Anaesthesia and neuromuscular block

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Chapter 19 Anaesthesia and neuromuscular block

Jerry P. Nolan

General anaesthesia

Until the mid-19th century such surgery as was possible had to be undertaken at tremendous speed. Surgeons did their best for terrified patients by using alcohol, opium, cannabis, hemlock or hyoscine.¹ With the introduction of general anaesthesia, surgeons could operate for the first time with careful deliberation. The problem of inducing quick, safe and easily reversible unconsciousness for any desired length of time in humans began to be solved only in the 1840s when the long-known substances nitrous oxide, ether and chloroform were introduced in rapid succession.

The details surrounding the first use of surgical anaesthesia were submerged in bitter disputes on priority following an attempt to take out a patent for ether. The key events around this time were:

• 1842 – W E Clarke of Rochester, New York, administered ether for a dental extraction; however, the event was not made widely known at the time.

• 1844 – Horace Wells, a dentist in Hartford, Connecticut, introduced nitrous oxide to produce anaesthesia during dental extraction.

• 1846 – On 16 October William Morton, a Boston dentist, successfully demonstrated the anaesthetic properties of ether.

• 1846 – On 21 December Robert Liston performed the first surgical operation in England under ether anaesthesia.²

• 1847 – James Y Simpson, professor of midwifery at the University of Edinburgh, introduced chloroform for the relief of labour pain.

The next important developments in anaesthesia were in the 20th century when the appearance of new drugs, both as primary general anaesthetics and as adjuvants (muscle relaxants), new apparatus and clinical expertise in rendering prolonged anaesthesia safe enabled surgeons to increase their range. No longer was the duration and type of surgery determined by patients’ capacity to endure pain.

Phases of general anaesthesia

Balanced surgical anaesthesia (hypnosis, analgesia and muscle relaxation) with a single drug would require high doses that would cause adverse effects such as slow and unpleasant recovery, and depression of cardiovascular and respiratory function. In modern practice, different drugs are used to attain each objective so that adverse effects are minimised.

The perioperative period may be divided into three phases, and several factors determine the choice of drugs given in each of these. In brief:

Before surgery,

an assessment is made of:

• the patient’s physical and psychological condition

• any concurrent illness

• the relevance of any existing drug therapy.

All of these may influence the choice of anaesthetic technique and anaesthetic drugs.

When appropriate, peripheral nerve block with a local anaesthetic, or neural axis block, e.g. spinal or epidural, provides intraoperative analgesia and muscle relaxation. These local anaesthetic techniques provide excellent postoperative analgesia.

After surgery

The anaesthetist ensures that the effects of neuromuscular blocking drugs and opioid-induced respiratory depression have either worn off or have been adequately reversed by an antagonist; the patient is not left alone until conscious, with protective reflexes restored, and with a stable circulation.

Relief of pain

after surgery can be achieved with several techniques. An epidural infusion of a mixture of local anaesthetic and opioid provides excellent pain relief after major surgery such as laparotomy. Parenteral morphine, given intermittently by a nurse or a patient-controlled system, will also relieve moderate or severe pain but has the attendant risk of nausea, vomiting, sedation and respiratory depression. The addition of regular paracetamol and a NSAID, given orally or parenterally (the rectal route is used much less commonly now), will provide additional pain relief and reduce the requirement for morphine.

Postoperative nausea and vomiting

(PONV) is common after laparotomy and major gynaecological surgery, e.g. abdominal hysterectomy. The use of propofol, particularly when given to maintain anaesthesia, has reduced the incidence of PONV. Antiemetics, such as cyclizine, metoclopramide and ondansetron, may be helpful. Dexamethasone also reduces the incidence of PONV. Many anaesthetists use a combination of two or three of these drugs, a strategy which has been shown to be particularly effective.

Some special techniques

Dissociative anaesthesia

is a state of profound analgesia and anterograde amnesia with minimal hypnosis during which the eyes may remain open; it can be produced by ketamine (see p. 301). It is particularly useful where modern equipment is lacking or where access to the patient is limited, e.g. in prehospital or military settings.

Sedation and amnesia

without analgesia is provided by intravenous midazolam or, less commonly nowadays, by diazepam. These drugs can be used alone for procedures causing mild discomfort, e.g. endoscopy, and with a local anaesthetic where more pain is expected, e.g. removal of impacted wisdom teeth. Benzodiazepines produce anterograde, but not retrograde, amnesia. By definition, the sedated patient remains responsive and cooperative. (For a general account of benzodiazepines and the competitive antagonist flumazenil, see Ch. 20.)

Benzodiazepines can cause respiratory depression and apnoea, especially in the elderly and in patients with respiratory insufficiency. The combination of an opioid and a benzodiazepine is particularly dangerous. Benzodiazepines depress laryngeal reflexes and place the patient at risk of inhalation of oral secretions or dental debris. A continuous infusion of low-dose propofol provides very effective sedation that can be rapidly titrated to produce the desired effect. Use of propofol in this way should be undertaken only by those with advanced airway skills, such as anaesthetists and some emergency physicians.

Entonox,

a 50:50 mixture of nitrous oxide and oxygen, is breathed by the patient using a demand valve. It is particularly useful in the prehospital environment and for brief procedures, such as splinting limbs.

Pharmacology of anaesthetics

All successful general anaesthetics are given intravenously or by inhalation because these routes enable closest control over blood concentrations and thus of effect on the brain.

Mode of action

General anaesthetics act on the brain, primarily on the midbrain reticular activating system, and the spinal cord. Many anaesthetics are lipid soluble and there is good correlation between this and anaesthetic effectiveness (the Overton–Meyer hypothesis); the more lipid soluble tend to be the more potent anaesthetics, but such a correlation is not invariable. Some anaesthetic agents are not lipid soluble and many lipid-soluble substances are not anaesthetics.

Until recently it was thought that the principal site of action of general anaesthetics was relatively non-specific action in the neuronal lipid bilayer membrane. The current view is that anaesthetic agents interact with proteins to alter the activity of specific neuronal ion channels, particularly the fast neurotransmitter receptors such as nicotinic acetylcholine, γ-aminobutyric acid (GABA) and glutamate receptors. The suppression of motor responses to painful stimuli by anaesthetics is mediated mainly by the spinal cord, whereas hypnosis and amnesia are mediated within the brain.

Comparison of the efficacy of inhalational anaesthetics is made by measuring the minimum alveolar concentration (MAC) in oxygen required to prevent movement in response to a standard surgical skin incision in 50% of subjects. The MAC of the volatile agent is reduced by the co-administration of nitrous oxide.

Inhalation anaesthetics

The preferred inhalation anaesthetics are those that are minimally irritant and non-flammable, and comprise nitrous oxide and the fluorinated hydrocarbons, e.g. sevoflurane.

