Muscle relaxants block transmission at the neuromuscular junction (NMJ) by interfering with nicotinic cholinergic receptors (AChRs). They are large polar molecules with small volumes of distribution that are not orally bioavailable and do not cross the placenta or blood-brain barrier.
They have no analgesic, anaesthetic or amnestic properties and so should never be given without appropriate sedative/anaesthetic drugs.
The clinical indications for muscle relaxation are:
- to facilitate intubation of the trachea
- to improve surgical and/or procedural working conditions
- to facilitate intra-hospital and inter-hospital transfers
- to prevent shivering in patients being therapeutically cooled
- to facilitate mechanical ventilation including using mechanical ventilation to manipulate PaCO2 and acid-base status
- to improve post-operative stability (especially in high-risk cardiac surgery and laryngo-tracheal surgery with or without complex / abnormal airway anatomy)
Drugs are classified as depolarising (mimic the actions of ACh) and non-depolarising (interfere with the actions of ACh).
Suxamethonium is the only depolarising neuromuscular blocking drug still in clinical use.
Non-depolarising neuromuscular blocking drugs are classified as long-acting (pancuronium), intermediate-acting (rocuronium, vecuronium, atracurium & cisatracurium) and short-acting (mivacurium).
Drug selection is influenced by desired speed of onset, duration of action and the possibility of drug induced side effects (see table of drugs).
Among suxamethonium’s myriad of adverse effects it is also a known trigger for malignant hyperthermia (genetically abberant muscle sarcoplasmic reticulum calcium channels) – the treatment is active cooling and dantrolene 1 mg/kg up to 10 mg/kg.
Patients with genetically abdnormal pseudocholinesterase will have prolonged neuromuscular blockade with suxamethonium (choline apnoea) – they need supportive care until it is cleared (severe cases require dialysis to clear the drug) and an assessment of their pseudocholinesterase function (dibucaine number).
Suxamethonium and rocuronium (see table: muscle relaxants rapid onset) are the only drugs capable of producing intubating conditions in 60-90 seconds and so are the only drugs used for rapid sequence induction (RSI). Suxamethonium has a brief duration of action where as an RSI-dose of rocuronium will have a prolonged duration of action.
The duration of action of non-depolarising neuromuscular blocking drugs is prolonged by hypokalaemia, hypocalcaemia, hypoproteinaemia, hypermagnesaemia, dehydration, acidosis and hypercapnoea.
Potency of neuromuscular blocking drugs is described by the effective dose (ED) necessary to depress single-twitch depression by 95% in the adductor pollicis muscle – ED95 (intubating doses are generally two times the ED95 dose; the RSI-dose for rocuronium is four times its ED95); potency is centrally located, and central muscles (larynx, jaw and diaphragm) develop neuromuscular blockade faster, experience less profound block and recover more quickly than in more peripherally located muscles (adductor pollicis). Eyelash reflex and orbicularis inversely related to onset time.
Monitoring of depth of neuromuscular blockade:
Nerve stimulators are used to monitor the depth of neuromuscular blockade.
There is a margin of safety regarding nAChRs at the NMJ and the generation of a myocyte action potential such that >75% of nAChRs must be occupied by drug before clinically significant (and detectable) blockade is apparent.
Neuromuscular blocking drugs must occupy at least 75% of nAChRs before there is clinically significant and detectable blockade (this is the margin of safety with regard to nAChR numbers and transmission at the NMJ).
The ulnar or radial nerves are commonly used with the negative electrode on the volar surface of the wrist directly over the nerve to be stimulated and the positive electrode at least 3 cm distal where it cannot interfere with the relevant muscle groups.
A current of 60 mA (maximum 80 mA) is applied for 0.1 ms (maximum 0.3 ms) per stimulation; the patterns of stimulation used in PICU are the train-of-four (TOF) count, tetanic (>30 Hz) stimulation and post-tetanic count.
The TOF ratio is the ratio of the height of the first twitch (T1) to the fourth twitch (T4) – this is not easily interpretable if only using visual and tactile evaluation of the response. The TOF count (absolute number of twitches) is easier to detect and interpret:
- T4 begins to reduce in height at >70% receptor occupancy;
- T1 starts to reduce in height at >80% occupancy;
- T4 disappears at >90% occupancy;
- T1 disappears at >95% occupancy.
Tetanic stimulation (usually 50 Hz) is known to increase subsequent twitch height either by mobilising ACh stores and/or increasing calcium influx into the nerve ending; When the TOF count is zero (>95% blockade) then a tetanic stimulation and a post-tetanic (TOF) count can help define deep neuromuscular blockade.
