Physical Properties

Isoflurane is a colourless, volatile liquid with a slightly pungent odour. It is stable and does not react with metal or other substances. It does not require preservatives. Isoflurane is non-flammable in clinical concentrations. The MAC of isoflurane is 1.15% in oxygen and 0.56% in 70% nitrous oxide.

Uptake and Distribution

Isoflurane has a low blood/gas solubility of 1.4 and thus alveolar concentrations equilibrate fairly rapidly with inspired concentrations. The alveolar (or arterial) partial pressure of isoflurane increases to 50% of the inspired partial pressure within 4–8 min, and to 60% by 15 min (Fig. 2.2). However, the rate of induction is limited by the pungency of the vapour and in clinical practice may be no faster than that achieved with halothane. The incidence of coughing or breath-holding on induction is significantly greater with isoflurane than with halothane. It is not an ideal agent to use for inhalational induction. The rate of recovery is slower than that associated with desflurane or sevoflurane, but more rapid than after administration of halothane (Fig. 2.3).

Metabolism

Approximately 0.17% of the absorbed dose is metabolized. Metabolism takes place predominantly in the form of oxidation to produce difluoromethanol and trifluoroacetic acid; the former breaks down to formic acid and fluoride. Because of the minimal metabolism, only very small concentrations of serum fluoride ions are found, even after prolonged administration. The minimal metabolism renders hepatic and renal toxicity most unlikely.

Respiratory System

In common with other modern volatile agents, it causes dose-dependent depression of ventilation (Fig. 2.4); there is a decrease in tidal volume but an increase in ventilatory rate in the absence of opioid drugs. Isoflurane causes some respiratory irritation. This makes inhalational induction with isoflurane difficult.

Cardiovascular System

In vitro, isoflurane is a myocardial depressant, but in clinical use there is less depression of cardiac output than with halothane or enflurane (Fig. 2.5). Systemic hypotension occurs predominantly as a result of a reduction in systemic vascular resistance (Figs 2.6, 2.7). Arrhythmias are uncommon and there is little sensitization of the myocardium to catecholamines (Fig. 2.8).

In addition to dilating systemic arterioles, isoflurane causes coronary vasodilatation. In the past there has been some controversy regarding the safety of isoflurane in patients with coronary artery disease because of the possibility that the coronary steal syndrome may be induced; dilatation in normal coronary arteries offers a low resistance to flow and may reduce perfusion through stenosed neighbouring vessels. It has been shown that isoflurane affects small arterioles (which makes coronary steal a theoretical possibility), but this does not appear to be of any clinical significance. Production of myocardial ischaemia in clinical practice may be a result of many factors in addition to coronary vasodilatation, including tachycardia, hypotension, increase in left ventricular end-diastolic pressure and reduced ventricular compliance. Attention should be directed to these factors before a diagnosis of isoflurane- induced coronary steal is considered.

Uterus

Isoflurane has an effect on the pregnant uterus similar to that of halothane.

Central Nervous System

Low concentrations of isoflurane do not cause any change in cerebral blood flow at normocapnia. In this respect, the drug is superior to halothane, which causes cerebral vasodilatation. However, higher inspired concentrations of isoflurane cause vasodilatation and increase cerebral blood flow. It does not cause seizure activity on the EEG.

Muscle Relaxation

Isoflurane causes dose-dependent depression of neuromuscular transmission with potentiation of non-depolarizing neuromuscular blocking drugs.

In summary, the advantages of isoflurane are:

Its disadvantage is:

Physical Properties

It is a colourless agent, which is stored in amber-coloured bottles without preservative. It is not broken down by soda lime, light or metals. It is non-flammable.

Desflurane has a boiling point of 23.5 °C and a vapour pressure of 88.5 kPa (664 mmHg) at 20 °C and therefore it cannot be used in a standard vaporizer. A special vaporizer (the TEC-6) has been developed which requires a source of electric power to heat and pressurize it.

The MAC of desflurane is approximately 6% in oxygen (3% in 60% nitrous oxide). As with all volatile agents, its MAC is higher in children (9–10% in the neonate in oxygen, 7% in 60% nitrous oxide).

It has an ethereal and pungent odour.

Uptake and Distribution

Desflurane has a blood/gas partition coefficient of 0.42, almost the same as that of nitrous oxide. The rate of equilibration of alveolar with inspired concentrations of desflurane is virtually identical to that for nitrous oxide (Fig. 2.2). Induction of anaesthesia is therefore extremely rapid in theory but limited somewhat by its pungent nature. However, it is possible to alter the depth of anaesthesia very rapidly and the rate of recovery of anaesthesia is faster than that following any other volatile anaesthetic agent (Fig. 2.3).