Pharmacokinetics (volatile liquids, gases)

The depth of anaesthesia is correlated with the tension (partial pressure) of anaesthetic drug in brain tissue. This is driven by the development of a series of tension gradients from the high partial pressure delivered to the alveoli and decreasing through the blood to the brain and other tissues. The gradients are dependent on the blood/gas and tissue/gas solubility coefficients, as well as on alveolar ventilation and organ blood flow.

An anaesthetic that has high solubility in blood, i.e. a high blood/gas partition coefficient, will provide a slow induction and adjustment of the depth of anaesthesia. Here, the blood acts as a reservoir (store) for the drug so that it does not enter the brain readily until the blood reservoir is filled. A rapid induction can be obtained by increasing the concentration of drug inhaled initially and by hyperventilating the patient.

Anaesthetics with low solubility in blood, i.e. a low blood/gas partition coefficient (nitrous oxide, desflurane, sevoflurane), provide rapid induction of anaesthesia because the blood reservoir is small and anaesthetic is available to pass into the brain sooner.

During induction of anaesthesia the blood is taking up anaesthetic selectively and rapidly, and the resulting loss of volume in the alveoli leads to a flow of anaesthetic into the lungs that is independent of respiratory activity. When the anaesthetic is discontinued the reverse occurs and it moves from the blood into the alveoli. In the case of nitrous oxide, this can account for as much as 10% of the expired volume and so can significantly lower the alveolar oxygen concentration. Mild hypoxia occurs and lasts for as long as 10 min. Oxygen is given to these patients during the last few minutes of anaesthesia and the early post-anaesthetic period. This phenomenon, diffusion hypoxia, occurs with all gaseous anaesthetics, but is most prominent with gases that are relatively insoluble in blood, for they will diffuse out most rapidly when the drug is no longer inhaled, i.e. just as induction is faster, so is elimination. Nitrous oxide is especially powerful in this respect because it is used at concentrations of up to 70%.

Nitrous oxide

Nitrous oxide (1844) is a gas with a slightly sweetish smell that is neither flammable nor explosive. It produces light anaesthesia without demonstrably depressing the respiratory or vasomotor centre provided that normal oxygen tension is maintained.

Advantages

Nitrous oxide reduces the requirement for other more potent and intrinsically more toxic anaesthetics. It has a strong analgesic action; inhalation of 50% nitrous oxide in oxygen (Entonox) may have similar effects to standard doses of morphine. Induction is rapid and not unpleasant, although transient excitement may occur, as with all anaesthetics. Recovery time rarely exceeds 4 min even after prolonged administration.

Disadvantages

Nitrous oxide is expensive to buy and to transport. It must be used in conjunction with more potent anaesthetics to produce full surgical anaesthesia.

Uses

Nitrous oxide is used to maintain surgical anaesthesia in combination with other anaesthetic agents, e.g. isoflurane or propofol, and, if required, muscle relaxants. Entonox provides analgesia for obstetric practice and for emergency treatment of injuries.

Dosage and administration

For the maintenance of anaesthesia, nitrous oxide must always be mixed with at least 30% oxygen. For analgesia, a concentration of 50% nitrous oxide with 50% oxygen usually suffices.

Contraindications

Any closed, distensible, air-filled space expands during administration of nitrous oxide, which moves into it from the blood. It is therefore contraindicated in patients with: demonstrable collections of air in the pleural, pericardial or peritoneal spaces; intestinal obstruction; arterial air embolism; decompression sickness; severe chronic obstructive airway disease; emphysema. Nitrous oxide will cause pressure changes in closed, non-compliant spaces such as the middle ear, nasal sinuses and the eye.

Precautions

Continued administration of oxygen may be necessary during recovery, especially in elderly patients (see diffusion hypoxia, above).

Adverse effects

The incidence of nausea and vomiting increases with the duration of anaesthesia. Exposure to nitrous oxide for more than 4 h can cause megaloblastic changes in the bone marrow. Because prolonged and repeated exposure of staff, as well as of patients, may be associated with bone marrow depression and teratogenic risk, scavenging systems are used to minimise ambient concentrations in operating theatres.

Halogenated anaesthetics

Halothane was the first halogenated agent to be used widely, but in the developed world it has been largely superseded by isoflurane, sevoflurane and desflurane. A description of isoflurane is provided, and of the others in so far as they differ. The MAC in oxygen of some volatile anaesthetics is:

Isoflurane

Isoflurane is a volatile colourless liquid that is not flammable at normal anaesthetic concentrations. It is relatively insoluble and has a lower blood/gas coefficient than halothane or enflurane, which enables rapid adjustment of the depth of anaesthesia. It has a pungent odour and can cause bronchial irritation, making inhalational induction unpleasant. Isoflurane is minimally metabolised (0.2%), and none of the breakdown products has been related to anaesthetic toxicity.

Respiratory effects

Isoflurane causes respiratory depression and diminishes the ventilatory response to carbon dioxide. Although it irritates the upper airway, it is a bronchodilator.

Cardiovascular effects

Anaesthetic concentrations of isoflurane, i.e. 1–1.5 MAC, cause only slight impairment of myocardial contractility. Isoflurane causes peripheral vasodilation and reduces blood pressure. It does not sensitise the heart to catecholamines. In low concentrations (< 1 MAC), cerebral blood flow, intracranial pressure and cerebral autoregulation are maintained. Isoflurane is a potent coronary vasodilator and in the presence of a coronary artery stenosis it may cause redistribution of blood away from an area of inadequate perfusion to one of normal perfusion. This phenomenon of ‘coronary steal’ may cause regional myocardial ischaemia.

Other effects

Isoflurane relaxes voluntary muscles and potentiates the effects of non-depolarising muscle relaxants. Isoflurane depresses cortical EEG activity and does not induce abnormal electrical activity or convulsions.

Sevoflurane

Sevoflurane is less chemically stable than the other volatile anaesthetics in current use. About 2.5% is metabolised in the body and it is degraded by contact with carbon dioxide absorbents, such as soda lime. The reaction with soda lime causes the formation of a vinyl ether (compound A), which may be nephrotoxic. Sevoflurane is less soluble than isoflurane and is very pleasant to breathe, which makes it an excellent choice for inhalational induction of anaesthesia, particularly in children. The respiratory and cardiovascular effects of sevoflurane are very similar to isoflurane, but sevoflurane does not cause ‘coronary steal’. In many hospitals, despite its higher cost, sevoflurane is displacing isoflurane as the most commonly used volatile anaesthetic.

