Neuromuscular Blockers

Anaesthesia. Intensive care. Tetanus

Neuromuscular blockers (myoneuronal blockers) affect transmission at the neuromuscular junction and are used as adjuncts to general anaesthesia, particularly to enable adequate muscle relaxation to be achieved with light anaesthesia. There are 2 main types of neuromuscular blockers: competitive (non-depolarising neuromuscular blockers) and depolarising neuromuscular blockers (Table: Classification of neuromuscular blockers).

Table: Classification of neuromuscular blockers

Competitive		Depolarising
Aminosteroidal	Benzylisoquinolinium	Suxamethonium
Pancuronium	Alcuronium
Pipecuronium	Atracurium
Rapacuronium	Cisatracurium
Rocuronium	Doxacurium
Vecuronium	Gallamine
	Metocurine
	Mivacurium
	Tubocurarine

Competitive neuromuscular blockers act by competing with acetylcholine for receptors on the motor end-plate. Their action can be opposed by increasing the local concentration of acetylcholine, for example by giving an anti-cholinesterase such as neostigmine. Tubocurarine was formerly the standard reference drug of this type but its use has declined, therefore details of the actions and uses of competitive neuromuscular blockers are discussed under Atracurium.

Depolarising neuromuscular blockers act by depolarising the motor end-plate to prevent the normal response to acetylcholine; their action is not reversed by anticholinesterases. Suxamethonium is the standard reference drug of this type.

Other drugs that have muscle relaxant properties and which are used in the management of musculoskeletal and neuromuscular disorders are discussed in the chapter on Muscle Relaxants.

Anaesthesia

Neuromuscular blockers are used in general anaesthesia for their muscle relaxant effects to facilitate intubation at induction and to provide continued relaxation during maintenance. Their use is determined partly by their onset and duration of action (see Table: Relative speed of onset and duration of action of neuromuscular blockers), but both onset and duration are dose-dependent and can therefore vary.

Generally, competitive neuromuscular blockers, due to their slower onset and longer duration of action, are used in major operations, while the depolarising neuromuscular blockers (usually suxamethonium), with a much faster onset and shorter duration, are used for minor operations or manipulations and particularly for intubation.

After use of suxamethonium to aid intubation, a longer-acting competitive drug may men be given to maintain muscle relaxation throughout the operation. Competitive neuromuscular blockers with a short to intermediate duration of action, such as atracurium and vecuronium, are more widely used man those with a longer duration of action such as pancuronium.

Suxamethonium has been widely used after induction of anaesthesia to aid intubation; however, because of the adverse effects such as myalgia associated with suxamethonium (see also below), alternative neuromuscular blockers have been investigated for intubation and some questioned the use of suxamethonium for elective procedures, especially in day-case patients. Some competitive blockers such as vecuronium have a relatively rapid onset of action and have been used for intubation during routine, planned surgery.

However, they act too slowly to enable rapid intubation in an emergency, when suxamethonium remains the drug of choice. Although rocuronium, a competitive blocker, is only slightly slower in onset, and may be suitable in emergencies if suxamethonium is contra-indicated, it has a much longer duration of action, and needs to be given with an opioid such as alfentanil, or with propofol, to obtain equivalent intubating conditions. In attempting to create more favourable conditions for rapid intubation with competitive neuromuscular blockers and thus provide an alternative to suxamethonium, anaesthetists have tried using large doses or combinations of competitive blockers.

Other methods tried include giving competitive neuromuscular blockers in divided doses in an attempt to shorten the onset to paralysis. This so-called priming principle involves giving a small initial dose, termed the priming dose, followed by a large paralysing dose. Priming may be with 2 doses of the same competitive relaxant or a combination of 2 different relaxants which may then exhibit synergism.

However, some consider that priming techniques are associated with unacceptable adverse effects such as muscle weakness and aspiration, and that they are not safe, especially in the elderly In another technique, a single large dose of a neuromuscular blocker is given, followed by the induction anaesthetic as soon as the patient complains of weakness. This is called the timing principle and although it has been successfully used with some neuromuscular blockers, problems such as perceived muscle weakness or shortness ofbreathmay occur if the anaesthetic is not injected at the right moment.

