Count, ratio, and the difference
between them that costs marks every year.

• Every pattern uses a supramaximal stimulus of 60–80 mA lasting 0.1 ms, so that all fibres are depolarised and any change is the drug rather than the recruitment.
• Train-of-four count measures depth. Train-of-four ratio measures recovery. They are different numbers from the same four stimuli.
• Fade is presynaptic and occurs only in non-depolarising and phase II block.
• Adequate recovery is a train-of-four ratio of at least 0.9, measured objectively.
• Neostigmine has a ceiling and needs some spontaneous recovery first. Sugammadex does not, but only works on the aminosteroids.

A peripheral nerve stimulator delivers a monophasic square pulse of 0.1 ms. The pulse must be supramaximal — about 60 to 80 mA — meaning larger than the current needed to depolarise every fibre in the nerve. That matters because if only some fibres are recruited, a change in the evoked response could mean either a change in the block or a change in how many fibres the stimulus reached, and the two cannot be told apart.

It is the electrical charge — current multiplied by duration — that determines whether a nerve is stimulated, which is why pulse width is specified along with current. A pulse much longer than 0.1 ms risks stimulating muscle directly, producing a contraction that is not a test of the junction at all.

A single supramaximal stimulus, conventionally at 0.1 Hz — one every ten seconds — and the height of the evoked twitch compared with a control. The comparison is the problem: without a baseline recorded before the relaxant was given, a single twitch tells you nothing, because you do not know what full looks like in this patient. And because of the margin of safety, no reduction is seen at all until most of the receptor reserve is gone.

Both depolarising and non-depolarising block reduce single-twitch height, so the pattern also cannot distinguish between them.

Four supramaximal stimuli of 0.1 ms delivered at 2 Hz, over two seconds. Its advantage over the single twitch is that each response is compared with the first response in the same train, so no pre-drug baseline is needed. Two numbers come out of it, and conflating them is the error the reports keep recording.

Stimulation at frequencies above about 30 Hz fuses individual twitches into a sustained contraction. Fifty hertz is the standard because it approximates maximal voluntary effort and gives the greatest sensitivity; five seconds is the standard duration.

In an unblocked patient the contraction is sustained. In a partial non-depolarising block it fades. The mechanism is presynaptic and worth stating precisely, because it is the reason the two block types differ: acetylcholine release during sustained high-frequency demand depends on a positive-feedback loop through presynaptic nicotinic receptors, which mobilise transmitter from the reserve pool. Non-depolarising drugs block those presynaptic receptors as well as the postjunctional ones, the loop fails, transmitter release cannot keep up, and the response declines. Suxamethonium does not block them, so a phase I block reduces the response without fading it.

Post-tetanic facilitation follows: for a few minutes after a tetanic stimulus the twitches are larger, because the tetanus has increased transmitter synthesis and mobilisation and raised calcium in the nerve terminal. That is a real improvement in transmission and not a change in the block, which is why a tetanic stimulus distorts everything measured for the next 6 minutes and can give a false impression of recovery.

When the train-of-four evokes nothing at all, it can no longer distinguish a deep block from a deeper one. The post-tetanic count uses facilitation to get a response where none was available: a five-second tetanus at 50 Hz, then a pause of 3 seconds, then single stimuli at 1 Hz. The number of twitches that appear is inversely related to the depth of block — fewer twitches, deeper block — and it is the pattern of choice above about 95% occupancy.

A partial depolarising block shows no post-tetanic facilitation, so the count is not applicable to it.

Two bursts of 3 stimuli of 0.2 ms, each burst delivered at 50 Hz — that is, 20 ms apart — with 750 ms between the two bursts. Each burst is felt as a single strong contraction, and the question is simply whether the second feels weaker than the first.

It exists because human fingers are poor at detecting a train-of-four ratio above about 0.4, and the ratio that matters clinically is 0.9. Comparing two strong contractions is easier than comparing the first and fourth of four smaller ones. When measured objectively, double-burst stimulation is no more sensitive than a train-of-four; its advantage is entirely in manual detection.

A list of interacting drugs is almost useless without the mechanism attached, because the mechanism is what lets you predict the interaction you have not seen before. Grouped by mechanism, the list collapses into four ideas: less transmitter released, the postjunctional membrane stabilised, the membrane made harder to depolarise, or more transmitter made available.

Adequate recovery is a train-of-four ratio of at least 0.9, measured objectively at the adductor pollicis. The figure is not arbitrary; it is where measurable harm begins.

