Maintenance of anaesthesia involves constant vigilance of the patient's state of hypnosis, analgesia and paralysis, as well as attention to the condition of the airway, ventilation and cardiovascular system. Although no absolute monitor of depth of anaesthesia exists, several attempts have been made to provide some indication. One such monitor is bis-pectral index (BIS) monitoring, which is a mathematical interpretation of electroencephalogram (EEG) patterns to give a number between 0 and 100. The lower numbers refer to anaesthetised patients and higher numbers are in awake patients.
Anaesthesia is maintained either by inhalational agents or by i.v. anaesthetic agents. The former is by far the commonest.
With continuous administration of anaesthetic drugs, a steady-state is reached where the partial pressures of anaesthetic in the breathing system, alveoli and brain are directly related. This occurs after about 20-30 min, depending mostly on the agent, breathing system and patient haemodynamics.
Clinical observation of sympathetic activity, pupil size, lacrimation and perspiration remains the commonest method of assessing anaesthetic depth. These signs may, however, be masked by many drugs and diseases. Therefore, it is customary to administer anaesthetic agents at concentrations known to provide unawareness, titrated according to individual response. Together with the use of nitrous oxide and allowing for premedication, induction agents and opioid analgesics, a properly conducted anaesthetic following these principles should produce hypnosis (see below).
The advantages of inhalational anaesthesia are that it is simple to administer and its extensive use over many decades has resulted in increased safety and efficacy. It has certain disadvantages:
• wash-in, wash-out times are relatively slow and there is some residual drowsiness;
• all inhalational agents are cardiorespiratory depressants.
This consists of the infusion of an i.v. anaesthetic agent, almost exclusively propofol. It can be commenced on or shortly after induction. Pharmacokinetic and pharmacological evidence has contributed to the development of safe infusion regimens. These vary depending on clinical observation and whether propofol is supplemented by other drugs. A common combination is propofol and remifentanil infusions in a Total Intravenous Anaesthetic (TIVA) technique.
The i.v. anaesthesia is smooth, stable, probably requires less muscle relaxation and provides a speedy recovery, perhaps with less residual drowsiness. It necessitates constant attention to the i.v. infusion site. There is greater interindividual variation in dose requirements than for inhalational anaesthesia.
It is difficult to separate anaesthesia from analgesia and most anaesthetists are cautious in this respect.
The i.v. opioids are the agents of choice. They are given on induction and during anaesthesia, depending on their pharmacokinetic properties and the patient's renal, hepatic and cardiovascular function. Other methods of analgesia include nitrous oxide, non-steroidal anti-inflammatory drugs (NSAIDs) and nerve blocks with local anaesthetics and/or opioids.
There are three groups of indications for neuromuscular paralysis:
1. intubation (usually) of the trachea (see above);
2. relaxation to facilitate positive pressure ventilation;
3. provision of ideal conditions for surgery, usually, for major abdominal, cardiothoracic and neurosurgical procedures.
Great interindividual variations make it difficult to predict how much muscle paralysis individual patients will need and the dose of muscle relaxant required to achieve this. In practice, it is customary to aim for the minimum paralysis which is clinically satisfactory and to monitor the neuro-muscular block with a nerve stimulator. The disadvantages of neuromuscular paralysis are:
• hypoxaemia due to failure to secure the airway;
• disconnection from the breathing system;
• unrecognised awareness;
• side-effects of neuromuscular blocking drugs.
Pharmacology of anaesthetic agents
Modern inhalational drugs are fluorinated hydrocarbons. Most are liquids at room temperature. Due to their high-saturated vapour pressure a significant proportion of the liquid is in the vapour or 'volatile' phase. Their lipid solubility, which is directly related to potency, is high. Their blood solubility is relatively low, and this is an advantage; see below.
Potency of anaesthetic agents is gauged by the minimum alveolar concentration (MAC). This is defined as the alveolar anaesthetic concentration that abolishes reflex response to a standard skin incision in 50% of subjects. MAC is expressed as a percentage of volume concentrations at atmospheric pressure in healthy adults not receiving other drugs. MAC is additive. About 1.5 MAC abolishes response in 95% of the population. At about 0.4 MAC amnesia ensues; awakening occurs at around 0.6 MAC. Many factors such as temperature, premedication, nitrous oxide and age influence MAC. MAC is a theoretical concept but useful in that it is intuitive and measurable.
