Twitch, summation and tetanus

This chapter addresses Section L1(vi) from the 2023 CICM Primary Syllabus, which expects the exam candidates to "describe the monosynaptic stretch reflex, single twitch and tetanus".  Monosynaptic reflexes are mentioned elsewhere (twice!), which means this chapter can focus on the topic of muscle twitches and tetany. For the CICM exam candidate, this topic has low- but not zero - revision relevance, as it has never appeared in written papers before, but is absolutely fair game, considering its importance to the monitoring of neuromuscular blockade.

  • Single twitch of a skeletal muscle follows a single action potential, and consists of:
    • Latent period (perhaps 2 milliseconds)
    • Period of contraction (10-100 milliseconds)
    • Period of relaxation (100-400 milliseconds)
    • These periods are different for different muscles and fibre types
  • Summation is the additive effect of frequent contractions, where a muscle fibre is stimulated again before it has relaxed completely from a prior contraction: 
    • The tension generated by the second contraction is additive with the tension already being produced by the fibre
    • The result is the generation of more force than any single contraction is capable of
    • The additive effect of multiple frequent stimuli is referred to as frequency summation
    • The additive effect of multiple fibres being simultaneously stimulated is referred to as multiple fibre summation.
  • Tetanus, tetany or tetanisation is the term given to the summation of stimuli that are so frequent that there is no discernable relaxation phase between twitches
    • The frequency at which this is achieved is usually 50-100 Hz, and the specific critical frequency depends on the duration of the action potential of the cell
    • The maximum tension developed is usually about four times the tension generated by a single twitch
    • Sustained tetany will fatigue the muscle, and over 10-20 seconds the tension will begin to decrease
  • Post-tetanic potentiation is the augmentation of the force of any contraction that occurs after tetany, and  and is thought to be due to the increase in the availability of calcium in the presynaptic nerve terminal.
  • With nondepolarising neuromuscular junction blockade:
    • Complete blockade abolishes all twitches
    • With train-of-four, fade is observed
    • Post-tetanic potentiation is preserved ​​​​
  • With depolarising neuromuscular junction blockade:
    • Complete blockade abolishes all twitches
    • With train-of-four, no fade is observed
    • There is no post-tetanic potentiation.

The use of a conventional textbook chapter (like Kam or Stoelting) would be reasonable for this topic, not because it is without depth, but rather because depth would be harmful, as the explanations one might derive from a deep dive into the literature would often be more complex and less certain than the simplified statements made by textbook authors, and there is no reason for the CICM First Part exam candidate to be more accurate or deeper than Kam and Stoelting. Fortunately, as this forms a part of standard undergraduate biology offerings, there is no shortage of online resources ready to describe these concepts across a range of media, and one merely needs to Goodle some combination of the terms "twitch", "tetany" and "summation" for immediate access to a huge range of suitable results.

A single muscle contraction

When an action potential comes along, a relaxed muscle fibre will contract. More accurately, when an electrophysiologist tortures a severed motor axon with some electricity, the axon will discharge and the resulting (solitary) action potential will produce a twitch in the associated motor unit, which can be recorded and studied. This phenomenon is so well known that the best diagrams to describe it come from papers that describe horrific rat experiments with which to nauseate your physiology undergrads. Without endorsing these nightmares by reproducing them, a diagram can be offered to exam candidates, so that they may reproduce it one day in a paper:

Single twitch myogram

The exact numbers are not especially relevant, considering especially that there are distinct fast-twitch and slow-twitch muscle fibres, and that even within the same category individual fibres will be slightly different. A seminal paper by Ebstein & Goodgold (1968), for example, had listed the following results:

Muscle  Contraction time (msec)
Rectus abdominus  58-140
Multifidus 55-140
Pectoralis minor  110-130
Internal oblique 60-88
External oblique 140
Biceps brachii 65-70
Sternocleidomastoid      50-55
Semispinalis capitis 54-74
Deltoid 110
Abductor hallucis 55

As you can see, there's quite a distribution; moreover all kinds of ambient factors (temperature,  pressure, ambient calicum levels) have an effect on the precise duration of the contraction and latent period. Even more variable is the amplitude, which would obviously depend on the beefiness of the muscle fibre being tested. In short, labelling the gradations on the x and y axis on this graph would be a fairly pointless exercise, and any trainee that can vaguely blurt a ballpark figure for the duration of a muscle twitch is already ahead of their peers in terms of remembering pointless facts, which is what this exam seems to often be about. 

