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.