Anaesthesia is directly related to partial pressure of anaesthetic drug in the brain. Blood acts as an inactive reservoir between the lung and brain. The greater the solubility in blood, the greater the amount required to generate a given partial pressure; this means the time to reach equilibrium (partial pressure alveolus-partial pressure blood-partial pressure brain) is greater and therefore that induction and recovery are slower. Inhalational anaesthetics are metabolised by the liver to a variable extent, but mostly eliminated unchanged by the lungs.
To different degrees the inhalational agents depress heart rate and contractility, dilate vascular smooth muscle, lower arterial blood pressure, and may alter the conduction system. Their effects on the respiratory system vary with the individual agent; in general their effects are bronchodilatation, airway irritability which may precipitate bronchospasm, and respiratory depression.
Although all modern volatile agents have similar characteristics, some differential features may occasionally prove clinically significant and are briefly discussed below.
It is the classical fluorocarbon, in clinical use since the mid 1950's. It can cause depression of the sino-atrial node, leading to atrial or nodal bradycardias and ventricular ectopics. It is a potent depressant of myocardial contractility. Halothane provides a smooth induction of anaesthesia with little airway irritation, and is still preferred by many anaesthetists for inhalational induction in the difficult paediatric airway. Very rarely, its oxidative metabolites can induce immune mediated hepatic necrosis, which has dramatically curtailed its use. It is now rarely used in the UK.
It is probably the strongest depressant of cardiac output and of blood pressure. Prolonged administration of high concentrations yields fluoride metabolites potentially associated with renal tubular dysfunction. At high doses it can produce epileptiform-like EEG paroxysms. Most anaesthetists do not use enflurane in the presence of renal failure or epilepsy.
It has less myocardial depressant than halothane or enflu-rane. It is a potent vasodilator and has been implicated in steal of blood from diseased rigid coronary arteries to more healthy ones. It is the agent of choice in neuroanaesthesia, as it is associated with least increases in cerebral blood flow and intracranial pressure. It is rather pungent and irritant to the airway; this makes inhalational induction more difficult and prone to laryngeal spasm.
Introduced into clinical practice over the last few years, it has the lowest blood solubility (0.4), and therefore the shortest equilibrium time. Its boiling point is 23.5°C, so near to room temperature that it requires a special vaporiser. It resembles isoflurane in its clinical performance.
It is also relatively new and almost as short acting as desflu-rane. It is not irritable to the airway, and is becoming an agent of choice for induction of anaesthesia in children.
Nitrous oxide (N2O; MAC = 104)
Together with ether it is the oldest anaesthetic agent, dating back at least to 1846. Unlike the others it is a gas at room temperature (boiling point -88°C). Nitrous oxide is very insoluble in blood (0.47) and its equilibrium time is very short. It is a weak anaesthetic but a good analgesic and is therefore used as an adjuvant to the inhalational vapours in concentrations of up to 70% in oxygen.
Although relatively insoluble, nitrous oxide is nevertheless much more soluble than nitrogen. This is an advantage on induction as it diffuses out of the alveoli faster than nitrogen diffuses in, and increases the alveolar concentration of the remaining substances, oxygen and the volatile drug. During recovery, nitrous oxide diffuses into the alveoli quicker than nitrogen, causing a reduction in alveolar oxygen. This effect is known as diffusion hypoxia. A similar mechanism is responsible for its preferential diffusion into closed spaces such as the middle ear, pneumothorax, gut lumen, etc. In some circumstances, nitrous oxide is a potent cardiovascular depressant. Prolonged exposure may have deleterious effect on the metabolism of vitamin B12 and folic acid.
Intravenous anaesthetic drugs
Thiopentone is a sulphur containing barbiturate administered at a concentration of 25 mg/ml. It is the most widely used induction agent in the world. It is highly lipid soluble and protein bound. It is smooth and predictable, inducing unconsciousness within 30-45 s. Awakening occurs after some 3-5 min due to redistribution from the brain to the skeletal muscle. It is metabolised mainly in the liver at a rate proportional to the dose administered. Its elimination halflife is around 11.5 h; after 24 h, some 30% of the dose still remains in the body. The induction dose is 2-6mg/kg i.v. over 20-40 s and it is important to administer the drug slowly to avoid overshooting.
Thiopentone decreases the rate of GABA breakdown, leading to neuronal hyperpolarisation. It produces unconsciousness and inhibition of the reticular activating system and is a potent anticonvulsant. Thiopentone significantly depresses myocardial contractility; it also produces moderate vasodilatation. There is a baroreceptor mediated reflex tachycardia which is not sufficient to prevent an important reduction in arterial blood pressure. In those with cardiovascular compromise, even if only mild hypovolaemia, the fall in blood pressure may be profound and can induce cardiac arrest. Thiopentone produces apnoea and can induce laryngeal spasm, especially with early and abrupt manipulation of the airway. Recovery is normally associated with a hangover effect as a consequence of its lipid affinity and slow elimination.
Thiopentone can produce tissue necrosis if injected into subcutaneous tissue and arterial vasoconstriction leading to ischaemia if injected into an artery. For these reasons it is important, while injecting the drug slowly, to check for pain.
Contraindications to thiopentone include contraindications of i.v. induction in general, such as upper airway obstruction, and more specific ones, namely porphyria and known anaphylaxis.
Propofol is a phenol derivative which comes in a white aqueous solution of egg phosphatide and soyabean oil, at a concentration of 20 mg/ml. It has gained enormous popularity since its introduction into clinical practice in the mid to late 1980's. Propofol has a higher lipid solubility, protein binding, and a larger volume of distribution than thiopentone. Metabolism is hepatic and probably also extrahepatic. Propofol produces a speedy recovery with less drowsiness. There is less accumulation of propofol after large doses or i.v. infusions, as its elimination remains relatively constant.
For induction of anaesthesia the dose of propofol is 1 to 3.5 mg/kg, administered slowly and titrated to response, but there seems to be considerable interindividual variation. For infusion as the primary anaesthetic the dose, after initial loading, is 6-9mg/kgh. For sedation the recommended dose is 2-6 mg/kg h.
In addition to loss of consciousness, propofol produces amnesia, and has some antiemetic effect. Its effects on the cardiovascular system consist of a marked fall in peripheral resistance and a variable reduction in cardiac output; often propofol is associated with a bradycardia, particularly in young healthy patients who have been premedicated. Together these effects probably produce a greater fall in blood pressure than thiopentone. Apnoea ensues very rapidly after administration and at widely varying doses; readily available equipment for oxygenation is essential even if only 'sedation' is intended. Propofol produces greater depression of the laryngeal reflexes, making laryngeal spasm less likely.
Propofol, especially when injected rapidly into a small vein, frequently produces pain on injection. Propofol is safe in malignant hyperpyrexia and porphyria. There have been reports of epileptiform activity associated with its use in susceptible individuals and it is recommended that extreme care be exercised if it is to be administered in epileptic patients.
Etomidate is a carboxylated imidazole. It is less cardio-depressant than other agents, but not innocuous, and is associated with less histamine release. Many anaesthetists prefer it for induction of anaesthesia in cardiovascularly compromised patients and severe asthmatics.
Even one dose produces inhibition of the 11b and 17a hydroxylase enzymes involved in cortisol synthesis. It often produces excitatory type movements on induction. Etomidate has been associated with epileptiform EEG activity. It may be painful on injection and has a relatively high incidence of thrombophlebitis.
Some of the more important locations of opioid receptors are the periaqueductal matter of the brainstem, hypothalamus, and substantia gelatinosa of the spinal cord. When stimulated they inhibit adenylate cyclase, which leads to hyperpolarisation of cell membranes and reduction in electrical discharge; this interferes with the release of Substance P and other pain mediators.
The effects of opioids on the central nervous system range, with progressively higher doses, from slight alteration of mood to deep unconsciousness. It must be emphasised that at ordinary clinical doses opioids act as supplements to anaesthesia, and if used on their own or with insufficient anaesthetic agent may be associated with awareness. Some important side-effects include miosis, increased smooth muscle tone (intestinal and sphincter of Oddi spasm), urinary retention and pruritus.
A naturally occurring alkaloid, it is the standard opioid. It can be administered orally, i.m., i.v., subcutaneously, and also by the neuraxial (epidural, etc.) route. The i.v. dose is 0.1-0.2 mg/kg. It can be associated with histamine release and should probably be avoided in asthma.
Papaveretum contains a mixture of morphine, thebaine and papaverine. Until recently it contained noscapine, which was eliminated because of potential teratogenic effects in animals. It causes more sedation and less smooth muscle spasm.
A synthetic phenoperidine derivative of morphine, it is some 100 times more potent. Its short onset and redistribution times give it rapid onset and recovery after a single administration. Because of its high-lipid solubility, high doses or multiple administrations lead to accumulation in the lipid tissue, which acts as a reservoir; its action can be prolonged.
Fentanyl, even at high doses, has little effect on the cardiovascular system (small reduction in heart rate and blood pressure) and is considered an ideal drug for anaesthesia in those with cardiovascular compromise. The dose varies from 1 to 100 mg/kg. The higher doses ablate the stress response associated with surgery but do not guarantee abolition of awareness, and necessitate prolonged ventilation and observation.