However, occasionally we can see glimpses of practically relevant meaning in physiology that transcend the need to regurgitate facts for exams. In this topic, that window opens on to summation, tetany, "fade", and the effect of neuromuscular junction blockers on the response of muscles to action potentials.

Summation and frequency summation

The fairly short duration of a myocyte action potential (4 milliseconds) and the fairly long duration of the muscle contraction (hundreds of milliseconds) gives rise to the possibility that an action potential might arrive before the end of the contraction, rudely intruding into the relaxation period. The result would be further contraction, of course, as the skeletal muscle fibre does not have much of a refractory period. In fact the tension generated by the muscle in response to the second stimulus would be added to the already-generated tension, i.e. the twitches would merge into one contraction which has a greater force than an individual twitch. This additive effect is referred to as "summation".

Summation of muscle twitches

If the returning reader is accustomed to seeing genuine experimental data from obscure early twentieth-century papers and is unimpressed by the simplistic lines of a homecooked diagram, here's an almost identical set of summed contractions from a classic paper by Cooper & Eccles (1930) to restore their confidence in this online resource. The investigators were double-zapping the peroneal nerves of a cat, and measuring the contractions of the gastrocnemius.

summation of muscle contraction from Cooper & Eccles, 1930

Summation is an important factor in the generation of force. The reader, on reflection, will agree that a 150-millisecond muscle twitch is not something that could be used to perform any sort of purposeful activity in the world of adult human behaviour. Single action potential bursts are not enough to fold the washing and put the kids to bed.  From this, it follows that in the living human organism muscle tension must be coordinated by the asynchronous arrival of multiple action potentials, constantly, to generate some controlled and constant tension in muscle. Physiology textbooks tend to refer to this as "frequency summation", as opposed to "multiple fibre summation", where multiple motor units twitch simultaneously with additive force. Occasionally it is also referred to as "wave summation", referring probably to the wavelike appearance of the resulting tension/time curve. Again, from the cats tormented by Cooper & Eccles:

wave summation from Cooper & Eccles, 1930.jpg

The mechanism underlying this is calcium release. Each action potential arrives before the calcium from the last action potential has had time to be packed away, and the increased availability of calcium continues to stimulate the contractile apparatus, leading to greater and greater actin/myosin heroics. Logically, from this it follows that there would be some maximum here, where the contractile proteins can no longer generate any further force, and that this maximum could be reached by sustained high-frequency electrotorture. This is exactly what happens in the case of tetany, which brings us to:

Tetanus or "tetanisation"

If action potentials come to depolarise the muscle fibre so frequently that no relaxation is observed, the wavelike force diagram becomes smooth, representing a gradual increase in tension until a peak is reached. That peak is usually about four times higher than the force of single twitch. Here, again from the awful cat paper, the investigators demonstrated the effect of increasing the frequency of the stimuli. The image on the right is a traced representation of record A (frequency of 19 Hz) overlaid with  Record D (frequency of 115 Hz), the latter demonstrating the classical pattern of tetanus.

Tetanus from Cooper & Eccles (1930)

"Practically no extra tension is developed by stimulus rates higher than this", the investigators noted, cleaning soot off their electrodes over piles of smoking cat muscles. As the stimulus is sustained, the force of the contraction will begin to decline - something usually described by the term "high-frequency fatigue" - and it will decline faster if the frequency of stimulation is higher. Here, Bigland-Ritchie et al (1979) demonstrated this on an isolated mouse soleus.

high frequency fatigue from Bigland-Ritchie et al, 1979

It is probably not essential to recall these details for exam purposes, and the diagrams are included here mainly as a means of demonstrating how long a muscle can maintain this sort of maximal contraction. In general, in their routine practice ICU clinicians will rarely (hopefully, never) be needing to observe these phenomena. The more important factoid to recall is that cardiac muscle, which has a long refractory period and a short contraction, cannot be tetanised, as the last contraction will have finished before the next has a chance to begin - i.e. summation of contractions is impossible. 

