneasy eye behind them, knowing that they neglect it at their peril. To ameliorate some of that anxiety, a short grey box is offered, so that at least some pointform information may adsorb onto their synapses before they move on to reading about neuromuscular junction blocker pharmacology.

The reader is reminded that this material is a fundamental expectation for many anaesthesia programs, and therefore ample material is available online or on paper, and so nobody will ever starve and wither for lack of sufficient NMJ blocker monitoring literature. It is more important to cleverly manage the confusing abundance by limiting one's reading to just one or two papers, so as not to become bogged in minutiae. In case recommendations are called for, these two excellent free articles by McGrath et al (2006) and Naguib et al (2017) will satisfy all the CICM learning objectives.

Rationale for monitoring neuromuscular blockade

"Why are we even doing this" would be a reasonable remark from anybody placing electrodes onto the limp forearm of an inert-appearing patient who is clearly not triggering the ventilator. Yes, reader, neuromuscular junction blockers are usually given to achieve a clinical effect (optimal intubating conditions, tolerance of mechanical ventilation, ideal surgical tissue compliance) and we know the dose we gave is appropriate when this effect is achieved, which begs the question: why is it important to quantify exactly how paralysed they are? Well. Quite right, there are some largely anaesthetic considerations, where the objective is to get the tube out safely and quickly to keep the economy running. The rationale for quantitatively monitoring NMJ blockade has the following applications in anaesthesia:

• Assessing the readiness for extubation in the context of slowly fading blockade, and to reveal any residual block
• To guide the dosing of reversal agents at the end of anaesthesia

These are less relevant in the ICU where the patient often ends up ventilated long beyond the point where the NMJ blocker has worn off. There are however several other reasons to attach the nerve stimulator to an ICU patient. 

• To rule out NMJ blockade as the cause of a "decreased level of consciousness", for example in the apparently unresponsive intubated patient who has severe liver or kidney disease that prevents them from clearing the NMJ blocking agent
• To adjust the dose of NMJ blocker, thereby minimising the exposure to these agents, as they are thought to have deleterious effects on muscle catabolism (i.e., theoretically,  the less of the aminosteroid agent you use, the less severe the ICU-acquired weakness is going to be when the ARDS finally resolves). According to Rudis et al (1997), you could almost halve your vecuronium dose this way.

Specifically for the ICU environment, the excellent "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient" by Murray et al (2016) make several other important points, which are completely peripheral to the chapter objectives but which should be introduced here anyway, because they have relevance for the future independent practice of CICM trainees:

• Peripheral nerve stimulator monitoring alone is insufficient: in other words, don't fixate on the TOF; an inclusive assessment of the patient is essential. As an example, if one's objective is to ensure the tolerance of mechanical ventilation, and the patient is not experiencing dyssynchrony, then there is no added advantage to deepening their blockade, even if they have all four twitches on TOF.
• CNS monitoring is much more important than PNS monitoring: the much larger risk for the ICU patient is to be aware while paralysed, which means monitoring their level of consciousness (eg. with EEG or BIS) is a lot more important than the depth of blockade per se (as the latter can be assessed clinically anyway). If you're going to monitor anything, make it the brain instead.

So, in case you need to ever pull one of these devices out, and put it on a person:

The peripheral nerve stimulator

These devices are as numerous and variable as there are methods of delivering current, because there are a myriad different methods for achieving the same design specifications:

• Convenience (eg. they are usually small and battery operated)
• Capable of delivering a constant current of at least 80 mA (though usually 50-60 mA would be enough). Constant current is better than constant voltage because with a constant voltage the current will vary with skin resistance (because V = IR) and it is current, rather than voltage, which is the most important parameter that depolarises the nerve.
• Capable of delivering this current as a pulse. The pulse these things produce is usually a short monophasic shock lasting no more than 0.3 ms.
• Capable of delivering a pattern of current. These devices usually do train-of-four, but should ideally also be able to do single twitches, tetanic stimulation (at 50Hz) and double burst stimulation. 