The enzyme, and its two binding sites

Acetylcholinesterase sits in the junctional clefts of the postsynaptic membrane and has two binding sites. The anionic site attracts the positively charged quaternary ammonium end of acetylcholine; the esteratic site binds its ester group. Acetylcholine occupies both, is hydrolysed, and leaves the enzyme acetylated — a state that is itself hydrolysed within microseconds, freeing the enzyme for the next molecule. That speed is why transmission can be a discrete event rather than a smear.

Every anticholinesterase interferes with one or both of those sites, and how firmly it attaches decides how long it lasts. That single idea sorts the whole class into three groups.

Three classes, by how tightly they hold the enzyme

The middle group is the one used for reversal, and its three members differ in ways that follow from their structure rather than from anything at the junction:

• Neostigmine — a quaternary amine, so no central effects. 0.05 mg/kg intravenously for reversal; 15–30 mg orally in myasthenia gravis, where the effect lasts up to four hours. About 55% is excreted unchanged in urine.
• Pyridostigmine — also quaternary, with a slower onset and a longer duration than neostigmine and fewer autonomic effects, which is why it is the one preferred for maintenance treatment of myasthenia gravis. More renally dependent: about 75% excreted unchanged.
• Physostigmine — the odd one out, because it is a tertiary amine. It is well absorbed from the gut and does cross the blood–brain barrier, which makes it useless as a routine reversal agent and useful in central anticholinergic poisoning.

Neostigmine in detail

Neostigmine is a quaternary amine that inhibits acetylcholinesterase. It carbamylates the enzyme, and the carbamylated enzyme is hydrolysed far more slowly than the acetylated enzyme acetylcholine produces, so the enzyme is out of action for a relatively long time. Junctional acetylcholine accumulates and competes with the non-depolarising blocker for the receptor. The block is not removed; it is outcompeted.

The dose for reversal is 0.05 mg/kg intravenously.

One consequence of that mechanism is worth stating before the side effects, because it is the reason neostigmine is never the answer to a suxamethonium block. Raising acetylcholine helps only where acetylcholine is being competed with. Against a competitive antagonist it displaces the blocker and the block lifts. Against a depolarising agonist there is no competition to win — the end-plate is already depolarised, and more agonist sustains that depolarisation. So the same drug that reverses a non-depolarising block augments a phase I block, and additionally prolongs it by inhibiting the plasma cholinesterase that would have cleared the suxamethonium.

Because acetylcholinesterase is not confined to the neuromuscular junction, inhibiting it raises acetylcholine everywhere. The muscarinic consequences are the reason an antimuscarinic is co-administered:

The nicotinic effects are the ones most easily forgotten, because the muscarinic list is longer and more familiar. Both follow from the same cause — acetylcholine accumulating everywhere the enzyme was working, not only at the junction you meant to act on.

Sugammadex is a modified gamma-cyclodextrin: a ring of eight sugars with a hydrophobic interior and a hydrophilic exterior. Aminosteroid molecules fit inside that cavity and are held there by van der Waals forces, hydrophobic interactions and electrostatic attraction. The encapsulated complex is inactive and renally excreted. Because the drug is removed from plasma, the concentration gradient reverses and the blocker diffuses away from the junction.

It is therefore a non-competitive antagonist, where neostigmine acts indirectly as a competitive one. That difference is not a technicality: a competitive antagonist can always be overcome by more agonist and is therefore surmountable, which is precisely why neostigmine has a ceiling and sugammadex does not. Sugammadex has no action at any receptor and no autonomic effects of its own, so no antimuscarinic is needed.

Monitoring and reversal are one continuous piece of reasoning, not two topics that happen to sit together. Followed in order:

1. The stimulus must be supramaximal, or a change in response could be a change in recruitment rather than a change in block. Everything downstream assumes this.
2. Occupancy determines the pattern you can use. Above about 95% the train-of-four evokes nothing, so the post-tetanic count takes over; below that the count reports depth; once all four twitches return, only the ratio still carries information.
3. Fade distinguishes the mechanism. It is presynaptic, so it appears in non-depolarising and phase II block and not in phase I. That is how the monitor tells you which kind of block you are looking at, not merely how much.
4. Depth determines which reversal agent can work. Neostigmine is surmountable competition and has a ceiling; sugammadex removes the drug and does not. This is why the count is taken before the syringe is chosen.
5. The endpoint is a ratio, not a clinical sign. A train-of-four ratio of at least 0.9 at the adductor pollicis, measured objectively — because the diaphragm and larynx recover well before the pharynx, so a patient can breathe comfortably and still be unable to protect their airway.

The interactions sit alongside this chain rather than inside it: they change how deep the block is and how long it lasts, but not how any of the above is read.