"Basic and Clinical Science in Neuromuscular Blockade”
Prof Lars Eriksson, Karolinska Institute and University Hospital, Stockholm
Dr Janice Fazackerley opened the meeting and ran through the AGM (see seperate Minutes). She then asked Professor Hunter to introduce the speaker, Professor Lars Eriksson from the Karolinska Institute in Stockholm.
Professor Eriksson started by expressing his sincere gratitude for being invited to give the second T.Cecil Gray/BJA medal lecture. He noted that there had been 7 Nobel laureates from the University of Liverpool. He then spoke about T. Cecil Gray and his contribution to anaesthesia. Professor Gray’s first publication was in 1946 describing the use of d-tubocurarine, with his final publication coming in 1970. Professor Eriksson came back to the Nobel Prize winners by describing the work of Sir Henry Dale and Otto Loewi who were jointly awarded the Nobel Prize for Physiology or Medicine in 1936, for their work on neuro-muscular transmission.
Professor Eriksson then demonstrated the quaternary ammonium structure common to all modern neuro-muscular blocking drugs. It is this positively charged part of these molecules which, like acetyl choline, bind with the negatively charged ligand of the receptor. When acetyl choline binds with the post synaptic receptor it produces a conformational change by a twisting action of the receptor resulting in the opening up of the centre. This allow the passage of ions into the cell, causing ultimately the depolarisation of the post-synaptic membrane. This effect is prevented by the binding of neuro-muscular blocking drugs. These receptors also bind other anaesthetic drugs, in particular volatile agents, which in clinical practice would explain the potentiation of neuro-muscular blocking drugs by these agents. Propofol is also bound at the neuro-muscular junction although no obvious effect has been demonstrated.
Professor Eriksson then looked at recovery from neuro-muscular blockade and described two time constants. The first was recovery of the first twitch of the train of four and the second was full recovery of neuromuscular transmission with the absence of fade.
Professor Eriksson went on to speak about presynaptic nicotinic receptors which had originally been demonstrated by Bowman. The post-synaptic receptors at the neuromuscular junction are pentameric structures with 2 alpha, 1 beta, 1 gamma and 1 delta sub-units. The composition of these subunits varies in other nicotinic receptors but in particular the presynaptic receptors at the neuromuscular junction are made up of 3 alpha and 2 beta sub-units. When these are blocked, they lead to fade in neuro-muscular transmission. All the classical non-depolarising muscle relaxants interfere with the action of these presynaptic nicotinic receptors, and therefore demonstrate fade. In contrast, succinyl choline only works on post synaptic nicotinic receptors in clinical doses. However in higher doses, succinyl choline does have an action on these presynaptic receptors and this may be an explanation of phase 2 block with this drug and its characteristic fade. Consequently, during recovery from neuro-muscular blockade, the first twitch is an indicator of post-synaptic binding of the muscle relaxant and the fourth twitch, with the degree of fade, indicative of the level of pre-synaptic binding.
Professor Eriksson spoke about the complications of residual neuro-muscular blockade. He firstly demonstrated the patterns of recovery of different muscle types. He showed the larynx to be one of the fastest muscles to recover whereas the small muscles of the hand are one of the slowest. He then demonstrated that the pharyngeal muscles were even slower than the hand. He quoted the work of Eikermann (Anesthesiology 2009, June; 110;1253-60), which demonstrated the impairment of upper airway function with minimal neuro-muscular blockade. The order of sensitivity to the effects of these drugs appeared to be; pharynx, head and neck, hand and abdomen, larynx followed by the diaphragm which was the most resistant.
Professor Eriksson then looked at the co-ordination of swallowing. He showed that swallowing required transient apnoea with co-ordination of the diaphragm. He demonstrated studies which showed that neuro-muscular blocking drugs cause a discoordination of this process which may lead to a greater risk of aspiration despite patients having clinically fully recovered from neuromuscular blockade by being able to speak normally. He showed that elderly people have a much greater tendency for pharyngeal discoordination. This can then be greatly worsened by residual amounts of neuro-muscular blocking drugs. In 1998 pancuronium was shown to increase pulmonary complications particularly in the elderly due to residual neuro-muscular blockade. This is further worsened by centrally acting sedative drugs such as midazolam which can cause the disintegration of pharyngeal and respiratory co-ordination.
Professor Eriksson spoke finally about ventilatory control during hypoxia and demonstrated that neuromuscular blocking drugs caused an impaired and sometimes complete abolition of the response to hypoxia (although there was significant inter-individual variability.) However these drugs had no effect on CO2 response. He demonstrated that the chemoreceptors within the carotid body had nicotinic receptors with 3 alpha and 2 beta sub-units (similar to pre-synaptic receptors at the neuromuscular junction) and were therefore prone to blockade by muscle relaxants. He ended his lecture by quoting from the address that Professor Cecil Grey had given to the Royal Society of Medicine in 1947.
After questions were taken from the floor, the medal was presented to Professor Eriksson by James Gray, son of Professor Cecil Gray. The vote of thanks was given by Dr Janice Fazackerley, President of the Society, and the meeting ended at 20.30.
12th May 2013