By convention of design, they usually have a black (negative) electrode and a red (positive) electrode. The negative black electrode is supposed be placed directly over the most superficial part of the nerve, and the red positive electrode usually goes somewhere proximally along the nerve, ideally not over any muscle (so as not to depolarise the muscle directly), which was best demonstrated in this classic study by Buonarroti (1509):

Why the distance of five centimetres, and who decided? There does not seem to be a scientific reason for this, other than the experience of a million practitioners. Reputable sources (eg. Thilen & Bhanenker, 2016) repeat this recommendation without elaborating on it, which suggests that the answer is so basic that nobody needs it explained to them, as everyone will immediately and intuitively understand the principles. It does appear that the proximal forearm contains some meaty muscles over the ulnar nerve (its nestled between the flexor carpii ulnaris and the flexor digitorum profundis), which means direct muscle stimulation would occur if you were to zap there, whereas more distally the ulnar nerve is superficial, nestled between the FCU medially and FDS laterally).

Why not just zap the muscle? Electrical muscle stimulation, which is what you'd get if you directly depolarise the myocytes with current, has its uses, but monitoring neuromuscular blockade is not one of them. Consider that the muscle itself is basically intact in the presence of a curare toxin: only the neuromuscular junction is affected, which means that only the transmission between nerves and muscles is interrupted; but each individual component still functions normally. To inflict a current upon a myocyte in these conditions would still produce a twitch, and give the operator the false impression that the neuromuscular junction blocker is not working.

Why the ulnar nerve? Convenience. Often enough it is possible to sneak the wrist out from under the drapes or have it secured to an arm board and have continuous access to this limb during the operation, whereas the same cannot be said for other superficial nerve sites. Still, alternatives do exist. At a basic level all you need is a superficially exposed nerve that has motor fibres and innervates a muscle that does something visually identifiable, like the adductor pollicis. The posterior tibial nerve and the facial nerve have both been used, though the latter is apparently unreliable because of the muscles around the eye are weirdly resistant to NMJ blockers. 

Single twitch

So, with the muscle and nerve selected, and the electrodes placed, one is now able to manipulate the current and discharge pattern to measure the depth of neuromuscular blockade. To do this, one must first reassure themselves that the stimulus being applied will reliably depolarise the nerve and produce a motor response. This is done with a single 0.2 second twitch which establishes the current setting required to produce a supramaximal stimulus (usually 50-60 mA). The stimulus is described as "supramaximal" because the current here is more than what would be required to merely depolarise all of the nerve fibres and activate all of the innervated motor units. It needs to be higher to assure the user that any subsequent decrease in motor activity is purely due to the neuromuscular junction blocker and nothing to do with (for example) changes in the skin resistance of the patient.

To the unready reader, this last statement may sound bizarre. The electrical resistance of the human skin does not sound like something that should fluctuate wildly, at least surely not over the course of a single theatre case? Well. According to Fish & Geddes (2009), the resistance of the skin can vary from 1000 to 100,000 Ω, and these figures appear to be repeated throughout the literature, suggesting that they and their 100-fold range represent some sort of fact. NASA research from the 1960s seems to be the origin for a lot of these claims, and is excellently detailed, specifying the difference in resistance due to changes in prevailing conditions (ambient humidity, skin perfusion, eccrine gland function, etc). It will suffice to summarise that dry skin, though it has an extremely high resistance, is still sufficiently conductive that it would considered ESD-safe if it was used as an industrial flooring material, which means the peripheral nerve stimulator should be expected to work over this entire range of resistance values. And yes, they would change dramatically over the course of a single operation, as demonstrated in this classical study by Goddard from 1982. The authors measured skin conductance (the reciprocal of resistance) over the course of surgical procedures. As one can see, in the annotated case below, conductance increased tenfold over the course of the first 15 minutes.

In summary, single twitch is a calibration step which can be taken to determine that the PNS is working correctly and will produce reliable data. As such, this step is usually not taken, as the ideal time to do it would be before the induction of the NMJ blockade, and the patient may protest to being lightly electrocuted. As such, the first exposure to neuromuscular junction monitoring CICM trainees may have would be to train-of-four (TOF) monitoring. 