Metabolism

There is very little defluorination of desflurane, and after prolonged anaesthesia there is only a very small increase in serum and urine trifluoroacetic acid concentrations. Approximately 0.02% of inhaled desflurane is metabolized in the body.

Respiratory System

Desflurane causes respiratory depression to a degree similar to that of isoflurane up to a MAC of 1.5. It increases PaCO₂ (Fig. 2.4) and decreases the ventilatory response to imposed increases in PaCO₂. It is irritant to the upper respiratory tract, particularly at concentrations greater than 6%. It is therefore not recommended for gaseous induction of anaesthesia because it causes coughing, breath-holding and laryngospasm.

Cardiovascular Effects

Desflurane appears to have two distinct actions on the cardiovascular system. Firstly, its main actions are those which are similar to isoflurane: dose-related decreases in systemic vascular resistance, myocardial contractility and mean arterial pressure (Figs 2.5–2.7). Heart rate is unchanged at lower steady-state concentrations, but increases with higher concentrations (Fig. 2.9). Addition of nitrous oxide maintains heart rate unchanged. Cardiac output tends to be maintained as with isoflurane. The second cardiovascular action occurs when its inspired concentration is increased rapidly to greater than 1 MAC. In the absence of premedicant drugs, this increases sympathetic activity, leading to increased heart rate and arterial pressure. Experimental studies in animals have not detected a coronary steal phenomenon. Desflurane, in common with isoflurane and sevoflurane, does not sensitize the myocardium to catecholamines (Fig. 2.8).

Central Nervous System

The effects of desflurane are similar to those of isoflurane. It depresses the EEG in a dose-related manner. It does not cause seizure activity at any level of anaesthesia, with or without hypocapnia. Desflurane decreases cerebrovascular resistance and increases intracranial pressure in a dose-related manner. In dogs, it increases cerebral blood flow at deep levels of anaesthesia if systemic arterial pressure is maintained.

Musculoskeletal System

Desflurane causes muscle relaxation in a dose-related manner. Concentrations exceeding 1 MAC produce fade in response to tetanic stimulation of the ulnar nerve. It enhances the effect of muscle relaxants. Studies in susceptible swine indicate that desflurane may trigger malignant hyperthermia.

Therefore, in summary, desflurane offers some advantages over other agents:

However, it has some significant drawbacks:

Physical Properties

It is non-flammable and has a pleasant smell. The blood/gas partition coefficient of sevoflurane is 0.69, which is about half that of isoflurane (1.43) and closer to those of desflurane (0.42) and nitrous oxide (0.44). The MAC value of sevoflurane in adults is between 1.7 and 2% in oxygen and 0.66% in 60% nitrous oxide. The MAC, in common with other volatile agents, is higher in children (2.6% in oxygen and 2.0% in nitrous oxide) and neonates (3.3%) and it is reduced in the elderly (1.48%). It is stable and is stored in amber-coloured bottles. In the presence of water, it undergoes some hydrolysis and this reaction also occurs with soda lime.

Uptake and Distribution

Sevoflurane has a low blood/gas partition coefficient and therefore the rate of equilibration between alveolar and inspired concentrations is faster than that for halothane or isoflurane but slower than that for desflurane (Fig. 2.2). It is non-irritant to the upper respiratory tract and therefore the rate of induction of anaesthesia should be faster than that with any of the other agents.

Because of its higher partition coefficients in vessel-rich tissues, muscle and fat than corresponding values for desflurane, the rate of recovery is slower than that after desflurane anaesthesia (Fig. 2.3).

Metabolism

Approximately 5% of the absorbed dose is metabolized in the liver to two main metabolites. The major breakdown product is hexafluoroisopropanol, an organic fluoride molecule which is excreted in the urine as a glucuronide conjugate. Although this molecule is potentially hepatotoxic, conjugation of hexafluoroisopropanol occurs so rapidly that clinically significant liver damage seems theoretically impossible. The second breakdown product is inorganic fluoride ion. The mean peak fluoride ion concentration after 60 min of anaesthesia at 1 MAC is 22 μmol L^–1, which is significantly higher than that after an equivalent dose of isoflurane. The metabolism of sevoflurane is catalysed by the 2E1 isoform of cytochrome P450 which may be induced by phenobarbital, isoniazid and ethanol and inhibited by disulfiram.

Respiratory System

The drug is non-irritant to the upper respiratory tract. It produces dose-dependent ventilatory depression, reduces respiratory drive in response to hypoxaemia and increases carbon dioxide partial pressure to a similar degree to other volatile agents (Fig. 2.4). The ventilatory depression associated with sevoflurane may result from a combination of central depression of medullary respiratory neurones and depression of diaphragmatic function and contractility. It relaxes bronchial smooth muscle but not as effectively as halothane.

Cardiovascular System

The properties of sevoflurane are similar to those of isoflurane, with slightly smaller effects on heart rate (Fig. 2.9) and less coronary vasodilatation. It decreases arterial pressure (Fig. 2.7) mainly by reducing peripheral vascular resistance (Fig. 2.6), but cardiac output is well maintained over the normal anaesthetic maintenance doses (Fig. 2.5). There is mild myocardial depression resulting from its effect on calcium channels. Sevoflurane does not differ from isoflurane in its sensitization of the myocardium to exogenous catecholamines (Fig. 2.8). It is a less potent coronary arteriolar dilator and does not appear to cause coronary steal. Sevoflurane is associated with a lower heart rate and therefore helps to reduce myocardial oxygen consumption.

Central Nervous System

CNS effects are similar to those of isoflurane and desflurane. Intracranial pressure increases at high inspired concentrations of sevoflurane but this effect is minimal over the 0.5–1.0 MAC range. It decreases cerebral vascular resistance and cerebral metabolic rate. It does not cause excitatory effects on the EEG.

Renal System

The peak concentration of inorganic fluoride after sevoflurane is similar to that after enflurane anaesthesia and there is a positive correlation between duration of exposure and the peak concentration of fluoride ions. Serum fluoride concentrations greater than 50 μmol L^–1 have been reported. However, renal toxicity following anaesthesia with sevoflurane does not appear to be related to inorganic fluoride concentrations as opposed to that associated with methoxyflurane. The apparent lack of renal toxicity with sevoflurane may be related to its rapid elimination from the body. This reduces the total amount of drug available for in vivo metabolism.

Renal blood flow is well preserved with sevoflurane.

Musculoskeletal System

Sevoflurane potentiates non-depolarizing muscle relaxants to a similar extent to isoflurane. Sevoflurane may trigger malignant hyperthermia in susceptible patients.

Obstetric Use

There are limited data on the use of sevoflurane in the obstetric population.

Interaction with Carbon Dioxide Absorbers

Sevoflurane is absorbed and degraded by both soda lime and Baralyme. When mixed with soda lime in artificial situations, five breakdown products are identified, which are termed compounds A, B, C, D and E. These products are thought to be toxic in rats, primarily causing renal, hepatic and cerebral damage. However, in clinical situations, it is mainly compound A and, to a lesser extent, compound B that are produced. The evidence suggests that the concentration of compound A produced is well below the level that is toxic to animals. The use of Baralyme is associated with production of higher concentrations of compound A and this may be related to the higher temperature which is attained when Baralyme is used. The presence of moisture reduces compound A formation. The concentration of compound A is highest during low-flow anaesthesia (< 2 L min^–1) and is reduced by increasing fresh gas flow rate. The toxicity of sevoflurane in combination with carbon dioxide absorbers is probably more a theoretical than a clinical problem.

In summary, sevoflurane is a newer inhalational anaesthetic agent which offers many advantages over other volatile agents. These are:

Its disadvantages are:

Uptake and Distribution

Halothane has a blood/gas solubility coefficient of 2.5, which is the highest of all the modern agents. It is not irritant to the airway and therefore inhalational induction with halothane is relatively fast compared with either desflurane or isoflurane. However, it may take at least 30 min for the alveolar inspired concentration to reach 50% of the inspired concentration (Fig. 2.2); this is slower than for the other agents. As with all the volatile agents, it is customary to use the technique of ‘over-pressure’ and induce halothane anaesthesia with concentrations two to three times higher than the MAC value; the inspired concentration is reduced when a stable level of anaesthesia has been achieved. The MAC of halothane in oxygen is approximately 1.1% in the neonate, 0.95% in the infant, 0.9% at 1–2 years, 0.75% at 40 years (0.29 in 70% nitrous oxide) and 0.65% at 80 years.

Recovery from halothane anaesthesia is slower than with the other agents because of its high blood/gas solubility, and recovery is prolonged with increasing duration of anaesthesia (Fig. 2.3).

Metabolism

Approximately 20% of halothane is metabolized in the liver, usually by oxidative pathways. The end products are excreted in the urine. The major metabolites are bromine, chlorine, trifluoroacetic acid and trifluoroacetylethanol amide.

A small proportion of halothane may undergo reductive metabolism, particularly in the presence of hypoxaemia and when the hepatic microsomal enzymes have been stimulated by enzyme-inducing agents such as phenobarbital. Reductive metabolism may result in the formation of reactive metabolites and fluoride, although normally serum fluoride ion concentrations are considerably lower than those likely to induce renal dysfunction.

Respiratory System

Halothane is non-irritant and pleasant to breathe during induction of anaesthesia. There is rapid loss of pharyngeal and laryngeal reflexes and inhibition of salivary and bronchial secretions. In the unpremedicated subject, halothane anaesthesia is associated with an increase in ventilatory rate and reduction in tidal volume. PaCO₂ increases as the depth of halothane anaesthesia increases (Fig. 2.4).

Halothane causes a dose-dependent decrease in mucociliary function, which may persist for several hours after anaesthesia. This may contribute to postoperative sputum retention.

Halothane antagonizes bronchospasm and reduces airway resistance in patients with bronchoconstriction, possibly by central inhibition of reflex bronchoconstriction and relaxation of bronchial smooth muscle. It has been suggested that halothane exerts a β-mimetic effect on bronchial muscle.

Cardiovascular System

Halothane is a potent depressant of myocardial contractility and myocardial metabolic activity as a result of inhibition of glucose uptake by myocardial cells. During controlled ventilation, halothane anaesthesia is associated with dose-related depression of cardiac output (by decrease in myocardial contractility) with little effect on peripheral resistance (Figs 2.5, 2.6). Thus, there is a reduction in arterial pressure (Fig. 2.7) and an increase in right atrial pressure. In spontaneously breathing patients, some of these effects may be offset by a small increase in PaCO₂ which leads to a reduction in systemic vascular resistance and a shift in cardiac output back towards baseline values as a result of indirect sympathoadrenal stimulation.

The hypotensive effect of halothane is augmented by a reduction in heart rate, which commonly accompanies halothane anaesthesia. Antagonism of the bradycardia by administration of atropine frequently leads to an increase in arterial pressure.

The reduction in myocardial contractility is associated with reductions in myocardial oxygen demand and coronary blood flow. Provided that undue elevations in left ventricular diastolic pressure and undue hypotension do not occur, halothane may be advantageous in patients with coronary artery disease because of the reduced oxygen demand caused by a low heart rate and decreased contractility.

The depressant effects of halothane on cardiac output are augmented in the presence of β-blockade.

Arrhythmias are very common during halothane anaesthesia and far more frequent than with any of the other agents. Arrhythmias are produced by:

During local infiltration with local anaesthetic solutions containing Adrenaline, multifocal ventricular extrasystoles and sinus tachycardia have been observed and cardiac arrest has been reported. Thus, caution should be exercised when these solutions are used. The following recommendations have been made:

Approximately 20% of patients breathing 1.25 MAC of halothane and who receive subcutaneous infiltration of 2 μg kg^–1 Adrenaline exhibit ventricular ectopics. This increases to 100% of patients receiving 2.5–3 μg kg^–1 (Fig. 2.8).

Patients undergoing dental surgery with halothane anaesthesia are particularly prone to developing arrhythmias.

Central Nervous System

Halothane produces anaesthesia without analgesia. Cerebral blood flow and intracranial pressure are raised. It does not cause seizure activity on EEG.

Gastrointestinal Tract

Gastrointestinal motility is inhibited. Postoperative nausea and vomiting are seldom severe.

Uterus

Halothane relaxes uterine muscle and may cause post-partum haemorrhage. It is said that a concentration of less than 0.5% is not associated with increased blood loss during anaesthesia for Caesarean section, but this concentration causes increased blood loss during therapeutic abortion.

Skeletal Muscle

Halothane causes skeletal muscle relaxation and potentiates non-depolarizing relaxants. Postoperative shivering is common; this increases oxygen requirements and results in hypoxaemia unless oxygen is administered. Halothane may trigger malignant hyperthermia in susceptible patients.

Halothane-Associated Hepatic Dysfunction

There are two types of dysfunction which may occur after halothane anaesthesia. The first is mild and is associated with derangement in liver function tests. These changes are transient and generally resolve within a few days. Similar changes in liver function tests have also been reported after enflurane anaesthesia and, to a lesser extent, isoflurane anaesthesia.

This subclinical type of hepatic dysfunction, evidenced by an increase in glutathione-S-transferase (GST) concentrations, probably occurs as a result of metabolism of halothane in the liver, where it reacts with hepatic macromolecules, resulting in tissue necrosis, which is worsened by hypoxaemia.

The second type of hepatic dysfunction is extremely uncommon and takes the form of severe jaundice, progressing to fulminating hepatic necrosis. The mortality of this condition varies between 30 and 70%. The likelihood of this type of hepatic dysfunction is increased by repeated exposure to the drug. The mechanism of these changes is probably the formation of a hapten-protein complex. The hapten is probably one of the metabolites of halothane, notably trifluoroacetyl (TFA) halide, as antibodies to TFA proteins have been detected in patients who develop jaundice after halothane anaesthesia.

The incidence of type 2 liver dysfunction after halothane anaesthesia is extremely low – so low that it is extremely difficult to mount well-controlled studies of the condition, and consequently this whole subject has been an area of great controversy in the past. Nonetheless, as a result of this concern, the UK Committee on Safety of Medicines made the following recommendations in respect of halothane anaesthesia:

The incidence of halothane hepatotoxicity in paediatric practice is extremely low, although there have been case reports in children. Nevertheless, halothane is still used in paediatric anaesthesia

In summary, halothane is a useful inhalational anaesthetic agent. Its main advantages are:

The disadvantages are:

Pharmacokinetics

The rate of equilibration of alveolar with inspired concentrations is related to blood/gas solubility. The rate of uptake of desflurane is faster than that of any of the other volatile agents and similar to that of nitrous oxide (Fig. 2.2). Despite its low blood/gas solubility, the rate of induction of anaesthesia with desflurane (and isoflurane) may be reduced because of the pungent odour compared with the more pleasant odours of sevoflurane and halothane. Sevoflurane provides a smooth rapid induction and it has largely replaced halothane for induction in children. Potency, on the other hand, is related to the lower oil/water solubility. Sevoflurane and desflurane are less potent than the older agents, as reflected by their higher MAC values.

On recovery from anaesthesia, the rate of elimination of desflurane is faster than that for the other agents (Fig. 2.3).

Respiratory System

All inhalational agents cause dose-related respiratory depression. This results in reduced tidal volume, increased respiratory rate and reduced minute ventilation. PaCO₂ increases (Fig. 2.4). In unstimulated volunteers, desflurane causes greater ventilatory depression than isoflurane, halothane or sevoflurane. Nitrous oxide does not cause hypercapnia. Thus the reduction in inspired volatile anaesthetic concentration permitted by addition of nitrous oxide is associated with less ventilatory depression. In addition, surgical stimulation is responsible for considerable antagonism of ventilatory depression during anaesthesia and PaCO₂ does not normally reach the values shown in Figure 2.4 during surgery.

With all agents, depression of ventilation is associated with depression of whole body oxygen consumption and carbon dioxide production.

Halothane and, to a lesser extent, sevoflurane, causes bronchodilation.

Cardiovascular System

All the agents reduce arterial pressure because of reduced systemic vascular resistance and myocardial depression to varying degrees. Desflurane and isoflurane tend to maintain cardiac output, decreasing arterial pressure mainly by decreasing systemic vascular resistance. Halothane reduces arterial pressure principally by decreasing cardiac output with little effect on systemic vascular resistance.

Isoflurane and desflurane increase heart rate as a result of sympathetic stimulation, whereas halothane and sevoflurane reduce heart rate.

The data in Figures 2.5–2.7 and 2.9 were derived from studies in volunteers who were not subjected to surgical stimulation and in whom artificial ventilation was used to achieve normocapnia.

Some of the cardiovascular effects of these volatile agents are antagonized by the addition of nitrous oxide. In addition, during spontaneous ventilation, the modest hypercapnia which occurs with all agents also offsets some of the changes. With isoflurane, for example, cardiac output may be increased compared with pre-anaesthesia levels, although there is little effect on systemic arterial pressure.

Desflurane, isoflurane and sevoflurane do not sensitize the myocardium to exogenous catecholamines, but halothane predisposes to arrhythmias.

Isoflurane causes coronary vasodilatation and experimentally this was found to cause coronary steal syndrome but this has now been demonstrated to be of no clinical significance. Sevoflurane causes some coronary vasodilatation but does not appear to cause coronary steal syndrome. The other two agents do not cause any coronary vasodilatation.

Central Nervous System

All agents cause dose-related depression of cerebral activity. All the agents decrease cerebrovascular resistance and increase intracranial pressure in a dose-related manner.

Neuromuscular Junction

All agents produce muscle relaxation sufficient to perform lower abdominal surgery in spontaneously breathing thin subjects. In addition, there is potentiation of non-depolarizing muscle relaxants. In this respect, isoflurane, sevoflurane and desflurane are similar and cause markedly greater potentiation than that produced by halothane.

Uterus

Halothane and isoflurane relax uterine muscle in a dose-related manner. There is limited experience with desflurane and sevoflurane in the obstetric population. Sevoflurane appears to have similar uterine effects to isoflurane. In practice, isoflurane seems to be the standard volatile anaesthetic agent used for obstetric anaesthesia in the UK.

Metabolism

Halothane and sevoflurane are metabolized to potentially toxic metabolites and desflurane is the most resistant to metabolism. Halothane is associated with liver toxicity while sevoflurane is associated with production of inorganic fluoride ions.

Carbon Dioxide Absorbers

Sevoflurane and halothane react with soda lime, while the other two do not.

A comparison of other characteristics of the agents is shown in Tables 2.1 and 2.2.

Physical Properties

Enflurane is a clear, colourless, volatile anaesthetic agent with a pleasant ethereal smell. It is non-flammable in clinical concentrations, stable with soda lime and metals and does not require preservatives. The MAC of enflurane is 1.68% in oxygen and 0.57% in 70% nitrous oxide.

Uptake and Distribution

Enflurane has a blood/gas solubility coefficient of 1.9, which is between that of halothane and isoflurane. Thus, induction of and recovery from anaesthesia are faster than halothane but slower than isoflurane, desflurane and sevoflurane (Fig. 2.2).

Metabolism

Approximately 2.5% of the absorbed dose is metabolized, predominantly to fluoride. In common with other ether anaesthetic agents, the presence of the ether bond imparts stability to the molecule.

Defluorination of enflurane is increased in patients treated with isoniazid, but not with a classic enzyme-inducing agent such as phenobarbital. Serum fluoride ion concentrations are greater after administration of enflurane to obese patients. Extensive studies have failed to demonstrate that the serum concentrations of fluoride ion reach toxic levels after enflurane anaesthesia. The plasma fluoride ion concentrations attained after enflurane anaesthesia are approximately 20 μmol L^–1 (which is below the 50 μmol L^–1 thought to be associated with renal damage after anaesthesia with methoxyflurane).

Respiratory System

Enflurane is non-irritant and does not increase salivary or bronchial secretions; thus inhalational induction is relatively pleasant and rapid.

In common with all other volatile anaesthetic agents, enflurane causes dose-dependent depression of alveolar ventilation with a reduction in tidal volume and an increase in ventilatory rate in the unpremedicated subject. This results in an increase in arterial PCO₂ (Fig. 2.4).

Cardiovascular System

Enflurane causes dose-dependent depression of myocardial contractility, leading to a reduction in cardiac output (Fig. 2.5). In association with a small reduction in systemic vascular resistance, this leads to a dose-dependent reduction in arterial pressure (Figs 2.6, 2.7). Because enflurane (unlike halothane) has no central vagal effects, hypotension leads to reflex tachycardia.

Enflurane anaesthesia is associated with a much smaller incidence of arrhythmias than halothane and much less sensitization of the myocardium to catecholamines, either endogenous or exogenous (Fig. 2.8).

Uterus

Enflurane relaxes uterine muscle in a dose-related manner.

Central Nervous System

Enflurane produces a dose-dependent depression of EEG activity, but at moderate to high concentrations (more than 3%) it produces epileptiform paroxysmal spike activity and burst suppression. These are accentuated by hypocapnia. Twitching of the face and arm muscles may occur occasionally. Enflurane should be avoided in the epileptic patient.

Muscle Relaxation

Enflurane produces dose-dependent muscle relaxation with potentiation of non-depolarizing neuromuscular blocking drugs to a greater extent than that produced by halothane. It may trigger malignant hyperthermia.

Hepatotoxicity

There have been several case reports of jaundice attributable to the use of enflurane, and derangement of liver enzymes also occurs after enflurane anaesthesia, although to a lesser extent than after halothane.

In summary, the advantages of enflurane are:

Its disadvantages are:

Uptake and Distribution

Ether has a high blood/gas solubility coefficient of 12 and thus the rate of equilibration of alveolar with inspired concentrations is slow. Therefore induction and recovery with ether are slow.

Central Nervous System

In common with all general anaesthetic agents, there is depression of cortical activity. Because induction of anaesthesia with ether is so slow, the classical stages of anaesthesia are seen; these are described in detail on page 448 and in Figure 21.2.

Ether anaesthesia is associated with stimulation of the sympathoadrenal system and increased levels of circulating catecholamines, which offset the direct myocardial depressant effect of the drug.

Respiratory System

Ether is irritant to the respiratory tract and provokes coughing, breath-holding and profuse secretions from all mucus-secreting glands. Premedication with an anticholinergic agent is therefore essential.

Ether stimulates ventilation and minute volume is maintained with increasing depth of anaesthesia until surgical anaesthesia is achieved; thereafter, there is a gradual diminution in alveolar ventilation as plane 4 of stage 3 is approached (see Chapter 21).

Because ether is irritant to the respiratory tract, laryngeal spasm is not uncommon during induction with ether, but during established anaesthesia there is dilatation of the bronchi and bronchioles; at one time, the drug was recommended for the treatment of bronchospasm.