Desflurane

Desflurane has the lowest blood/gas partition coefficient of any inhaled anaesthetic agent and thus gives particularly rapid onset and offset of effect. As it undergoes negligible metabolism (0.03%), any release of free inorganic fluoride is minimised; this characteristic favours its use for prolonged anaesthesia. Desflurane is extremely volatile and cannot be administered with conventional vaporisers. It has a very pungent odour and causes airway irritation to an extent that limits its rate of induction of anaesthesia. Despite this limitation, its very rapid recovery characteristics, even after very prolonged anaesthesia, make it an increasingly popular choice for major surgery.

Halothane

Halothane has the highest blood/gas partition coefficient of the volatile anaesthetic agents and recovery from halothane anaesthesia is comparatively slow. It is pleasant to breathe. Halothane reduces cardiac output more than any of the other volatile anaesthetics. It sensitises the heart to the arrhythmic effects of catecholamines and hypercapnia; arrhythmias are common, in particular atrioventricular dissociation, nodal rhythm and ventricular extrasystoles. Halothane can trigger malignant hyperthermia in those who are genetically predisposed (see p. 309).

About 20% of halothane is metabolised and it induces hepatic enzymes, including those of anaesthetists and operating theatre staff. Hepatic damage occurs in a small proportion of exposed patients. Typically fever develops 2–3 days after anaesthesia, accompanied by anorexia, nausea and vomiting. In more severe cases this is followed by transient jaundice or, very rarely, fatal hepatic necrosis. Severe hepatitis is a complication of repeatedly administered halothane anaesthesia (incidence of 1 in 50 000) and follows immune sensitisation to an oxidative metabolite of halothane in susceptible individuals. This serious complication, along with the other disadvantages of halothane and the popularity of sevoflurane for inhalational induction, has almost eliminated its use in the developed world. It remains in common use in other parts of the world because it is comparatively inexpensive.

Oxygen in anaesthesia

Supplemental oxygen is always used with inhalational anaesthetics to prevent hypoxia, even when air is used as the carrier gas. The concentration of oxygen in inspired anaesthetic gases is usually at least 30%, but oxygen should not be used for prolonged periods at a greater concentration than is necessary to prevent hypoxaemia. After prolonged administration, concentrations greater than 80% have a toxic effect on the lungs, which presents initially as a mild substernal irritation, progressing to pulmonary exudation and atelectasis. Use of unnecessarily high concentrations of oxygen in incubators causes retrolental fibroplasia and permanent blindness in premature infants.

Intravenous anaesthetics

Intravenous anaesthetics should be given only by those fully trained in their use and who are experienced with a full range of techniques of managing the airway, including tracheal intubation.

Pharmacokinetics

Intravenous anaesthetics enable an extremely rapid induction because the blood concentration can be raised quickly, establishing a steep concentration gradient and expediting diffusion into the brain. The rate of transfer depends on the lipid solubility and arterial concentration of the unbound, non-ionised fraction of the drug. After a single induction dose of an intravenous anaesthetic, recovery occurs quite rapidly as the drug is redistributed around the body and the plasma concentration reduces. Recovery from a single dose of intravenous anaesthetic is thus dependent on redistribution rather than rate of metabolic breakdown. With the exception of propofol, repeated doses or infusions of intravenous anaesthetics will cause considerable accumulation and prolong recovery. Attempts to use thiopental as the sole anaesthetic in war casualties led to it being described as an ideal form of euthanasia.³

It is common practice to induce anaesthesia intravenously and then to use a volatile anaesthetic for maintenance. When administration of a volatile anaesthetic is stopped, it is eliminated quickly through the lungs and the patient regains consciousness. The recovery from propofol is rapid, even after repeated doses or an infusion. This advantage, and others, has resulted in propofol displacing thiopental as the most popular intravenous anaesthetic.

Propofol

Induction of anaesthesia with 1.5–2.5 mg/kg occurs within 30 s and is smooth and pleasant with a low incidence of excitatory movements. Some preparations of propofol cause pain on injection, but adding lidocaine 20 mg to the induction dose eliminates this. The recovery from propofol is rapid, and the incidence of nausea and vomiting is extremely low, particularly when propofol is used as the sole anaesthetic. Recovery from a continuous infusion of propofol is relatively rapid as the plasma concentration decreases by both redistribution and metabolic clearance (predominantly as the glucuronide). Special syringe pumps incorporating pharmacokinetic algorithms enable the anaesthetist to select a target plasma propofol concentration (e.g. 4 micrograms/mL for induction of anaesthesia) once details of the patient’s age and weight have been entered. This technique of target-controlled infusion (TCI) provides a convenient method for giving a continuous infusion of propofol.

Central nervous system

Propofol causes dose-dependent cortical depression and is an anticonvulsant. It depresses laryngeal reflexes more than barbiturates, which is an advantage when inserting a laryngeal mask airway.

Cardiovascular system

Propofol reduces vascular tone, which lowers systemic vascular resistance and central venous pressure. The heart rate remains unchanged and the result is a fall in blood pressure to about 70–80% of the pre-induction level and a small reduction in cardiac output.

Respiratory system

Unless it is undertaken very slowly, induction with propofol causes transient apnoea. On resumption of respiration there is a reduction in tidal volume and increase in rate.

Thiopental

Thiopental is a very short-acting barbiturate ⁴ that induces anaesthesia smoothly, within one arm-to-brain circulation time. The typical induction dose is 3–5 mg/kg. Rapid distribution (initial t_½ 4 min) allows swift recovery after a single dose. The terminal t_½ of thiopental is 11 h and repeated doses or continuous infusion lead to significant accumulation in fat and very prolonged recovery. Thiopental is metabolised in the liver. The incidence of nausea and vomiting after thiopental is slightly higher than that after propofol. The pH of thiopental is 11 and extravasation causes considerable local damage. Accidental intra-arterial injection will also cause serious injury distal to the injection site.

Central nervous system

Thiopental has no analgesic activity and may be antanalgesic. It is a potent anticonvulsant. Cerebral metabolic rate for oxygen consumption (CMRO₂) is reduced, causing cerebral vasoconstriction, reduction in cerebral blood flow and intracranial pressure.

Cardiovascular system

Thiopental reduces vascular tone, causing hypotension and a slight compensatory increase in heart rate. Antihypertensives or diuretics may augment the hypotensive effect.

Respiratory system

Thiopental reduces respiratory rate and tidal volume.

Methohexitone

Methohexitone is a barbiturate similar to thiopental but its terminal t_½ is considerably shorter. Since the introduction of propofol, its use is confined almost entirely to inducing anaesthesia for electrocontrovulsive therapy (ECT). Propofol shortens seizure duration and may reduce the efficacy of ECT.

