24. NEUROMUSCULAR BLOCKADE (muscle relaxants)

Neuromuscular blocking drugs produce skeletal muscle relaxation, which allows easier intubation of the trachea, mechanical ventilation and improved operating conditions. Always remember that a neuromuscular blocking drug is not an anaesthetic agent. They have no effect on consciousness and must never be given to a conscious patient.

Neuromuscular blocking drugs will stop the patient’s breathing. They must never be given to a patient unless the doctor is certain they can ventilate the patient (either by mask or endotracheal intubation).

Always give reversal drugs (neostigmine and atropine). Never attempt to reverse neuromuscular blocking drugs before there is evidence of return of muscle tone and breathing or wait at least 20 minutes after the last dose of muscle relaxant. The anaesthetist must never extubate a patient until they are certain that the paralysis has been reversed and the patient has adequate muscle strength to protect their airway and breathe.

Mechanism of Action

Activation of a motor nerve causes release of acetylcholine (Ach) from the nerve ending. The nerve ending and adjacent muscle are called the motor end-plate. Electrical depolarisation of the motor nerve causes increase permeability of calcium ions, which causes release of Ach. The space between the nerve ending and the muscle is called the synaptic cleft. The Ach crosses from the nerve ending to receptors on the muscle. Activation of these Ach receptors causes muscle contraction.

In general, depolarising muscle relaxants (suxamethonium) are used for paralysis of rapid onset and short duration. The non-depolarising muscle relaxants are used for prolonged paralysis when rapid intubation of the trachea is not required.

Non-depolarising

Non-depolarising muscle relaxant drugs compete with Ach to bind with muscle Ach receptors. They therefore block the action of Ach and prevent depolarisation of the muscle.

Non-depolarising muscle relaxant drugs include alcuronium, atracurium, cisatracurium, fazadinium, gallamine, mivacurium, pancuronium, pipecuronium, rocuronium, tubocurarine and vecuronium.

The selection of a non-depolarising muscle relaxant drug will depend on many factors including availability, expense, time needed to intubate the trachea, expected duration of surgery, patient’s health, drug side-effects and method of metabolism.

Different muscle groups differ in their sensitivity to muscle relaxants. The muscles of the eye are the most sensitive. The muscles of the limbs, intercostals and abdomen are the next most sensitive. The diaphagm is the least sensitive.

Non-depolarising muscle relaxing drugs need reversal of their action by an anticholinesterase (plus atropine to control the side-effects of the anticholinesterase).

Depolarising

Depolarising muscle relaxants (suxamethonium or succinylcholine or scoline) mimic the action of Ach. They bind to the Ach receptors and cause brief irregular muscle contractions (fasciculations) followed by a brief period of relaxation.

Depolarising muscle relaxants do not require reversal. They are rapidly metabolised. Suxamethonium is hydrolysed by plasma cholinesterase to choline and succinylmonocholine (a depolarising agent with about 1/20 the potency of suxamethonium), and then converted to choline and succinic acid.

Reversal of Action of Non-Depolarising Muscle Relaxant Drugs

All non-depolarising muscle relaxing drugs should be reversed (anticholinesterase and atropine) at the end of an operation.

The anaesthetist should not attempt to reverse the non-depolarising muscle relaxing drugs before evidence of return of muscle function (peripheral nerve stimulator or patient attempting to breathe). Most non-depolarising muscle relaxing drugs (except mivacurium) must not be reversed for at least 20 minutes after the last dose.

The anaesthetist must never extubate a patient until they are certain that the paralysis has been reversed and that the patient has adequate muscle strength to protect their airway and breathe.

Ideally the anaesthetist can monitor muscle function with a peripheral nerve stimulator. If a peripheral nerve stimulator is not available the anaesthetist must use clinical signs of adequate reversal. Rapid shallow breaths are not evidence of adequate muscle strength. Even with a tidal volume of 5 ml/kg the patient may still have 80% of Ach receptors blocked. A tidal volume of 5 ml/kg is a poor sign of adequate muscle strength.

Signs of adequate muscle strength include a vital capacity of 20 ml/kg, head lift for 5 seconds and normal handgrip. Unfortunately all require some patient cooperation. The head lift should be done with the patient lying flat and must be unassisted. Handgrip needs to be tested before anaesthesia.

Anticholinesterases

Common anticholinesterases include edrophonium (0.5 to 1.0 mg/kg), neostigmine (0.03 to 0.06 mg/kg) and pyridostigmine (0.25 mg/kg). Anticholinesterases increase the concentration of Ach by inhibiting acetylcholinesterase, which normally metabolises Ach. Anticholinesterases will increase Ach concentrations at both the motor end plate (reversing non-depolarising muscle relaxant drugs) and at the muscarinic receptors of the vagus nerve. Increasing Ach at the vagus nerve can cause severe salivation, bradycardia and bronchoconstriction. To prevent this complication atropine (0.02 mg/kg) must always be given with the anticholinesterase.

