Second thoughts on the train‐of‐four

Tetanic fade has long been recognised as a characteristic of neuromuscular block produced by nondepolarising drugs. The original interpretation of this phenomena was that it was the result of a reduced responsiveness of the postsynaptic receptors to acetylcholine. This was challenged by Ostuka, Endo and Nonamurd [l] and in 1967 Hubbard, Wilson and Miyamato [2] produced evidence of a presynaptic action of tubocurarine causing a diminished release of transmitter during repetitive nerve stimulation. This was confirmed by the experiments of Blaber in 1973 [3]. Blaber suggested that this effect might be the result of a presynaptic channel block. Over the intervening years substantial evidence has accumulated indicating a presynaptic action of nondepolarising drugs and that this causes the fade seen during tetanic stimulation at 25 Hz and 50 Hz [4-8]. It has been suggested that there are two varieties of presynaptic nicotinic receptors, the n, receptors which are blocked by tubocurarine and other nondepolarising drugs and activated by suxamethonium and decamethonium in low doses and the nz receptors, which are blocked at high doses of agonist drugs. The presynaptic n, receptors have been shown to be sensitive to block by hexamethonium, but not a-bungarotoxin [9, 101. This separates them from the postsynaptic nicotinic receptors which are readily blocked by a-bungartoxin but not by hexamethonium. It is proposed that the nondepolarising neuromuscular blocking drugs act at both presynaptic and postsynaptic nicotinic sites. In addition to the two populations of presynaptic nicotinic receptors, it is suggested that mascarinic receptors are present, which are blocked by drugs such as gallamine, contributing to the tachycardia produced by this drug. In 1961, Lilleheil and Naess [ I 11 suggested that the release of acetylcholine was under the influence of a feedback mechanism. The evidence in favour of such a mechanism has been extensively reviewed by Bowman, Marshall and Gibb [12], and Bowman et al. [13, 141. Such a mechanism is analagous to the negative feedback mechanisms found in the sympathetic nervous system. It is proposed that a positive feedback mechanism maintains the store of immediately releasable acetylcholine and hence the amount of transmitter release during normal motor nerve activity. At these rates of stimulation (25 Hz to 50 Hz) a small initial decrease in acetylcholine output is followed by increased mobilisation from reserve stores preventing a further fall in the amount of transmitter released. A presynaptic n, blocking effect of nondepolarising muscle relaxants would prevent this positive feedback mechanisms and would explain tetanic fade characteristic of a partial nondepolarising block. An overshoot of this mechanism is believed to be responsible for the post-tetanic facilitation, which is seen when stimulation rates less than 5 Hz follow a tetanus. This explanation has been confirmed by measurements of the acetylcholine output during 25 and 50 Hz stimulation of motor nerves in partially curarised animal preparations [IS]. In 1970 Ali, Utting and Gray [I61 suggested that the fade of evoked twitch response at 0.5 s for 2 s might be used as a test of residual nondepolarising neuromuscular block. This train-of-four test (ToF), originally used to detect patients with myasthenia gravis, is now widely used to monitor recovery from neuromuscular block. A correlation exists between tetanic fade at 50 Hz and the fade of the ToF, irrespective of the drug used and the anaesthetic technique, although the ToF is recognised as the more sensitive test. This has inevitably resulted in the suppositions that the two observations share a similar causal mechanism. It is suggested that the ToF at 2 Hz reveals the rundown of acetylcholine stores consequent upon the block of the presynaptic autofacilitatary mechanism. This assumption seems reasonable, sensible and probable. However, evidence is accumulating to suggest that it may only be part of the explanation. It is difficult to explain, on the basis of a presynaptic n, block, why the ToF fade should occur in patients with myasthenia gravis, as all the evidence points to an increase in the neurology evoked quantal acetylcholine release in this disease. The quantal theory of acetylcholine release suggests that only a fraction of the immediately available store is released upon motor nerve stimulation. This is some 2&30 times the quantity required to produce threshold depolarisation [ 1 1 . It seems surprising therefore that a partial block of n, receptors should cause a sufficient rundown in releasable acetylcholine that a second stimulus 0.5 s after the first should produce fade of the evoked muscle response. This is supported by the finding of Wessler et al. [I81 who measured acetylcholine output and demonstrated that following partial curarisation the amount of acetylcholine released only started to fall after 10 to 15 motor nerve stimulations. If an agonist such as suxamethonium or decamethonium is administered during a partial tubocurarine block, it is possible to demonstrate the reversal of TI, presumably a result of agonist/antagonist interaction, at the postsynaptic receptor site. However, under these conditions T4 block is less affected and may be increased resulting in an increase in ToF fade. This demonstrates that ToF fade can occur even in the presence of an excess of agonist. It also indicates that reversal of T4 block is by a different mechanism than TI. During reversal of antagonist block by neostigmine, the ToF fade continues in spite of an increase in available acetylcholine. It is usually only reversed when the height of the first twitch has reached 90-100% control. If ToF fade were due to a decreased output of transmitter then this should have been more than compensated for by the increase in acetylcholine consequent to the diminished hydrolysis and increased quantal release caused by neostigmine [ 191. In the 17th century Blaise Pascal, arguing in favour of the logic of mathematical calculus, said that if an explanation was logical and common sense suggested it to be correct it should not be abandoned for the lack of detailed proof. This is true of the current explanation of ToF fade; however, it would be prudent to keep an open mind before accepting the theory of a block of pre-