Etomidate

Etomidate is a carboxylated imidazole. It causes pain on injection and excitatory muscle movements are common on induction of anaesthesia. There is a 20–50% incidence of nausea and vomiting associated with its use. Etomidate causes adrenocortical suppression by inhibiting 11β- and 17β-hydroxylase, and for this reason is not used for prolonged infusion. Even after a single dose of etomidate, adrenocortical suppression can last for as long as 72 h and in septic patients is associated with an increased incidence of organ failure. Despite all of these disadvantages it remains in common (although decreasing) use, particularly for emergency anaesthesia, because it causes less cardiovascular depression and hypotension than thiopental or propofol. It should not be used in patients with sepsis.

Ketamine

Ketamine is a phencyclidine (hallucinogen) derivative and an antagonist of the NMDA receptor.⁵ In anaesthetic doses it produces a trance-like state known as dissociative anaesthesia (sedation, amnesia, dissociation, analgesia).

Advantages

Anaesthesia persists for up to 15 min after a single intravenous injection and is characterised by profound analgesia. Ketamine may be used as the sole analgesic for diagnostic and minor surgical interventions. In contrast to most other anaesthetic drugs, ketamine usually causes a tachycardia and increases blood pressure and cardiac output, making it an increasingly popular choice for inducing anaesthesia in shocked patients. Because pharyngeal and laryngeal reflexes are only slightly impaired, the airway may be less at risk than with other general anaesthetic techniques. It is a potent bronchodilator and is sometimes used to treat severe bronchospasm in asthmatics requiring mechanical ventilation.

Disadvantages

Ketamine produces no muscular relaxation. It increases intracranial and intraocular pressure. Hallucinations with delirium can occur during recovery (the emergence reaction), but are minimised if ketamine is used solely as an induction drug and followed by a conventional inhalational anaesthetic. Their incidence is reduced by giving a benzodiazepine both as a premedication and after the procedure.

Uses

Subanaesthetic doses of ketamine can be used to provide analgesia for painful procedures of short duration such as the dressing of burns, radiotherapeutic procedures, marrow sampling and minor orthopaedic procedures. Ketamine can be used for induction of anaesthesia before giving inhalational anaesthetics, or for both induction and maintenance of anaesthesia for short-lasting diagnostic and surgical interventions that do not require skeletal muscle relaxation. It is of particular value for children requiring frequent, repeated anaesthetics. It is increasingly popular for inducing anaesthesia in critically ill patients.

Dosage and administration

Induction. A dose of 2 mg/kg i.v. over a period of 60 s produces surgical anaesthesia within 1–2 min, lasting for 5–10 min; alternatively 5–10 mg/kg by deep intramuscular injection produces surgical anaesthesia within 3–5 min, lasting for up to 25 min.

Maintenance. Serial doses of 50% of the original intravenous dose or 25% of the intramuscular dose are given to prevent movement in response to surgical stimuli. Tonic and clonic movements resembling seizures occur in some patients but do not indicate a light plane of anaesthesia or a need for additional doses of the anaesthetic.

Recovery of consciousness is gradual. Emergence reactions (above) are lessened by benzodiazepine premedication and by avoiding unnecessary disturbance of the patient during recovery.

Contraindications

include: moderate to severe hypertension, cerebral trauma (although this is controversial), intracerebral mass or haemorrhage, or other causes of raised intracranial pressure; eye injury and increased intraocular pressure; psychiatric disorders such as a schizophrenia and acute psychoses.

Use in pregnancy

Ketamine is contraindicated in pregnancy before term, as it has oxytocic activity. It is also contraindicated in patients with eclampsia or pre-eclampsia. It may be used for assisted vaginal delivery by an experienced anaesthetist. Ketamine is better suited for use during caesarean section; it causes less fetal and neonatal depression than other anaesthetics.

Muscle relaxants

Neuromuscular blocking drugs

A lot of surgery, especially of the abdomen, requires that voluntary muscle tone and reflex contraction be inhibited. This could be attained by deep general anaesthesia (but with risk of cardiovascular depression, respiratory complications and slow recovery) or by regional nerve blockade (which may be difficult to do or contraindicated, e.g. if there is a haemostatic defect).

Selective relaxation of voluntary muscle with neuromuscular blocking drugs enables surgery under light general anaesthesia with analgesia; it also facilitates tracheal intubation, quick induction and quick recovery. However, mechanical ventilation and technical skill are required. Neuromuscular blocking drugs should be given only after induction of anaesthesia.

Neuromuscular blocking drugs first attracted scientific notice because of their use as arrow poisons by the natives of South America, who used the most famous of all, curare, for killing food animals ⁶ as well as enemies. In 1811 Sir Benjamin Brodie smeared ‘woorara paste’ on wounds of guinea pigs and noted that death could be delayed by inflating the lungs through a tube introduced into the trachea. Though he did not continue until complete recovery, he did suggest that the drug might be of use in tetanus.

Despite attempts to use curare for a variety of diseases including epilepsy, chorea and rabies, the lack of pure and accurately standardised preparations, as well as the absence of convenient techniques of mechanical ventilation if overdose occurred, prevented it from gaining any firm place in medical practice until 1942, when these difficulties were removed.

Drugs acting at the myoneural junction produce complete paralysis of all voluntary muscle so that movement is impossible and mechanical ventilation is needed. It is plainly important that a paralysed patient should be unconscious during surgery.⁷

Using modern anaesthetic techniques and monitoring, awareness while paralysed for a surgical procedure is extremely rare. In the UK, general anaesthesia using volatile agents should always be monitored with agent analysers, which measure and display the end-tidal concentration of volatile agent. Increasing use of depth of anaesthesia monitors (e.g. bispectral index (BIS), which is based on the processed electroencephalogram) should further reduce the incidence of awareness. In the past, misguided concerns about the effect of volatile anaesthetics on the newborn led many anaesthetists to use little, if any, volatile agent when giving general anaesthesia for caesarean section. Under these conditions some mothers were conscious and experienced pain while paralysed and therefore unable to move. Despite its extreme rarity nowadays,⁸ fear of awareness under anaesthesia is still a leading cause of anxiety in patients awaiting surgery.

Mechanisms

When an impulse passes down a motor nerve to voluntary muscle it causes release of acetylcholine from the nerve endings into the synaptic cleft. This activates receptors on the membrane of the motor endplate, a specialised area on the muscle fibre, opening ion channels for momentary passage of sodium, which depolarises the endplate and initiates muscle contraction.

Neuromuscular blocking drugs used in clinical practice interfere with this process. Natural substances that prevent the release of acetylcholine at nerve endings exist, e.g. Clostridium botulinum toxin and some venoms.

There are two principal mechanisms by which drugs used clinically interfere with neuromuscular transmission:

1. By competition with acetylcholine (atracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuronium). These drugs are competitive antagonists of acetylcholine. They do not cause depolarisation themselves but protect the endplate from depolarisation by acetylcholine. The result is a flaccid paralysis. Reversal of this type of neuromuscular block can be achieved with anticholinesterase drugs, such as neostigmine, which prevent the destruction by cholinesterase of acetylcholine released at nerve endings, enable the concentration to build up and so reduce the competitive effect of a blocking agent. Rocuronium and vecuronium can also be reversed with the modified γ-cyclodextrin, sugammadex (see below).