Twitch and tetanus in neuromuscular blockade

Though this might overlap somewhat with the section that deals with "describe the monitoring of neuromuscular blockade", it's probably important to finish this chapter with something clinically relevant. So: here is a summary of single twitch and tetany behaviour in the context of neuromuscular blockade (which is really the only space where one might routinely encounter these physiological concepts in routine practice).

So, in short:

  • When you're blocked, you're blocked. Single twitch, train-of-four and sustained tetanic stimuli all have the same effect, which is to say, none. This is the same for both depolarising and nondepolarising blockers.
  • Partial block produces decreased twitch both with depolarising and nondepolarising blockade. This feels like an uncontroversial point that does not need to be explained with an extensive physiological digression.
  • The difference between depolarising and nondepolarising blockade is fade and post-tetanic potentiation: 
    • Non-depolarising blockade produces "fade" as it is wearing off, whereas with depolarising blockers there is no such phenomenon. In most textbooks (Kam, for example) fade is explained by the binding of the blocking agents to pre-synaptic α3β2 nicotinic receptors. For example, α-bungarotoxin, a non-depolarising blocker that binds to post-synaptic receptors only, does not produce fade. When presynaptic α3β2 nicotinic receptors are stimulated, they interfere with the recruitment and mobilisation of vesicles that would normally occur following repeated stimulation, limiting the number of vesicles that can bind to the presynaptic membrane, and therefore decreasing the force of subsequent contractions (because less acetylcholine is released with each subsequent electrical stimulus). As is often the case, things are probably more complicated than that, but for the purposes of regurgitating facts in the CICM exams, a trainee mainly needs to remember this presynaptic mechanism, and that depolarising blockers do not bind to those α3β2 nicotinic receptors, and produce no fade.
    • Post-tetanic potentiation is maintained with non-depolarising blockade. Usually, when a sustained tetanic stimulus is administered, it increases the force of the subsequent twitches, and for a reasonable period of time, perhaps minutes (this finding was surprising, as usually one might expect this sort of thing to produce fatigue). An increased release of acetylcholine is observed during these "potentiated" twitches. The mechanism this is usually attributed to - calcium accumulation in the presynaptic part of the terminal - is probably not the whole story, but that thread is not for us to unravel here. It will suffice to say that nondepolarising blockers preserve this effect, and depolarising ones do not; and that this phenomenon can be used to monitor deep neuromuscular blockade, by "potentiating" some twitches and allowing them to be measured (where ordinarily train-of-four would yield no twitches).

References

Prince, Neetu, et al. "Rat skeletal muscle-nerve preparation to teach skeletal muscle physiology." Advances in Physiology Education 45.4 (2021): 869-879.

Eberstein, Arthur., and Joseph Goodgold. "Slow and fast twitch fibers in human skeletal muscle." American Journal of Physiology-Legacy Content 215.3 (1968): 535-541.

Cooper, Sybil, and J. C. Eccles. "The isometric responses of mammalian muscles." The Journal of physiology 69.4 (1930): 377.

Bigland-Ritchie, B., D. A. Jones, and J. J. Woods. "Excitation frequency and muscle fatigue: electrical responses during human voluntary and stimulated contractions." Experimental neurology 64.2 (1979): 414-427.

Tajima, Takeshi, et al. "Difference of train-of-four fade induced by nondepolarizing neuromuscular blocking drugs: a theoretical consideration on the underlying mechanisms." Journal of anesthesia 9 (1995): 333-337.

Tajima, Takeshi, et al. "Kinetic analysis of neuromuscular blockade. II. Train-of-four fade induced by d-tubocurarine and α-bungarotoxin." Biological and Pharmaceutical Bulletin 17.8 (1994): 1089-1093.

Hughes, John R. "Post-tetanic potentiation." Physiological reviews 38.1 (1958): 91-113.

Loughnan, T. E., and A. J. Loughnan. "Overview of the introduction of neuromuscular monitoring to clinical anaesthesia." Anaesthesia and intensive care 41.1_suppl (2013): 19-24.