Neostigmine is the most frequently used reversal agent. Different countries have different standard concentrations of neostigmine and atropine. In some countries adults are given 1.2 mg atropine and 2.5 mg neostigmine.

Non-Depolarising Muscle Relaxants

Tubocurarine (1935)

Intubating dose 0.3 to 0.5 mg/kg, duration of action 30 to 40 minutes, supplementary doses 0.1 to 0.15 mg/kg. The onset of action is about 3 to 5 minutes.

Tubocurarine commonly causes histamine release and ganglion blockade, causing vasodilatation and hypotension. Occasionally causes bronchospasm. Severe anaphylaxis is very rare. 30% excreted unchanged in the urine, the reminder is metabolised in the liver.

Gallamine (1948)

Intubating dose 1.0 to 2.0 mg/kg, duration of action 20 to 30 minutes, supplementary doses 0.5 mg/kg. The onset of action is about 2 to 3 minutes.

Gallamine mostly excreted by the kidneys and should be avoided in renal failure. Increases the heart rate by 20 to 30 beats/minute due to vagal inhibition. Anaphylaxis is rare. Gallamine is potentiated by alkalosis and antagonised by acidosis.

Alcuronium (1961)

Intubating dose 0.2 to 0.3 mg/kg, duration of action 20 to 40 minutes, supplementary doses 0.05 to 0.1 mg/kg. The onset of action is about 3 minutes.

It may cause some histamine release and has caused anaphylaxis. Most is excreted unchanged in the urine but some is metabolised by the liver. Alcuronium should be stored at less than 25 degrees Celsius.

Atracurium (1980)

Intubating dose 0.3 to 0.6 mg/kg, duration of action 20 to 40 minutes, supplementary doses 0.1 to 0.2 mg/kg. Intubation is possible after about 2 minutes. Has been given by intravenous infusion at 0.3 to 0.6 mg/kg/h.

Atracurium may cause histamine release and has caused anaphylaxis. At body temperature and pH it undergoes spontaneous “breakdown” (Hofmann elimination) to laudanosine. Up to 50% may also be hydrolysed by blood esters. This makes atracurium very predictable and may be the drug of choice for patients with renal or liver failure. In high doses laudanosine can cause convulsions in animals. However, even after prolonged infusions of atracurium in humans, laudanosine concentrations are much less than those that produce convulsions. It needs to be stored at 2 to 8 degrees Celsius. Activity decreases by a few percent per month if stored at room temperature.

Pancuronium (1967)

Intubating dose 0.1 mg/kg, duration of action 30 to 60 minutes, supplementary doses 0.01 to 0.02 mg/kg. The onset of action is about 3 minutes.

Pancuronium may cause an increase in heart rate, blood pressure and cardiac output. Traditionally used in shocked patients. It rarely causes histamine release. Elimination may be prolonged in renal and liver failure.

Vecuronium (1983)

Intubating dose 0.08 to 0.1 mg/kg, duration of action 20 to 30 minutes, supplementary doses 0.03 to 0.05 mg/kg. The onset of action is about 2 to 3 minutes.

Vecuronium has minimal effect on blood pressure or pulse rate and does not cause histamine release.

Cisatracurium (1995)

Intubating dose 0.1 to 0.2 mg/kg, duration of action 30 to 40 minutes, supplementary doses 0.03 mg/kg. The onset of its action is about 2 minutes. Cisatracurium has been given as an intravenous infusion at 0.06 – 0.18 mg/kg/h.

It is derived from atracurium (stereoisomer) but causes less histamine release. Storage and metabolism is the same as for atracurium.

Rocuronium (1994)

Intubating dose 0.6 mg/kg, duration of action 30 to 40 minutes, supplementary doses 0.15 mg/kg. The onset of action is about 1 minute.

Rocuronium is similar to vecuronium but may cause some tachycardia.

Mivacurium (1993)

Intubating dose 0.07 to 0.25 mg/kg, duration of action 10 to 20 minutes, supplementary doses 0.1 mg/kg. The onset of action is about 3 minutes.

Histamine release may occur especially in high dosages and if given rapidly. Mivacurium is metabolised by plasma cholinesterase. The rapid recovery of muscle power may make reversal unnecessary.

Pipecuronium

Intubating dose 0.07 to 0.08 mg/kg, duration of action 90 to 120 minutes.

A more potent form of pancuronium. The onset of action is about 3 minutes.

Fazidinium

Onset within 1 minute lasts 40 to 60 minutes but causes marked vagal blockade.

Metocurine (dimethyl tubocuraine chloride/bromide)

More potent and longer acting (90 to 120 minutes) form of tubocurarine. The intubating dose is 0.2 to 0.4 mg/kg. The onset of action is about 3 minutes.

Depolarising Muscle Relaxants

Suxamethonium (1951)

Depolarising muscle relaxants include suxamethonium and decamethonium. Suxamethonium (succinylcholine or Scoline) is a depolarising muscle relaxant introduced in 1951. It is usually available as the chloride salt but may be presented as a bromide or iodide salt. All types of suxamethonium are destroyed by alkali and must not be mixed with thiopentone. Suxamethonium chloride must be stored at 4 degrees Celsius. Suxamethonium bromide may be available as a powder, which can be stored for longer.

Structurally suxamethonium is two acetylcholine molecules joined together.

Indications

Suxamethonium will produce the best intubating conditions in the shortest time and has the shortest duration of action. However suxamethonium has several associated adverse effects that can limit or even contraindicate its use.

Suxamethonium may be the ideal muscle relaxant for very short operations (e.g. bronchoscopy). 1 mg/kg will produce paralysis for 3 to 5 minutes. The muscle paralysis can be continued with intermittent doses of about 25% of the initial dose. The total dose must not exceed 4 to 6 mg/kg, or recovery may be very slow (phase 2 block). Bradycardia is common after the second dose, but may occur after the first dose, especially in children. This can be prevented by prior treatment with atropine.

The anaesthetist must ensure that the patient continues to receive an anaesthetic drug as well as the suxamethonium

Suxamethonium may be the ideal muscle relaxant for a difficult intubation. However if the anaesthetist is not skilled in difficult intubation or does not have the equipment necessary, he/she should never give any muscle relaxant. Other types of anaesthesia must be used, e.g. local anaesthetic, spinal anaesthetic or awake intubation.

Suxamethonium is the only choice of muscle relaxation for a difficult intubation because it has a rapid onset of action (30 seconds) and a short duration of action. Some of the new non-depolarising muscle relaxants (rocuronium) also have a rapid onset of action but they cannot be used instead of suxamethonium because they have a long duration of action.

If the anaesthetist has the skill and equipment to use suxamethonium for a difficult intubation they must have the patient breathe 100% oxygen for at least thee minutes (pre-oxygenation) before inducing anaesthesia and giving suxamethonium. This will replace all the nitrogen in the patient’s lung with oxygen and may allow the healthy patient to be apnoeic for 5 to 7 minutes without becoming hypoxic. If the anaesthetist is unable to intubate the trachea, the patient should begin to breathe before the oxygen supply in the lungs is consumed (duration of action of suxamethonium is 3 to 5 minutes). This will only occur if the patient is healthy, correctly pre-oxygenated and the muscle relaxant has a very short duration of action.

Suxamethonium may be the ideal muscle relaxant for patients at risk of aspiration of gastric contents. As with the difficult intubation, patients at risk of aspiration must be correctly pre-oxygenated. They also must have cricoid pressure (An assistant pushes the cricoid cartilage of the larynx backwards which compresses the oesophagus. Cricoid pressure prevents passive regurgitation of gastric contents).

Dose

Intravenous: 1 to 1.5 mg/kg plus intermittent doses of 25% of the initial dose (total dose must not exceed 4 to 6 mg/kg).

Intramuscular: 2 to 3 mg/kg. (In an emergency suxamethonium may be given intramuscularly but the onset of action is slower and less predictable).

Adverse Effects and contra-indications

Prolonged paralysis may be caused by excessive dosage (greater than 4 mg/kg) or reduced metabolism by cholinesterase.

Cholinesterase activity may be reduced because there is reduced production (liver failure, starvation, carcinoma, hypothyroidism), inhibition of cholinesterase by other drugs (nerve gas, insecticides, ecothiopate) or inherited abnormal cholinesterase. Approximately 1 in 2,800 patients will have an inherited homozygous abnormal cholinesterase. These patients may have a normal response to suxamethonium or an increase in the duration of action up to 4 hours.

Bradycardia may occur after the second dose of suxamethonium but may occur after the first dose, especially in children.

Raised intragastric pressure of 15 to 20 mmHg but the lower oesophageal tone is also raised so that the patient is not at an increased risk of aspiration.

Raised intracranial and intraocular pressure is transient after suxamethonium. There is an increase within 1 minute but the pressure has returned to normal within 6 minutes. Suxamethonium is usually avoided in patients with penetrating eye injuries however the anaesthetist must consider the risk of aspiration in the non-fasted patient. Coughing and vomiting can cause the loss of intraocular contents.

Muscle pain in the muscles of the neck, back and abdomen may occur after suxamethonium, especially in young adults.

Hyperkalaemia. Plasma potassium increases usually by 0.5 to 1 mmol/l in normal patients. A greater rise in potassium (enough to cause cardiac arrest) may occur in patients with unhealed third degree burns, spinal cord injury, muscle atrophy and severe intraabdominal sepsis. Suxamethonium is best avoided 48 hours after the injury and for the next 2 years.

Malignant hyperthermia and anaphylaxis can be triggered by suxamethonium.