Table: Relative speed of onset and duration of action of neuromuscular blockers

Neuromuscular blocker	Onset *	Duration **
Alcuronium	Intermediate	Intermediate
Atracurium	Intermediate	Short/Intermediate
Cisatracurium	Intermediate	Short/Intermediate
Doxacurium	Slow	Long
Gallamine	Rapid	Intermediate
Mivacurium	Intermediate	Short
Pancuronium	Rapid	Long
Pipecuronium	Intermediate	Intermediate/Long
Rocuronium	Rapid	Intermediate
Suxamethonium	Ultra-rapid	Ultra-short
Tubocurarine	Intermediate/Slow	Intermediate
Vecuronium	Rapid	Intermediate

*Onset:
Ultra-rapid, less than 1 minute
Rapid, 1 to 2 minutes
Intermediate, 2 to 4 minutes
Slow, more than 4 minutes

**Duration:
Ultra-short, less than 8 minutes
Short, 8 to 20 minutes
Intermediate, 20 to 50 minutes
Long, more than 50 minutes

Onset and duration of action are dose-dependent

The use of anaesthetic regimens that avoid or reduce the need for a neuromuscular blocker during intubation has also been investigated. The anaesthetic propofol with a short-acting opioid such as alfentanil has often been tried. In addition to its use alone, such a regimen has been combined successfully with low doses of suxamethonium or rocuronium, or standard doses of vecuronium, to produce suitable conditions for intubation.

Procedures such as intubation can cause complications: an undesirable pressor response may occur, resulting in increased heart rate and arterial blood pressure. There may also be an increase in intracranial pressure and intra-ocular pressure. Furthermore, the use of suxamethonium to aid intubation is itself associated with a transient increase in intra-ocular pressure. Small doses of a competitive neu-romuscular blocker have been given before suxamethonium to prevent this rise in intra-ocular pressure, although some consider such a measure ineffective.

Opioids such as alfentanil and fentanyl appear to be effective in attenuating bom the pressor response and the rise in intra-ocular pressure associated with intubation, but the use of lidocaine has produced conflicting results. Many anaesthetics, with the exception of ketamine, reduce intra-ocular pressure to some extent and giving miopental beforehand may help to counteract the effect of suxamethonium.

Other drugs mat have been used or tried in the prevention of the haemodynamic response to intubation include magnesium sulfate and propofol.

Competitive neuromuscular blockers are usually used to provide muscle relaxation during maintenance anaesthesia. Patients given a neuromuscular blocker generally require less anaesthetic permitting a state of Tighter anaesthesia’ and hence reducing the adverse effects of the anaesthetic. At the end of the procedure any residual block should be reversed with an anticholinesterase and the patient should be monitored until spontaneous respiration has resumed. For further details see Anaesthesia under Uses of General Anaesthetics.

Intensive care

The use of neuromuscular blockers in patients requiring mechanical ventilation as part of intensive care has been discussed in a number of reviews and guidelines. Neuromuscular blockers are used to provide additional relaxation and facilitate ventilatory support in patients who fail to respond to sedation alone. It is important to ensure mat such patients are adequately sedated and relatively pain free before these drugs are used.

Patients who are considered most likely to benefit are those with spontaneous respiration mat is counterproductive to mechanical ventilation. Patients with little inherent respiratory muscle activity are less likely to obtain an improvement in oxygenation. Neuromuscular blockers may also improve control of intracranial pressure in patients with intracranial hypertension, including prevention of rises in intracranial pressure associated with routine tracheobronchial suction.

Pancuronium has been widely used as a neuromuscular blocker in intensive care because of its tendency to increase arterial pressure and the majority of patients requiring a neuromuscular blocker can be adequately managed with pancuronium; however, its long duration of action may be a problem in some circumstances, and its vagolytic activity can also produce tachycardia.

Vecuronium, atracurium, and cisatracurium have relatively few cardiovascular effects, but mere has been some concern over the ability of the atracurium metabolite laudanosine to accumulate in the CNS (see Biotransformation, under Pharmacokinetics). Atracurium and cisatracurium may also be more suitable in patients with hepatic or renal impairment as their metabolism does not lead to the accumulation of active metabolites. Other neuromuscular blockers mat have been used in intensive care include doxacurium, pipecuronium, and rocuronium.

Close monitoring of neuromuscular blockade is recommended since the pharmacodynamics and pharmacokinetics of neuromuscular blockers may be altered in patients in intensive care, mis should also allow the lowest effective neuromuscular blocking dose to be used, and reduce adverse events. Prolonged neuromuscular blockade has been related to dosage.

Other factors mat may potentiate neuromuscular blockade include drug interactions, electrolyte imbalance, hypothermia, or changes in acid-base balance. Conversely, dosage requirements may be increased in patients with burns or in those receiving prolonged therapy. Tachyphylaxis has occurred with some neuromuscular blockers, but may resolve on switching to another blocker.

Prolonged neuromuscular blockade has been associated with adverse effects and should be avoided when possible. Recovery after withdrawal of prolonged treatment may be longer than pharmacologically predicted due to the accumulation of active metabolites; mis is a particular problem for neuromuscular blockers with a long duration of action and for patients with hepatic or renal impairment. An acute myopathy has also followed prolonged use, most commonly with aminosteroid neuromuscular blockers (Table: Classification of neuromuscular blockers); mere are case reports suggesting mat use of corticosteroids might increase the risk.

When rapid reversal of paralysis is necessary an anti-cholinesterase such as neostigmine may be used, but relatively little is known about the efficacy of anticholineste-rases in reversing prolonged paralysis.