Train of four

Presumably in response to the reluctance of patients to surrender to electrical shocks for pre-induction control measurements,  Ali et al (1971) produced a method of testing neuromuscular conduction which did not require a comparison to pre-blocked twitch amplitude. The technique relied on the earlier observations of other authors, who pointed out that deepening turbicurarine blockade was associated with a progressive decrease in muscle twitch amplitude with regular repeated stimulus. Specifically, we owe the "four" in this train to the work of Rosenblueth & Morison (1937) who determined that cat gastrocnemiuses (gastrocnemi?) tend to stabilise at a particular twitch amplitude after four regular shocks, and the fifth and sixths pulses are essentially the same, meaning that there would nothing more to be gained by having a train-of-six or a train-of-ten. In case anybody cares, referring to these sequences of impulses as "trains" had appeared organically in the literature at some point in the 1930s, with authors referring to "trains of shocks" throughout the period.

Anyway: following this study, the train-of-four (hyphenated in modern literature) became standardised as a series of four suprmaximal twitch stimuli, occurring at a frequency of 2Hz (every 0.5 seconds), with the amplitude of the first stimulus compared to the amplitude of the last as a ratio (usually expressed as a percentage). When the last twitches disappear (with deep block) the ratio is no longer meaningful, and the user will instead refer to the TOF count, which is simply the number of twitches you see. A TOF count of one means there is only one twitch, and the last three are missing.  The physiology behind this "fade" phenomenon is discussed in some detail in the chapter on twitch summation and tetanus. To summarise, the binding of the NMJ blocker to presynaptic receptors reduces the recruitment of neurotransmitter vesicles, resulting in the progressive depletion of acetylcholine releasing capacity, as the unready membrane is not prepared to deal with the repeated requests.

Speaking of repeated requests. The TOF should not be performed repeatedly or continuously, i.e. one should leave the limb to rest for some time between TOFs. The reason behind this is potentiation: the TOF will increase in amplitude if it is done too soon after the last TOF. Naguib et al (2017) recommend a gap of 15-20 seconds as a minimum. 

So, what could be expected of the CICM exam candidate, when it comes to this monitoring technique? One might expect that some sort of diagrams might be asked for, in which case the reader will be ready with these:

Not much more would be expected of these, except perhaps a depiction of Phase 2 block, which would look identical to non-depolarising block. 

What are the uses and limitations of TOF? For the anaesthetist, the TOF count and the TOF ratio have some clinical relevance as they represent NMJ receptor occupancy, and can be reliably associated with clinical events - for example a TOF count of 1-2 gives appropriate surgical conditions, and a TOF ratio of 0.9 is enough to extubate the patient. For the intensivist, the relevance is somewhat diminished, as we rarely have the same sort of time pressure, and are able to titrate our NMJ dose to achieve a rather diffuse and nebulous cloud of clinical impressions and ventilator effects. The main limitation of TOF is that without specialised equipment it is entirely qualitative, which means the user is expected to just eyeball the movement of the stimulated muscle and assess whether there is fade, and whether the movement is more or less than the last batch of testing. Gross findings like TOF count have some validity, but most authors seem to agree that any TOF ratio beyond 0.4-0.6 is too difficult to detect clinically, as the amplitude of the twitches becomes too subtle for the human eye.

Double burst stimulation

TOF, as mentioned above, is a gross measure of neuromuscular blockade, and without a control measurement the user can be left to guess how high the twitch amplitude is supposed to be in the unblocked organism, which means subtle residual blockade may go unnoticed. The aforementioned TOF ratio of 0.9 may be rather difficult to recognise with the unaided eye. This is where the double burst method comes in: it is able to detect rather subtle residual blockade, which could mean the difference between extubation success or failure for fragile marginal patients.

Double burst stimulation consists of two shorts bursts of tetanic stimulation, each at 50Hz, usually of three impulses lasting 0.2ms, delivered every 20 ms. Each such burst is separated by 750 ms. The effect of NMJ blockers on this method is much greater, and the difference between the first and the second burst is more pronounced, such that even at a TOF ratio of 0.9 there is an easily appreciable fade on DPS testing: