Neuromuscular Blockade Suzanne Wake NEMSA SpR September 2008

Objective Safe use of Neuromuscular Blockade

Contents Physiology of neuromuscular junction (NMJ) Pharmacology of commonly used neuromuscular blocking drugs (NMBDs) Monitoring neuromuscular blockade (MNB)

Physiology - Structure of NMJ NMJ consists of Pre-synaptic motor neurone Synaptic cleft (20nm) Motor end plate ie post-synaptic membrane of striated muscle cell, rich in acetylcholine receptors (Ach-r) NMJ consists of Motor

Structure of NMJ

Physiology - Acetylcholine Synthesised in pre-synaptic neurone Nerve stimulus release into synaptic cleft Binds to post-synaptic Ach-r Hydrolysed by Acetylcholinesterase (Ach-E)

Physiology – Acetylcholine Receptor Nicotinic Pentameric cylinder 2 a sub-units = 2 Ach binding sites Transmembrane Central ion channel Ach binding conformation change channel opens a a

Pharmacology - Structure of NMBDs Quaternary ammonium compounds related to Ach

Pharmacology–Classification of NMBDs Depolarising NMBDs Non-depolarising NMBDs

Depolarising NMBDs Ach-r agonists Succinylcholine

Succinylcholine Binds to Ach-r causing Phase 1 (Accomodation) Block Membrane depolarisation Prolonged activation of Ach-r Muscle flaccidity (<60s) Phase 1 (Accomodation) Block Recovery as drug diffuses away (3-15 mins) Metabolised by plasma cholinesterase

Side Effects of Succinylcholine LETHAL Anaphylaxis Bradycardia Arrest (muscarinic effect) Hyperkalaemia MH trigger NON-LETHAL intraocular intracranial intragastric pressure Myalgia Prolonged action (pCh deficiency) Myotonia contracture

Non-Depolarising NMBDs Competitive, reversible antagonists at postsynaptic Ach-r 75% Ach-r block for loss of contraction Benzolisoquinoliniums (--curium) Aminosteroids (--curonium)

Benzolisoquinolonium Compounds Histamine release Atracurium Hofmann degradation (45%) Ester hydrolysis Mivacurium Short acting Hydrolysed by plasma cholinesterases

Aminosteroid Compounds No histamine release Depend on organ function for excretion Rocuronium Rapid onset Hepatic excretion Anaphylactoid rxns more common

Ideal NMBD Nondepolarising Rapid onset/offset Reversible with AchE No histamine release No CVS effects Non-cumulative No drug interactions No organ toxicity or excretion

Monitoring NMB – Why? Timing of tracheal intubation Intra-operative muscle relaxation Reversal of NMB Timing of tracheal extubation

Monitoring NMB – How? Supra-maximal stimulus (15-60mA) Elicit whole muscle response Square wave stimulus Duration < refractory period of NMJ

Patterns of Stimulation Single Twitch Train of Four (TOF) Tetany Double Burst Stimulation

Single Twitch 0.1-1Hz Requires control measurement (T1/Tc) Depolarising block 100% Tc T1 T2 T3 T4

Train of Four 2Hz Nondepolarising block TOF ratio (T4/T1) Fade (presynaptic Ach-r block) T4/T1>0.9 for safe extubation 100% T1 T2 T3 T4

Tetany 50-100Hz for 5s Nondepolarising and phase 2 block show fade Post Tetanic Facilitation 50Hz for 5s, 3s pause, 1Hz single stimuli Used in profound nondepolarising NMB

Double Burst Stimulation 3, 50Hz twitches, 750ms pause, repeat Improves manual detection of fade Perceived at TOF ratio 0.6 cf 0.4

Summary

Reversal of NMB Neostigmine PLUS Antimuscarinic OR Sugamadex (the future)