2. By depolarisation of the motor endplate (suxamethonium). Such agonist drugs activate the acetylcholine receptor on the motor endplate; at their first application voluntary muscle contracts but, as they are not destroyed immediately, like acetylcholine, the depolarisation persists. It might be expected that this prolonged depolarisation would cause muscles to remain contracted, but this is not so (except in chickens). With prolonged administration, a depolarisation block changes to a competitive block (dual block). Because of the uncertainty of this situation, a competitive blocking drug is preferred for anything other than short procedures.

Competitive antagonists

Atracurium

is unique in that it is altered spontaneously in the body to an inactive form (t_½ 30 min) by a passive chemical process (Hofmann elimination). The duration of action (15–35 min) is thus uninfluenced by the state of the circulation, the liver or the kidneys, a significant advantage in patients with hepatic or renal disease and in the aged. It has very little direct effect on the cardiovascular system but at doses of greater than 0.5–0.6 mg/kg histamine release may cause hypotension and bronchospasm.

Cisatracurium

is a stereoisomer of atracurium; it is less prone to cause histamine release.

Vecuronium

is a synthetic steroid derivative that produces full neuromuscular blockade about 3 min after a dose of 0.1 mg/kg, lasting for 30 min. It has no cardiovascular side-effects and does not cause histamine release.

Rocuronium

is another steroid derivative that has the advantage of a rapid onset of action, such that 0.6 mg/kg allows tracheal intubation to be achieved after 60 s. It has negligible cardiovascular effects and a similar duration of action to vecuronium.

Mivacurium

belongs to the same chemical family as atracurium and is the only non-depolarising neuromuscular blocker that is metabolised by plasma cholinesterase. It is comparatively short acting (10–15 min), depending on the initial dose. Mivacurium can cause some hypotension because of histamine release.

Pancuronium

was the first steroid-derived neuromuscular blocker in clinical use. It is longer acting than vecuronium and causes a slight tachycardia.

Tubocurarine

is now obsolete and no longer available in the UK. It is a potent antagonist at autonomic ganglia and causes significant hypotension.

Antagonism of competitive neuromuscular block

Neostigmine

The action of competitive acetylcholine blockers is antagonised by anticholinesterase drugs, which enable accumulation of acetylcholine. Neostigmine (see also p. 375) is given intravenously, mixed with glycopyrronium to prevent bradycardia caused by the parasympathetic autonomic effects of the neostigmine. It acts in 4 min and its effects last for about 30 min. Too much neostigmine can cause neuromuscular block by depolarisation, which will cause confusion unless there have been some signs of recovery before neostigmine is given. Progress can be monitored with a nerve stimulator.

Sugammadex

Sugammadex comprises a ring-like structure of low molecular weight sugars and became available in the UK in 2008. This γ-cyclodextrin was designed specifically to encapsulate rocuronium: the negatively charged hydrophilic outer core attracts the positively charged rocuronium and pulls the drug into its lipophilic core. The result is an inactive water-soluble complex that is excreted by the kidneys. A full neuromuscular block from rocuronium can be reversed with sugammadex in less than 3 min. Neostigmine can be used only when the block from rocuronium has started to recover spontaneously (perhaps 30 min after initial injection) and it has many unwanted effects that are not a feature of sugammadex. Vecuronium can also be reversed by sugammadex. The relatively high cost of sugammadex is currently prohibiting its widespread adoption.

Depolarising neuromuscular blocker

Suxamethonium (succinylcholine)

Paralysis is preceded by muscle fasciculation, and this may be the cause of the muscle pain experienced commonly after its use. The pain may last for 1–3 days and can be minimised by preceding the suxamethonium with a small dose of a competitive blocking agent.

Suxamethonium is the neuromuscular blocker with the most rapid onset and the shortest duration of action (although the onset of rocuronium is almost as fast and with sugammadex the recovery is faster than that of suxamethonium). Tracheal intubation is possible in less than 60 s and total paralysis lasts for up to 4 min with 50% recovery in about 10 min (t_½ for effect). It is indicated particularly for rapid sequence induction of anaesthesia in patients who are at risk of aspiration – the ability to secure the airway rapidly with a tracheal tube is of the utmost importance. If intubation proves impossible, recovery from suxamethonium and resumption of spontaneous respiration is relatively rapid. Unfortunately, if it is impossible to ventilate the paralysed patient’s lungs, recovery may not be rapid enough to prevent the onset of hypoxia.

Suxamethonium is destroyed by plasma pseudocholinesterase and so its persistence in the body is increased by neostigmine, which inactivates that enzyme, and in patients with hepatic disease or severe malnutrition whose plasma enzyme concentrations are lower than normal. Approximately 1 in 3000 of the European population have hereditary defects in amount or kind of enzyme, and cannot destroy the drug as rapidly as normal individuals.⁹ Paralysis can then last for hours and the individual requires ventilatory support and sedation until recovery occurs spontaneously.

Repeated injections of suxamethonium can cause bradycardia, extrasystoles and even ventricular arrest. These are probably due to activation of cholinoceptors in the heart and are prevented by atropine. It can be used in Caesarean section as it does not cross the placenta readily. Suxamethonium depolarisation causes a release of potassium from muscle, which in normal patients will increase the plasma potassium by 0.5 mmol/L. This is a problem only if the patient’s plasma potassium concentration was already high, for example in acute renal failure. In patients with spinal cord injuries and those with major burns, suxamethonium may cause a grossly exaggerated release of potassium from muscle, sufficient to cause cardiac arrest.

Uses of neuromuscular blocking drugs

Only those who are competent at tracheal intubation and ventilation of the patient’s lungs should use these drugs. The drugs are used:

• to provide muscular relaxation during surgery, to enable intubation in the emergency department, and occasionally to assist mechanical ventilation in intensive therapy units; and

• during electroconvulsive therapy to prevent injury to the patient from excessive muscular contraction.

Other muscle relaxants

Drugs that reduce spasm of the voluntary muscles without impairing voluntary movement can be useful in spastic states, low back syndrome and rheumatism with muscle spasm.

Baclofen

is structurally related to γ-aminobutyric acid (GABA), an inhibitory central nervous system (CNS) transmitter; it inhibits reflex activity mainly in the spinal cord. Baclofen reduces spasticity and flexor spasms, but, as it has no action on voluntary muscle power, function is commonly not improved. Ambulant patients may need their leg spasticity to provide support, and reduction of spasticity may expose the weakness of the limb. It benefits some cases of trigeminal neuralgia. Baclofen is given orally (t_½ 3 h).

Dantrolene

acts directly on muscle and prevents the release of calcium from sarcoplasm stores (see malignant hyperthermia, p. 309).

Anaphylaxis

Anaphylactic reactions are caused by the interaction of antigens with specific immunoglobulin (Ig) E antibodies, which have been formed by previous exposure to the antigen. Anaphylactoid reactions are clinically indistinguishable from anaphylaxis but are not caused by previous exposure to a triggering agent and do not involve IgE. Intravenous anaesthetics and muscle relaxants can cause anaphylactic or anaphylactoid reactions; rarely, they are fatal. Muscle relaxants are responsible for 70% of anaphylactic reactions during anaesthesia, and suxamethonium accounts for almost half of these.

Local anaesthetics

Cocaine had been suggested as a local anaesthetic for clinical use when Sigmund Freud investigated the alkaloid in Vienna in 1884 with Carl Koller. The latter had long been interested in the problem of local anaesthesia in the eye, for general anaesthesia has disadvantages in ophthalmology. Observing that numbness of the mouth occurred after taking cocaine orally, Koller realised that this was a local anaesthetic effect. He tried cocaine on animals’ eyes and introduced it into clinical ophthalmological practice, while Freud was on holiday. The use of cocaine spread rapidly and it was soon being used to block nerve trunks. Chemists then began to search for less toxic substitutes, with the result that procaine was introduced in 1905.

Desired properties

Innumerable compounds have local anaesthetic properties, but few are suitable for clinical use. Useful substances must be water soluble, sterilisable by heat, have a rapid onset of effect, a duration of action appropriate to the operation to be performed, be non-toxic, both locally and when absorbed into the circulation, and leave no local after-effects.

Mode of action

Local anaesthetics prevent the initiation and propagation of the nerve impulse (action potential). By reducing the passage of sodium through voltage-gated sodium ion channels they raise the threshold of excitability; in consequence, conduction is blocked at afferent nerve endings, and by sensory and motor nerve fibres. The fibres in nerve trunks are affected in order of size, the smallest (autonomic, sensory) first, probably because they have a proportionately greater surface area, and then the larger (motor) fibres. Paradoxically the effect in the CNS is stimulation (see below).

Pharmacokinetics

The distribution rate of a single dose of a local anaesthetic is determined by diffusion into tissues with concentrations approximately in relation to blood flow (plasma t_½ of only a few minutes). By injection or infiltration, local anaesthetics are usually effective within 5 min and have a useful duration of effect of 1–1.5 h, which in some cases may be doubled by adding a vasoconstrictor (below).

Most local anaesthetics are used in the form of the acid salts, as these are both soluble and stable. The acid salt (usually the hydrochloride) dissociates in the tissues to liberate the free base, which is biologically active. This dissociation is delayed in abnormally acid, e.g. inflamed, tissues, but the risk of spreading infection makes local anaesthesia undesirable in infected areas.

Absorption from mucous membranes on topical application varies according to the compound. Those that are well absorbed are used as surface anaesthetics (cocaine, lidocaine, prilocaine). Absorption of topically applied local anaesthetic can be extremely rapid and give plasma concentrations comparable to those obtained by injection. This has led to deaths from overdosage, especially via the urethra.

For topical effect on intact skin for needling procedures, a eutectic ¹⁰ mixture of bases of prilocaine or lidocaine is used (EMLA – eutectic mixture of local anaesthetics). Absorption is very slow and a cream is applied under an occlusive dressing for at least 1 h. Tetracaine gel 4% (Ametop) is more effective than EMLA cream and enables pain-free venepuncture 30 min after application.

Ester compounds

(cocaine, procaine, tetracaine, benzocaine) are hydrolysed by liver and plasma esterases, and their effects may be prolonged where there is a genetic enzyme deficiency.

Amide compounds

(lidocaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine) are dealkylated in the liver.

Impaired liver function, whether caused by primary cellular insufficiency or low liver blood flow as in cardiac failure, may both delay elimination and cause higher peak plasma concentrations of both types of local anaesthetic. This is likely to be important only with large or repeated doses or infusions.

Prolongation of action by vasoconstrictors

The effect of a local anaesthetic is terminated by its removal from the site of application. Anything that delays its absorption into the circulation will prolong its local action and can reduce its systemic toxicity when large doses are used. Most local anaesthetics, with the exception of cocaine, cause vascular dilation. The addition of a vasoconstrictor such as adrenaline/epinephrine reduces local blood flow, slows the rate of absorption of the local anaesthetic, and prolongs its effect; the duration of action of lidocaine is doubled from 1 h to 2 h. Normally, the final concentration of adrenaline/epinephrine should be 1 in 200 000, although dentists use up to 1 in 80 000.

Do not use a vasoconstrictor for nerve block of an extremity (finger, toe, nose, penis). For obvious anatomical reasons, the whole blood supply may be cut off by intense vasoconstriction so that the organ may be damaged or even lost. Enough adrenaline/epinephrine can be absorbed to affect the heart and circulation, and reduce the plasma potassium concentration.

This can be dangerous in cardiovascular disease, and with co-administered tricyclic antidepressants and potassium-losing diuretics. An alternative vasoconstrictor is felypressin (synthetic vasopressin), which, in the concentrations used, does not affect the heart rate or blood pressure and may be preferable in patients with cardiovascular disease.

Other effects

Local anaesthetics also have the following clinically important effects in varying degree:

• Excitation of parts of the CNS, which may manifest as anxiety, restlessness, tremors, euphoria, agitation and even convulsions, which are followed by depression.

• Quinidine-like actions on the heart.

Uses

Local anaesthesia is generally used when loss of consciousness is neither necessary nor desirable, and also as an adjunct to major surgery to avoid high-dose general anaesthesia and to provide postoperative analgesia. It can be used for major surgery, with sedation, although many patients prefer to be unconscious. It is invaluable when the operator must also be the anaesthetist, which is often the case in some parts of the developing world.

Local anaesthetics may be used in several ways to provide the following:

• Surface anaesthesia, as solution, jelly, cream or lozenge.

• Infiltration anaesthesia, to block the sensory nerve endings and small cutaneous nerves.

• Regional anaesthesia.

Regional anaesthesia

Regional anaesthesia requires considerable knowledge of anatomy and attention to detail for both success and safety.

Nerve block

means the anaesthetising of a region, small or large, by injecting the drug around, not into, the appropriate nerves, usually either a peripheral nerve or a plexus. The routine use of peripheral nerve stimulating needles and/or ultrasound guidance has increased significantly the success rate of peripheral nerve or plexus blocks. Nerve block provides its own muscular relaxation as motor fibres are blocked as well as sensory fibres, although with care differential block, affecting sensory more than motor fibres, can be achieved. There are various specialised forms: brachial plexus, paravertebral, paracervical block. Sympathetic nerve blocks may be used in vascular disease to induce vasodilation.