- The effects of tetany last for up to 6 minutes and this must be taken into consideration if repeat testing occurs
- If the TOF-count is zero and the post-tetanic count is also zero – this signifies either very deep neuromuscular blockade or a malfunctioning nerve stimulator (test it on yourself)
Reversal of neuromuscular blockade:
- Antagonist-assisted reversal of neuromuscular blockade using anticholinesterases (edrophonium, neostigmine or pyridostigmine) reflects their inhibition of acetylcholinesterase (AChE) and the resulting increased ACh at the NMJ to compete for nAChR binding sites.
- Neostigmine is generally used at a dose of 4-7 mcg/kg and is more suitable for reversing deeper levels of block.
- Anticholinesterases produce typical and expected muscarinic side effects (mainly bradycardia, bronchoconstriction, increased secretions & GI hyper-peristalsis) and so should be given with an antimuscarinic anticholinergic drug such as atropine (20 mcg/kg) or glycopyrrolate (10 mcg/kg).
- Sugammadex is a cyclodextrin that encapsulates rocuronium and vecuronium and effectively neutralises them; remaining drug diffuses away from the NMJ and its effects are reversed.
- It acts within 2 minutes and has no other effects (as yet). The complex is excreted in the urine. The dose for routine reversal is 2-4 mg/kg; the dose for emergent reversal in a cant intubate-can’t ventilate scenario is 16 mg/kg.
Table: Muscle relaxants rapid onset
|Type/class||Dicholine ester||Aminosteroid(intermediate acting)|
|Intubating dose||1mg/kg (adults)
|Metabolism||Plasma pseudocholinesterase||No significant metabolism|
|Excretion||Resulting choline is taken up into nerves<5% unchanged in urine||Bile (50% unchanged)Urine (30% unchanged)|
|Hepatic failure||No effect||t½-elim up to 100 minutes|
|Renal failure||No effect||t½-elim up to 100 minutes|
|Pros||Rapid onset & intense paralysis make it suitable for RSI||
Suitable for RSI due to shorter onset timeNo histamine releaseMinimally affected by renal & hepatic impairment
May be reversed with sugammadex
Raised intra-gastric, intra-ocular & intra-cranial pressuresFasciculations that can lead to severe myalgia & even rhabdomyolysisBradycardia (muscarinic) +/- brady-arrhythmias
Hyperkalaemia (more so with neuromuscular disease & burns)
|Will accumulate with prolonged infusions (ensure monitoring of depth of blockade)|
|Other points||80% of an administered dose is hydrolysed before reaching the NMJsRepeat doses should always be accompanied by an anticholinergic (consider routine anticholinergic administration in infants)||There are rare reports of anaphylaxisIt does cause a small increase in intra-occular pressure|
Table: Muscle Relaxans slow onset
|Type/class||Aminosteroid(intermediate acting)||Aminosteroid(long acting)||Benzylisoquinolinine(intermediate acting)|
|Metabolism||Hepatic with some active metabolites||Hepatic with some active metabolites||Hoffman elimination (no active metabolites)|
|Excretion||Urine (25% unchanged)Bile (25% unchanged)||Urine (80% unchanged)Bile (10% unchanged)||Urine|
|Hepatic failure||t½-elim up to 3 hours||t½-elim up to 6 hours||No change|
|Renal failure||t½-elim up to 2 hours||t½-elim up to 48 hours||No change|
|Pros||Commonly used medication with predictable onset & duration of actionNo histamine releaseMay be reversed with sugammadex||Long acting
(decreased dosing requirements)
|Non-organ clearance makes it unaffected by renal and/or hepatic impairmentStable offset time after prolonged infusions due to rapid Hoffman eliminationNo histamine release|
|Cons||Will accumulate with prolonged infusion (ensure monitoring of depth of blockade)||Minimally metabolized so sensitive to effects on hepatic & renal functionRisk of arrhythmias in patients on digoxin||Potent drug with prolonged onset time|
|Other points||Large doses may cause a slight (10-15%) drop in SVR and BP||
10-15% increase in HR (mainly anticholinergic effect)Mild increase in BP secondary to increased HR (no inotropy)Useful for obviating HR effects of induction doses of narcotics
It may decrease the PT and APTT
|One of 10 stereoisomers of atracurium (atracurium is not used often anymore due to histamine release and has a metabolite that can cause convulsions).|