Cardiovascular System

In vitro, ether is a direct myocardial depressant. However, during light planes of clinical anaesthesia, there is sympathetic nervous stimulation and this often results in little change in cardiac output, arterial pressure or peripheral resistance. In deep planes of anaesthesia, cardiac output decreases as a result of myocardial depression.

Cardiac arrhythmias occur rarely with ether and there is no sensitization of the myocardium to circulating catecholamines.

Alimentary System

Salivary and gastric secretions are increased during light anaesthesia but decreased during deep anaesthesia. Ether causes a very high incidence of postoperative nausea and vomiting.

Skeletal Muscle

Ether potentiates the effects of non-depolarizing muscle relaxants.

Uterus and Placenta

The pregnant uterus is not affected during light anaesthesia, but relaxation occurs during deep anaesthesia.

Metabolism

At least 15% of ether is metabolized to carbon dioxide and water; approximately 4% is metabolized in the liver to acetaldehyde and ethanol.

Ether stimulates gluconeogenesis and therefore causes hyperglycaemia.

Clinical Use of Ether

Ether has a much higher therapeutic ratio than other volatile anaesthetic agents and is therefore safer for administration in the hands of unskilled individuals or from an uncalibrated vaporizer. Because of its high blood/gas solubility coefficient and irritant properties to the respiratory tract, induction of anaesthesia is very slow.

Administration of ether may be undertaken using an anaesthetic breathing system with a non-calibrated vaporizer (Boyle’s bottle) or calibrated vaporizer (the EMO, which may be used as a draw-over or as a plenum vaporizer). It may be used safely in a closed circuit with soda lime absorption.

Vapour strengths of up to 20% are required for induction; light anaesthesia may be maintained with 3–5% and deep anaesthesia with 5–6% inspired concentrations.

Manufacture

Nitrous oxide is prepared commercially by heating ammonium nitrate to a temperature of 245–270 °C. Various impurities are produced in this process, including ammonia, nitric acid, nitrogen, nitric oxide and nitrogen dioxide.

After cooling, ammonia and nitric acid are reconstituted to ammonium nitrate, which is returned to the beginning of the process. The remaining gases then pass through a series of scrubbers. The purified gases are compressed and dried in an aluminium dryer. The resultant gases are expanded in a liquefier, with the nitrogen escaping as gas. Nitrous oxide is then evaporated, compressed and passed through another aluminium dryer before being stored in cylinders.

The higher oxides of nitrogen dissolve in water to form nitrous and nitric acids. These substances are toxic and produce methaemoglobinaemia and pulmonary oedema if inhaled. There have been several reports of death occurring during anaesthesia as a result of the inhalation of nitrous oxide contaminated with higher oxides of nitrogen.

Storage

Nitrous oxide is stored in compressed form as a liquid in cylinders at a pressure of 44 bar (4400 kPa; 638 lb in^–2). In the UK, the cylinders are painted blue.

Because the cylinder contains liquid and vapour, the total quantity of nitrous oxide contained in a cylinder may be ascertained only by weighing. Thus, the cylinder weights, full and empty, are stamped on the shoulder. Nitrous oxide cylinders should be kept in a vertical position during use so that the liquid phase remains at the bottom of the cylinder. During continuous use, the cylinder may cool as a result of the latent heat of vaporization of liquid anaesthetic and ice may form on the lower part of the cylinder. Large institutions use a pipeline supply of nitrous oxide. The nitrous oxide is delivered from a large central bank of cylinders to the pipeline.

Physical Properties

Nitrous oxide is a sweet-smelling, non-irritant colourless gas, with a molecular weight of 44, boiling point of −88 °C, critical temperature of 36.5 °C and critical pressure of 72.6 bar.

Nitrous oxide is not flammable but it supports combustion of fuels in the absence of oxygen.

Pharmacology

Nitrous oxide is often said to be a good analgesic but a weak anaesthetic. The latter refers to the fact that its MAC value is 105%. This value was calculated theoretically from its low oil/water solubility coefficient of 3.2 and has been confirmed experimentally in volunteers anaesthetized in a pressure chamber compressed to 2 ata, where the MAC value was found to be 52.5% in N₂O. As it is essential to administer a minimum F₁O₂ of 0.3 during anaesthesia, nitrous oxide alone is insufficient to produce an adequate depth of anaesthesia. Therefore, nitrous oxide is used usually in combination with other agents. When using nitrous oxide in a relaxant technique, the inspired gas mixture should be supplemented with a low concentration of a volatile agent to eliminate the risk of awareness, which occurs in 1–2% of patients if nitrous oxide anaesthesia is supplemented only by the administration of opioids.

Nitrous oxide has a low blood/gas solubility coefficient (0.47 at 37 °C) and therefore the rate of equilibration of alveolar with inspired concentrations is very fast (Fig. 2.2).