Intravenous

A double cuff is applied to the arm, inflated above arterial pressure after elevating the limb to drain the venous system, and the veins filled with local anaesthetic, e.g. 0.5–1% lidocaine without adrenaline/epinephrine. The arm is anaesthetised in 6–8 min, and the effect lasts for up to 40 min if the cuff remains inflated. The cuff must not be deflated for at least 20 min. The technique is useful in providing anaesthesia for the treatment of injuries speedily and conveniently, and many patients can leave hospital soon after the procedure. The technique must be meticulously conducted, for sudden release of the full dose of local anaesthetic accidentally into the general circulation may cause severe toxicity and even cardiac arrest. Bupivacaine is no longer used for intravenous regional anaesthesia as cardiac arrest caused by it is particularly resistant to treatment.

Extradural

(epidural) anaesthesia is used in the thoracic, lumbar and sacral (caudal) regions. Lumbar epidurals are used widely in obstetrics and low thoracic epidurals provide excellent analgesia after laparotomy. The drug is injected into the extradural space where it acts on the nerve roots. This technique is less likely to cause hypotension than spinal anaesthesia. Continuous analgesia is achieved if a local anaesthetic, often mixed with an opioid, is infused through an epidural catheter.

Subarachnoid (intrathecal) block (spinal anaesthesia)

The drug is injected into the cerebrospinal fluid (CSF) and, by using a solution of appropriate specific gravity and tilting the patient, it can be kept at an appropriate level. Sympathetic nerve blockade causes hypotension. Headache due to CSF leakage is virtually eliminated by using very narrow atraumatic ‘pencil point’ needles.

Serious local neurological complications, e.g. infection and nerve injury, are extremely rare.

Opioid analgesics

are used intrathecally and extradurally. They diffuse into the spinal cord and act on its opioid receptors (see p. 282); they are highly effective in skilled hands for post-surgical and intractable pain. Respiratory depression may occur. The effect begins in 20 min and lasts for up to 12 h.

Diamorphine or other more lipid-soluble opioids, such as fentanyl, may be used.

Adverse reactions

Excessive absorption causes paraesthesiae (face and tongue), anxiety, tremors and even convulsions. The latter are very dangerous, are followed by respiratory depression, and may require diazepam or thiopental for control. Cardiovascular collapse and respiratory failure occur with higher plasma concentrations of the local anaesthetic; the cause is direct myocardial depression compounded by hypoxia associated with convulsions. Cardiopulmonary resuscitation must be started immediately. Intravenous lipid may improve resuscitation success after cardiac arrest caused by local anaesthetics.

Anaphylactoid reactions are very rare with amide local anaesthetics and some of those reported have been due to preservatives. Most reported reactions to amide local anaesthetics are due to co-administration of adrenaline/epinephrine, intravascular injection or psychological effects (vasovagal episodes). Reactions with ester local anaesthetics are more common.

Individual local anaesthetics

See Table 19.1.

Table 19.1 Licensed doses for three widely used amide local anaesthetics

Amides

Lidocaine

is a first choice drug for surface use as well as for injection, combining efficacy with comparative lack of toxicity; the t_½ is 1.5 h. It is also useful in cardiac arrhythmias although it has been largely replaced by amiodarone for this purpose.

Prilocaine

Bupivacaine

is long acting (t_½ 3 h) (see Table 19.1) and is used for peripheral nerve blocks, and for epidural and spinal anaesthesia. Although onset of effect is comparable to that of lidocaine, peak effect occurs later (30 min).

Levobupivacaine

is the S-enantiomer of racemic bupivacaine. The relative therapeutic ratio (levobupivacaine:racemic bupivacaine) for CNS toxicity is 1.03, indicating that levobupivacaine is marginally less toxic.

Ropivacaine

may provide better separation of motor and sensory nerve blockade; effective sensory blockade can be achieved without causing motor weakness (although this fact is controversial). The rate of onset of ropivacaine is similar to that of bupivacaine, but its absolute potency and duration of effect are slightly lower. The indications for ropivacaine are similar to those of bupivacaine.

Esters

Cocaine

(alkaloid) is used medicinally solely as a surface anaesthetic (for abuse toxicity, see p. 157) usually as a 4% solution, because adverse effects are both common and dangerous when it is injected. Even as a surface anaesthetic, sufficient absorption may take place to cause serious adverse effects and cases continue to be reported; only specialists should use it and the dose must be checked and restricted.

Cocaine prevents the uptake of catecholamines (adrenaline/epinephrine, noradrenaline/norepinephrine) into sympathetic nerve endings, thus increasing their concentration at receptor sites, so that cocaine has a built-in vasoconstrictor action, which is why it retains a (declining) place as a surface anaesthetic for surgery involving mucous membranes, e.g. nose. Other local anaesthetics do not have this action; indeed, most are vasodilators and added adrenaline/epinepehrine is not so efficient.

Obstetric analgesia and anaesthesia

Although this soon ceased to be considered immoral on religious grounds, it has been a technically controversial topic since 1853 when it was announced that Queen Victoria had inhaled chloroform during the birth of her eighth child. The Lancet recorded ‘intense astonishment … throughout the profession’ at this use of chloroform, ‘an agent which has unquestionably caused instantaneous death in a considerable number of cases’. But the Queen (perhaps ignorant of these risks) took a different view, writing in her private journal of ‘that blessed chloroform’ and adding that ‘the effect was soothing, quieting and delightful beyond measure’.¹¹

The ideal drug must relieve labour pain without making the patient confused or uncooperative. It must not interfere with uterine activity nor must it influence the fetus, e.g. to cause respiratory depression by a direct action, by prolonging labour or by reducing uterine blood supply. It should also be suitable for use by a midwife without supervision.

Pethidine

is used widely. There is little difference between the effects of equipotent doses of morphine and pethidine on analgesia, respiratory depression, and nausea and vomiting. All opioids have the potential to cause respiratory depression of the newborn but this can be reversed with naloxone if necessary. The popular choice of pethidine for analgesia during labour in the UK is not because of any clear pharmacological advantage, but because it remains the only opioid licensed for use by midwives.

Nitrous oxide and oxygen

(50% of each: Entonox) may be administered for each contraction from a machine the patient works herself or supervised by a midwife (about 10 good breaths are needed for maximal analgesia).

Epidural

local anaesthesia provides the most effective pain relief, but the technique should be undertaken only after adequate training. In the UK, only anaesthetists insert epidural anaesthetics.

Spinal anaesthesia

is now used much more commonly than epidural anaesthesia for Caesarean section. The vast majority of caesarean sections are now undertaken with regional rather than general anaesthesia.