This is a synthetic derivative of fentanyl about 10-20 times more potent than morphine. It has a very rapid onset of action (1-2 min) despite less lipid solubility, as most of the compound is non-ionised. Its half-life and therefore recovery time is short; because of a relatively small volume of distribution, it shows less accumulation and hangover effect after large doses or i.v. infusions. Alfentanil has a more pronounced cardiodepressant effect than fentanyl. It is a potent emetic.
A short acting, quick offset, synthetic opioid, used as an infusion typically at 0.01-0.03 ^g/kgmin as a sedative or to supplement anaesthesia. It has a 3-5 min half-life so does not accumulate, and facilitates rapid awakening. Supplementary analgesia is required if pain is expected once the remi-fentanil infusion is stopped.
Neuromuscular blocking drugs
Suxamethonium (Succinylcholine) is a synthetic compound which depolarises the neuromuscular junction by mimicking the action of acetylcholine, the cholinergic transmitter; while the membrane remains depolarised muscle contraction cannot occur. The effect of suxamethonium ensues within 30-60 s of its administration and normally lasts a few minutes, until it is metabolised by plasma cholinesterase. Deficiencies in this enzyme cause suxamethonium apnoea.
Suxamethonium reliably provides the fastest and best conditions for intubation. The dose is 1-1.5 mg/kg after loss of consciousness. It is the drug of choice for emergency intubations. Some anaesthetists use it for difficult intubations in which ventilating the lungs is not likely to present a risk, as its rapid elimination facilitates the prompt return of breathing if intubation fails.
Suxamethonium has many side-effects. Hyperkaelemia, caused by the potent depolarisation, can be severe in extensive muscle damage, burns, peripheral neuropathy and paraplegia. Muscarinic stimulation can cause bradycardia. Fasciculations are thought to cause muscle pain. Anaphylactic or anaphylactoid reactions are more frequent than with other muscle relaxants and can be severe. Although it has traditionally been considered a trigger of malignant hyper-pyrexia, there is now some doubt regarding this point. Nevertheless, anaesthetists avoid suxamethonium in susceptible patients.
These agents bind reversibly to cholinergic receptors and prevent acetylcholine from activating them. Their onset time is 2-3 min. Their action is terminated by metabolism. The intricacies of neuromuscular pharmacology are outside the scope of this book.
The cholinergic block may also extend into other areas of the autonomic system. The differences between available drugs are due to their metabolism and degree of extranicotinic effects.
Pancuronium is an aminosteroid of moderate (1-2 h) duration; its sympathomimetic effect can cause tachycardia and a slight rise in cardiac output and blood pressure. It should be avoided in renal failure as it is partially excreted by the kidney.
Vecuronium is chemically very similar to pancuronium, but devoid of cardiovascular effect; it is shorter acting, and metabolised by the liver.
Atracurium has a time of onset and duration of action is similar to vecuronium. It may, however, release histamine.
It is degraded by a process which is independent of liver and kidney function. Atracurium is the most suitable for i.v. infusion as it is subject to little accumulation.
Rocuronium is another steroid based compound. It was initially developed to be used in place of suxamethonium. Although faster in onset than other non-depolarising muscle relaxants (90 s), it still falls short of suxamethonium. It lasts longer than atracurium and vecuronium.
Perioperative fluid management
Guidelines for perioperative fluid administration (Table 2.10)
In principle, administration of fluids should be guided by estimations of existing deficits, maintenance requirements and ongoing losses:
1. Deficit: The usual preoperative starvation period (8h) is likely to account for a water deficit of 800-1000 ml. This can be replaced by the appropriate volume of a crystalloid solution. Patients with gastrointestinal losses, for example, from fistulae or diarrhoea, are likely to have additional salt and potassium deficits.
2. Maintenance: The maintenance requirements can be met with an infusion of 50-150 ml/h of salt-containing solution.
3. Losses: Healthy adults have a circulating blood volume (CBV) of about 80 ml/kg or 4500-5000 ml. Blood losses beyond 15% of the CBV are normally replaced with blood. Increasingly, blood conservation methods are employed, such as cell salvage, in order to reduce the amount of donated blood used. Losses of less than this are normally replaced with equal volumes of colloid solutions. Alternatively, about triple volumes of crystalloid can be given, as these are distributed throughout the extracellular space, which is roughly three times greater in volume. Additional amounts of protein-rich fluid within the site of surgical trauma are sequestered from the extracellular space and lost into a metabolically inactive 'third space'. This fluid loss is variable but can be replaced by crystalloid or colloid solutions at rates of 1-10 ml/kg h.
Table 2.10. Contents of common crystalloid solutions.
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