Abstract
The neuromuscular junction (NMJ) forms a chemical bridge between the motor neurone and skeletal muscle. The final short section of the motor nerve is unmyelinated and comes to lie in a gutter on the surface of the muscle fibre at its mid-point – each being innervated by a single axonal terminal from a fast Aα neurone (en plaque appearance). However, for the intra-ocular, intrinsic laryngeal and some facial muscles the pattern of innervation is different with multiple terminals from slower Aγ neurones scattered over the muscle surface (en grappe appearance).
Physiology
The neuromuscular junction (NMJ) forms a chemical bridge between the motor neurone and skeletal muscle. The final short section of the motor nerve is unmyelinated and comes to lie in a gutter on the surface of the muscle fibre at its mid-point – each being innervated by a single axonal terminal from a fast Aα neurone (en plaque appearance). However, for the intra-ocular, intrinsic laryngeal and some facial muscles the pattern of innervation is different with multiple terminals from slower Aγ neurones scattered over the muscle surface (en grappe appearance). Here, muscle contraction depends on a wave of impulses throughout the terminals.
The postsynaptic membrane has many folds; the shoulders contain acetylcholine (ACh) receptors while the clefts contain the enzyme acetylcholinesterase (AChE), which is responsible for the hydrolysis of ACh (see Figure 12.1).
Acetylcholine
Synthesis
The synthesis of ACh (see Figure 12.2) is dependent on acetyl-coenzyme A and choline, which is derived from the diet and recycled from the breakdown of ACh. Once synthesised in the axoplasm it is transferred into small synaptic vesicles where it is stored prior to release.
Figure 12.2 Synthesis of ACh.
Release
When an action potential arrives at a nerve terminal it triggers Ca2+ influx, which then combines with various proteins to trigger the release of vesicular ACh. About 200 such vesicles (each containing about 10,000 ACh molecules) are released in response to each action potential.
Acetylcholine Receptor
Nicotinic ACh receptors are in groups on the edges of the junctional folds on the postsynaptic membrane. They are integral membrane proteins with a molecular weight of 250,000 Da and consist of five subunits (two α, and a single β, ε and δ in adults). They are configured with a central ion channel that opens when the α subunits (each of 40,000 Da) bind ACh. Binding the initial molecule of ACh increases the affinity of the second α subunit for ACh. It is the quaternary nitrogen group, -N+(CH3)3, of ACh (and all neuromuscular blocking drugs) which is attracted to the α subunit. The ACh receptors are also present on the prejunctional membrane and provide positive feedback to maintain transmitter release during periods of high activity. When blocked by non-depolarising muscle relaxants they may be responsible for ‘fade’ (see Figure 12.3).
Figure 12.3 Types of neuromuscular block in response to a train-of-four (TOF), tetanic stimulus, repeat TOF. (a) Control, no muscle relaxant present; (b) partial depolarising block, reduced but equal twitch height, no post-tetanic facilitation; (c) partial non-depolarising block, reducing twitch height, fade on tetanic stimulation, post-tetanic facilitation.
The ACh receptor ion channel is non-specific, allowing Na+, K+ and Ca2+ across the membrane, generating a miniature end-plate potential. These summate until the threshold potential is reached at which point voltage-gated Na+ channels are opened, causing a rapid depolarisation, leading to the propagation of an action potential across the muscle surface. On reaching the T tubular system, Ca2+ is released from the sarcoplasmic reticulum which initiates muscle contraction.
Metabolism
ACh is metabolised by AChE, which is located on the junctional clefts of the postsynaptic membrane. AChE has an anionic and an esteratic binding site. The anionic site binds with the positively charged quaternary ammonium moiety while the esteratic site binds the ester group of ACh. At the point of ACh breakdown choline is released and AChE becomes acetylated. The acetylated enzyme is rapidly hydrolysed and acetic acid is produced.
Monitoring Neuromuscular Block
Muscle relaxants are monitored by examining the effect they have on muscle contraction following stimulation of the relevant nerve. Nerve stimulators must generate a supramaximal stimulus (60–80 mA) to ensure that all the composite nerve fibres are depolarised. The duration of the stimulus is 0.1 milliseconds. The negative electrode should be directly over the nerve while the positive electrode should be placed where it cannot affect the muscle in question.