General anaesthesia

during labour presents special problems. Gastric regurgitation and aspiration are a particular risk (see p. 296). The safety of the fetus must be considered; all anaesthetics and analgesics in general use cross the placenta in varying amounts and, apart from respiratory depression, produce no important effects except that high doses interfere with uterine contraction and may be followed by uterine haemorrhage. Neuromuscular blocking agents can be used safely.

Anaesthesia in patients already taking medication

Anaesthetists are in an unenviable position. They are expected to provide safe service to patients in any condition, taking any drugs. Sometimes there is opportunity to modify drug therapy before surgery, but often there is not. Anaesthetists require a particularly detailed drug history from the patient.

Drugs that affect anaesthesia

Adrenal steroids

Chronic corticosteroid therapy with the equivalent of prednisolone 10 mg daily within the previous 3 months suppresses the hypothalamic–pituitary–adrenal (HPA) system. Without corticosteroid supplementation perioperatively the patient may fail to respond appropriately to the stress of surgery and become hypotensive (see Ch. 35).

Antibiotics

Aminoglycosides, e.g. neomycin, gentamicin, potentiate neuromuscular blocking drugs.

Anticholinesterases

can potentiate suxamethonium.

Antiepilepsy drugs

Continued medication is essential to avoid status epilepticus. Drugs must be given parenterally (e.g. phenytoin, sodium valproate) or rectally (e.g. carbamazepine) until the patient can absorb enterally.

Antihypertensives

of all kinds; hypotension may complicate anaesthesia, but it is best to continue therapy. Hypertensive patients are particularly liable to excessive increase in blood pressure and heart rate during intubation, which can be dangerous if there is ischaemic heart disease. After surgery, parenteral therapy may be needed for a time.

β-Adrenoceptor blocking drugs

can prevent the homeostatic sympathetic cardiac response to cardiac depressant anaesthetics and to blood loss.

Diuretics

Hypokalaemia, if present, will potentiate neuromuscular blocking agents and perhaps general anaesthetics.

Oral contraceptives

containing oestrogen, and post-menopausal hormone replacement therapy predispose to thromboembolism (see p. 621).

Psychotropic drugs

Neuroleptics potentiate or synergise with opioids, hypnotics and general anaesthetics.

Antidepressants

Monoamine oxidase inhibitors can cause hypertension when combined with certain amines, e.g. pethidine, or indirectly acting sympathomimetics, e.g. ephedrine. Tricyclics potentiate catecholamines and some other adrenergic drugs.

Anaesthesia in the diseased, and in particular patient groups

The normal response to anaesthesia may be greatly modified by disease. Some of the more important aspects include:

Respiratory disease and smoking

predispose the patient to postoperative pulmonary complications, principally infective. The site of operation, e.g. upper abdomen, chest, and the severity of pain influence the impairment to ventilation and coughing.

Cardiac disease

The aim is to avoid the circulatory stress (with increased cardiac work, which can compromise the myocardial oxygen supply) caused by hypertension and tachycardia. Intravenous drugs are normally given slowly to reduce the risk of overdosage and hypotension.

Patients with fixed cardiac output, e.g. with aortic stenosis or constrictive pericarditis, are at special risk from reduced cardiac output with drugs that depress the myocardium and vasomotor centre, for they cannot compensate. Induction with propofol or thiopental is particularly liable to cause hypotension in these patients. Hypoxia is obviously harmful. Skilled technique rather than choice of drugs on pharmacological grounds is the important factor.

Hepatic or renal disease

is generally liable to increase drug effects and should be taken into account when selecting drugs and their doses.

Malignant hyperthermia

(MH) is a rare pharmacogenetic syndrome with an incidence of between 1 in 15 000 and 1 in 150 000 in North America, exhibiting autosomal dominant inheritance with variable penetrance. The condition occurs during or immediately after anaesthesia and may be precipitated by potent inhalation agents (halothane, isoflurane, sevoflurane) or suxamethonium. The patient may have experienced an uncomplicated general anaesthetic previously. The mechanism involves an abnormally increased release of calcium from the sarcoplasmic reticulum, often caused by an inherited mutation in the gene for the ryanodine receptor, which resides in the sarcoplasmic reticulum membrane. High calcium concentrations stimulate muscle contraction, rhabdomyolysis and a hypermetabolic state. Malignant hyperthermia is a life-threatening medical emergency. Oxygen consumption increases by up to three times the normal value, and body temperature may increase as fast as 1°C every 5 min, reaching as high as 43°C. Rigidity of voluntary muscles may not be evident at the outset or in mild cases.

Dantrolene 1 mg/kg i.v. is given immediately. Further doses are given at 10-min intervals until the patient responds, to a cumulative maximum dose of 10 mg/kg. Dantrolene (t_½ 9 h) probably acts by preventing the release of calcium from the sarcoplasm store that ordinarily follows depolarisation of the muscle membrane.

Non-specific treatment is needed for the hyperthermia (cooling, oxygen), and insulin and dextrose are given for hyperkalaemia caused by potassium release from contracted muscle. Hyperkalaemia and acidosis may trigger severe cardiac arrhythmias.

Once the immediate crisis has resolved, the patient and all immediate relatives should undergo investigation for MH. This involves a muscle biopsy, which is tested for sensitivity to triggering agents.

Anaesthesia in MH-susceptible patients is achieved safely with total intravenous anaesthesia using propofol and opioids. Dantrolene for intravenous use must be available immediately in every location where general anaesthesia is given. The relation of malignant hyperthermia syndrome with neuroleptic malignant syndrome (for which dantrolene may be used as adjunctive treatment, see p. 328) is uncertain.

Muscle diseases

Patients with myasthenia gravis are very sensitive to (intolerant of) competitive, but not to depolarising, neuromuscular blocking drugs.

Those with myotonic dystrophy may recover less rapidly than normal from central respiratory depression and neuromuscular block; they may fail to relax with suxamethonium.

Sickle cell disease

Hypoxia and dehydration can precipitate a crisis.

Atypical (deficient) pseudocholinesterase

There is delay in the metabolism of suxamethonium and mivacurium. The duration of neuromuscular block depends on the level of pseudocholinesterase activity.

Raised intracranial pressure

will be made worse by high expired concentration inhalation agents, by hypoxia or hypercapnia, and in response to intubation if anaesthesia is inadequate. Without support from a mechanical ventilator, excessive doses of opioids will cause hypercapnia and increase intracranial pressure.

The elderly

(see p. 105) are liable to become confused by cerebral depressants, especially by hyoscine. Atropine also crosses the blood–brain barrier and can cause confusion in the elderly; glycopyrronium is preferable. In general, elderly patients require smaller doses of all drugs than the young. The elderly tolerate hypotension poorly; they are prone to cerebral and coronary ischaemia.