Nitrous oxide does not undergo metabolism in the body and is excreted unchanged.

Nitrous oxide appears to exert its activity at different types of receptors. It has an inhibitory action on N-methyl-D-aspartate (NMDA) glutamate receptors and stimulatory activity at dopamine, α₁ and α₂-adrenergic and opioid receptors. The analgesic action of nitrous oxide is thought to be mediated by activation of opioid receptors in the periaqueductal area of the midbrain. This leads to modulation of nociceptive pathways through the release of noradrenaline and activation of the α₂-adrenoreceptors in the dorsal horn of the spinal cord. Because of its analgesic properties, nitrous oxide is used in combination with volatile agents as part of a general anaesthetic, which reduces the dose of volatile agent required. It is used in obstetrics and in acute pain management as pre-mixed nitrous oxide 50% and oxygen 50% via a demand valve.

The Concentration Effect

The inspired concentration of nitrous oxide affects its rate of equilibration; the higher the inspired concentration, the faster is the rate of equilibration between alveolar and inspired concentrations. Nitrous oxide is more soluble in blood than is nitrogen. Thus, the volume of nitrous oxide entering pulmonary capillary blood from the alveolus is greater than the volume of nitrogen moving in the opposite direction. As a result, the total volume of gas in the alveolus diminishes and the fractional concentrations of the remaining gases increase. This has two consequences:

The result of the concentration effect on equilibration of nitrous oxide is illustrated in Figure 2.10.

The Second Gas Effect

When nitrous oxide is administered in a high concentration with a second anaesthetic agent, e.g. sevoflurane, the reduction in gas volume in the alveoli caused by absorption of nitrous oxide increases the alveolar concentration of sevoflurane, thereby augmenting the rate of equilibration with inspired gas. This is illustrated in the lower part of Figure 2.10. The second gas effect results also in small increases in PAO₂ and PaO₂.

Systemic Effects

Side-Effects of Nitrous Oxide

Oxygen

Carbon Dioxide

Carbon dioxide is a colourless gas with a pungent odour. It has a molecular weight of 44, a critical temperature of − 31°C and a critical pressure of 73.8 bar.

Carbon dioxide is obtained commercially from four sources:

In the UK, carbon dioxide is supplied in a liquid state in grey cylinders at a pressure of 50 bar. The liquid phase occupies approximately 90–95% of the cylinder capacity.

Medical Air

Nitrous oxide is still commonly used in combination with a volatile agent to maintain anaesthesia. However, there is growing concern regarding its toxic effects and its cost. Consequently, medical air is being used more frequently in combination with oxygen during anaesthesia.

Medical air is obtained from the atmosphere near to the site of compression. Great care is taken to position the air intake in order to avoid contamination with pollutants such as carbon monoxide from car exhausts. Air is compressed to 137 bar and then passed through columns of activated alumina to remove water.

Air for medical purposes is supplied in cylinders (grey body and black and white shoulders in the UK) or as a piped system. A pressure of 4 bar is available for attachment to anaesthetic machines, and 7 bar for orthopaedic tools. Its composition varies slightly depending on location of compression and moisture content.

Xenon

Inert gases such as argon, krypton and xenon, which form crystalline hydrates, have been reported to exert anaesthetic actions. Cullen and Gross first reported the anaesthetic properties of xenon in humans in 1951. Xenon offers many advantages over nitrous oxide, for which it could theoretically be a suitable replacement. The reasons that it is not routinely available are that it is expensive, there are no commercially available anaesthetic machines in which to use xenon, its concentration in inspired gas cannot be measured with conventional anaesthetic gas analysers and there is still limited clinical experience with its use. Xenon, in common with nitrous oxide and ketamine, acts by non-competitive inhibition of NMDA receptors in the CNS.

Helium

Helium is a light inert gas which is present in air and natural gas. It is the second most abundant element after hydrogen. It is presented as either Heliox (79% helium and 21% oxygen) in white cylinders with white/brown shoulders or as 100% helium in brown cylinders at 137 bar. Helium has a lower density than air, nitrogen and oxygen. During turbulent flow, velocity is higher when Heliox is used. The low density of gas results in a lowering of the Reynolds’ number and thus a return to laminar flow. By increasing laminar flow, the efficiency of breathing is increased. This physical characteristic is used to treat patients with upper airway obstruction to reduce the work of breathing and improve oxygenation.

Because of the lower density, patients receiving helium have a typical squeaky voice due to the higher frequency vocal sounds. Helium is used in the measurement of lung volumes because of its very low solubility. Helium/oxygen mixtures are also used for deep water diving to avoid nitrogen narcosis.