There are five main patterns of stimulation that are used and the characteristic responses observed in the relevant muscle reveal information about the block.
Single Twitch Stimulation
This is the simplest form of neurostimulation and requires a baseline twitch height for it to reveal useful information. It should be remembered that no reduction in twitch height will be observed until 75% of NMJ receptors have been occupied by muscle relaxant (see Figure 12.4). This margin of safety exists because only a small number of receptors are required to generate a summated mini end-plate potential, which triggers an action potential within the muscle. Partial NMJ block with depolarising muscle relaxants (DMRs) and non-depolarising muscle relaxants (NDMRs) reduce the height of single twitch stimulation.
Figure 12.4 Patterns of non-depolarising muscle-relaxant (NDMR) block against increasing NMJ, receptor blockade.
Tetanic Stimulation
When individual stimuli are applied at a frequency > 30 Hz the twitches observed in the muscle become fused into a sustained muscle contraction – tetany. The response may be larger in magnitude than a single stimulus as the elastic forces of the muscle do not need to be overcome for each twitch. Most stimulators deliver stimuli of 0.1 milliseconds duration at a frequency of 50 Hz, which provides maximum sensitivity. In the presence of a partial NDMR the tetanic stimulation fades with time. This is due to blockade by the NDMR of presynaptic ACh receptors, thereby preventing the positive feedback (see above) used to mobilise ACh at times of peak activity. Partial DMR block reduces but does not exhibit fade in response to tetanic stimulation.
Post-Tetanic Potentiation and Count
Following tetanic stimulation, subsequent twitches are seen to be larger. This may be due to increased synthesis and mobilisation of ACh and/or increased Ca2+ in the synaptic terminal. Post-tetanic potentiation forms the basis of the post-tetanic count where stimuli at 1 Hz are started 3 seconds after a tetanic stimulation. The number of twitches is inversely related to the depth of block. It is best used when the degree of receptor blockade is > 95%, that is, when single twitch or train-of-four (TOF) are unable to evoke muscle twitches. It should be remembered that the effects of tetanic stimulation may last for up to 6 minutes and may therefore give a false impression of inadequate block to single twitch or TOF analysis. Partial DMR block does not exhibit post-tetanic potentiation.
Train-of-Four
The TOF is four 0.1 millisecond stimuli delivered at 2 Hz. The ratio of the fourth twitch height to the first twitch height (T4:T1), or the number of twitches may be recorded, leading to the TOF ratio or the TOF count, respectively (see Figure 12.4). It does not require a baseline twitch height.
In a manner similar to that seen with tetanic stimulation, the rapid stimuli lead to a reducing twitch height in the presence of partial NDMR blockade, that is, T4 < T1. As receptor occupancy rises above 70%, T4 will start to decrease in size. When T4 has decreased by 25%, T1 starts to decrease, corresponding to 75–80% receptor occupancy. T4 disappears when T1 is approximately 25% of its original height. TOF ratio is difficult to assess in practice.
The TOF count records the number of twitches in response to a TOF. As receptor occupancy exceeds 90%, T4 disappears and only T1 is present at 95% receptor occupancy. So the TOF count assesses the degree of deep NDMR block.
Double Burst Stimulation
Double burst stimulation (DBS) describes the delivery of two bursts of stimulation separated by 0.75 seconds. Each burst consists of three 0.2 millisecond stimuli separated by 20 milliseconds (i.e. at a 50 Hz). DBS was developed to allow easy manual detection of small amounts of residual NMJ blockade so that, when the magnitude of the two stimuli are equal, clinically significant residual NMJ blockade does not exist. However, when assessed mechanically, DBS is no more sensitive than TOF (see Figure 12.4).
Depolarising Muscle Relaxants
Suxamethonium
Suxamethonium was first introduced in 1952 and provided a significant advantage over tubocurarine as profound muscle relaxation of short duration was achieved rapidly. It can be thought of as two molecules of ACh joined back-to-back through their acetyl groups.
Presentation and Uses
Suxamethonium is formulated as a colourless solution containing 50 mg.ml−1 and should be stored at 4°C. It is used to achieve rapid muscle relaxation required during rapid sequence induction and has also been used by infusion to facilitate short surgical procedures.