Neonatal intensive care

Neuromuscular blockers such as pancuronium bromide are used in neonatal intensive care to obtain muscle relaxation during mechanical ventilation in infants with severe pulmonary disease, especially in those whose respiratory efforts are out of phase with the ventilator. They are only used in infants at high risk of complications such as pneumothorax or intraventricular haemorrhage; their routine use in all ventilated neonates is not recommended.

Abolition of spontaneous respiration during mechanical ventilation has had variable effects on the incidence of pneumothorax in infants with respiratory distress syndrome. Although a reduced incidence was found in one study involving infants of less man 33 weeks’ gestation, in another study the incidence was reduced only in infants with a gestational age of 27 to 32 weeks; no reduction was obtained in those below 26 weeks’ gestation. Paralysis also failed to reduce the incidence of pneumothorax or interstitial emphysema in a study of infants with hyaline membrane disease but did appear to speed recovery of lung function.

The aetiology of intraventricular haemorrhage remains obscure but there is a well recognised association with gestational age; less mature neonates are more susceptible and the incidence decreases sharply after 30 weeks’ gestation. There appears to be an association between fluctuating cerebral blood-flow velocity in the first day of life and subsequent development of intraventricular haemorrhage.

Respiratory paralysis from the first day of life until 72 hours of age has been reported to stabilise both cerebral and arterial blood-flow velocity and to produce a decrease in the incidence and severity of intraventricular haemorrhage in infants with respiratory distress syndrome. However, respiratory paralysis has also been reported to have no effect on the development of intraventricular haemorrhage.

The use of neuromuscular blockers in the newborn is not without complications. Multiple joint contractures, possibly potentiated by use of aminoglycosides or phenobarbital, have been reported in infants given pancuronium, and regular passive limb movements should be performed during paralysis. Marked oedema, severe disturbances of fluid balance, renal failure and death have been reported in 2 neonates.

Hypoxaemia may develop after induction of paralysis unless a significant increase in ventilator support is made; hypotension may also occur. Drugs such as pancuronium which are metabolised in the liver and excreted in the urine have a prolonged action in premature infants. As with adults (see above), continuous use of neuromuscular blockers in neonates has been associated with prolonged neuromuscular block on withdrawal.

Tetanus

The clinical manifestations of tetanus after infection with Clostridium tetani are caused by the highly potent neuro-toxin tetanospasmin produced by its germinating spores. The muscular symptoms of generalised tetanus include trismus (lockjaw), glottal spasm, generalised muscle spasm, opisthotonus (spasm of the back muscles resulting in backward arching of the body), respiratory spasm, and paralysis. Other complications include electrolyte disturbances and autonomic dysfunction leading to cardiovascular effects such as hypertension, tachycardia, and peripheral vasoconstriction. Patients may have a milder form in which the twitching and muscle spasms are limited to the area near the site of the injury, but such localised tetanus is rare and can progress to the generalised form.

Treatment aims to destroy the causative organism and/or neutralise any unbound toxin in the body, to control rigidity and muscle spasms, and to control autonomic dysfunction. For the antibacterial treatment and prevention of tetanus and neutralisation of tetanospasmin. After antibacterial therapy the mainstay of treatment of rigidity and spasms is sedation with benzodiazepines such as diazepam or midazolam; they may also reduce patient anxiety. Opioid analgesics can be added to treatment to provide analgesia and additional sedation; in addition, fentanyl, morphine, and sufentanil may control autonomic overactivity. Antiepileptics, particularly phenobarbital, may also provide additional sedation. Chlorpromazine is sometimes used with benzodiazepines to minimise rigidity and muscle spasms. Sedation with propofol may also control spasms and rigidity without the need for an additional relaxant; however, mechanical ventilation is required.

Centrally acting muscle relaxants have also been tried to control muscle spasms. Baclofen has been given by the intrathecal route, but its therapeutic range in severe tetanus may be very narrow and deep coma and loss of spontaneous respiration has been reported. Dantrolene has also been reported to be effective. When muscle spasms are severe or interfere with respiration, competitive neuromuscular blockers have been used in addition to benzodiazepine sedation, to control spasms and to induce therapeutic paralysis so mechanical ventilation can be initiated.

Control of autonomic overactivity may be achieved with sedation; benzodiazepines, antiepileptics, and opioid analgesics have all been used (see above). Beta blockers such as propranolol have also been used; however, they are no longer recommended because of the potential for severe cardiovascular effects. Labetalol has bom alpha-and beta-blocking activity but offers no advantage over propranolol.

More recently, esmolol, a short-acting beta blocker, has been used. Magnesium sulfate has been found to minimise autonomic disturbance in ventilated patients and controls spasms in non-ventilated patients, but mere is need for further investigation. Electrolyte disturbance is corrected with calcium and magnesium salts.