Mechanism of Action
Suxamethonium mimics the action of ACh by attaching to the nicotinic ACh receptor and causing membrane depolarisation. However, because its hydrolysing enzyme (plasma or pseudo-cholinesterase) is not present at the NMJ its duration of action is longer than that of ACh. The persistent depolarisation produced initiates local current circuits that render the voltage-sensitive Na+ channels within 1–2 millimetres inactive. This area of electrical inexcitability prevents the transmission of further action potentials resulting in muscle relaxation. The concentration gradient from plasma to NMJ, down which ACh initially moved, is reversed by the actions of plasma cholinesterase, so that ACh moves in the opposite direction, away from the NMJ allowing recovery of NMJ signal transmission.
Initially this depolarising block is described as a Phase I block; however, if further doses of suxamethonium are given it may become a Phase II block. The characteristics of a Phase II block are similar to those of a non-depolarising block, but the mechanism is thought to be different (probably a presynaptic effect) (see Table 12.1; Figure 12.3).
| Partial depolarising or Phase I block | Partial non-depolarising or Phase II block | |
|---|---|---|
| Single twitch | reduced | reduced |
| Train-of-four ratio (T4:T1) |
|
|
| Sustained | fade |
| Post-tetanic potentiation | no | yes |
| Effect of anticholinesterases | block augmented |
|
Kinetics
Suxamethonium is rapidly hydrolysed by plasma or pseudo-cholinesterase (an enzyme of the liver and plasma – none being present at the NMJ), to such an extent that only 20% of the initial intravenous dose reaches the NMJ, so that the rate of hydrolysis becomes a critical factor in determining the duration of the neuromuscular block. Suxamethonium is hydrolysed to choline and succinylmonocholine, which is weakly active. Succinylmonocholine is metabolised further by plasma cholinesterase to succinic acid and choline. Because metabolism is rapid, less than 10% is excreted in the urine (see Figure 12.5).
Figure 12.5 Metabolism of suxamethonium.
Other Effects
Apart from its useful effects at the NMJ, suxamethonium has many other effects, all of which are detrimental:
Arrhythmias – sinus or nodal bradycardia, and ventricular arrhythmias can occur following suxamethonium, via stimulation of the muscarinic receptors in the sinus node. The bradycardia is often more severe after a second dose but may be prevented by atropine. This phenomenon is often more pronounced in children.
Hyperkalaemia – a small rise in serum K+ is expected following suxamethonium in the normal subject as depolarisation involves K+ efflux into extracellular fluid. Patients with burns (of > 10%) or neuromuscular disorders are susceptible to a sudden release of K+, which may be large enough to provoke cardiac arrest. Burn patients are at risk from about 24 hours after injury and for up to 18 months. Extra-junctional ACh receptors (which contain a fetal γ subunit in place of an adult ε subunit) proliferate over the surface of the muscle, and when activated release K+ into the circulation. Patients with paraplegia, progressive muscle disease or trauma-induced immobility are at risk via a similar mechanism. The period of particular risk in those with paraplegia is during the first 6 months but it continues in those with progressive muscle disease, becoming more severe as more muscle is involved.
Those with renal failure are not at increased risk of a sudden hyperkalaemic response to suxamethonium per se. However, serum K+ may be grossly deranged in acute renal failure leading to an increased risk of arrhythmias.
Myalgia – muscle pains are commonest in young females mobilising rapidly in the post-operative period. Pre-treatment with a small dose of NDMR (e.g. vecuronium), diazepam or dantrolene have all been used with limited success in an attempt to reduce this unpleasant side effect.
Intra-ocular pressure (IOP) – is raised by about 10 mmHg for a matter of minutes following suxamethonium (normal range 10–15 mmHg) and is significant in the presence of a globe perforation. However, concurrently administered thiopental will offset this rise so that IOP remains static or may even fall. The mechanism by which suxamethonium increases IOP has not been clearly defined, but it is known to involve contraction of tonic myofibrils and transient dilation of choroidal blood vessels.
Intragastric pressure – rises by about 10 cmH2O, but as the lower oesophageal sphincter tone increases simultaneously there is no increased risk of reflux.
Anaphylaxis – suxamethonium is twice as likely to cause anaphylaxis compared to NDMRs, with a rate of approximately 1 per 10,000 administrations.
Malignant hyperthermia (see ‘Malignant Hyperthermia’ below).
Prolonged neuromuscular block (see ‘Prolonged Block (Suxamethonium Apnoea)’ below).
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