Introduction

Halothane was introduced into veterinary anaesthesia by the late Dr Leslie Hall in 1957¹ at Cambridge, UK, and it is no exaggeration to say that without it, many of the advances in veterinary surgery would not have occurred. It is/was not without faults - it causes dose dependant cardiopulmonary depression, - but the reason for its withdrawal in humans (and therefore non-availability in many places to vets) was the occurrence of rare cases of immune-mediated hepatic necrosis following a second exposure within a certain time frame. During the last 50 plus years other inhalation agents have come and gone (e.g., enflurane, methoxyflurane). There are currently three agents in general anaesthetic use, - isoflurane, sevoflurane and desflurane.² The times at which these agents were introduced into different countries has varied, for example, isoflurane has had a veterinary licence in the USA for over 20 years, with sevoflurane a more recent introduction, whilst in contrast, I believe in Asia (please correct me if I am wrong), sevoflurane has been available for many years, and isoflurane comparatively recently introduced.

All three of the agents in current use provide adequate anaesthesia, they give a rapid induction and recovery, provide adequate analgesia (or at least lack of response to surgery), cause dose-dependent cardiopulmonary depression but at MAC (minimal alveolar concentration) at an acceptable level. However they are not perfect. This presentation will outline the similarities and differences between the three agents, and therefore their potential advantages/disadvantages in practice situations.

Physical Properties

Table 1 gives the physical properties and MAC values of the 3 agents, and of halothane and xenon for comparison. Physical properties give an indication of what to expect in a number of ways - speed of induction depends on solubility in blood - the less soluble the faster; speed of recovery from short anaesthetics again depends on blood solubility, but from long anaesthetics on tissue (in particularly fat) solubility. Thus from Table 1 it becomes obvious that relative speed of induction is desflurane faster > sevoflurane > isoflurane, and all a great deal faster than was halothane, whilst in recovery from prolonged anaesthesia the difference between isoflurane and sevoflurane is not as great.

Table 1. Some Properties of Inhalation Anaesthetic Agents.

MAC = minimum alveolar concentration. * Solubility coefficients differ with different tissues, different types of fat, and therefore different species - hence figures given here are only a guide to the relative solubilities of the agents.

Metabolism, Toxicity and Reactions with Carbon Dioxide Absorbents

Indirect toxicity through tissue hypoxia is induced by an overdose of any anaesthetic agent. Direct toxicity usually is mediated by metabolites.³ Approximately 20–25% of halothane is metabolised, - metabolites include trifluoacetyl halides that may attach to liver proteins, and on very rare occasions in humans, anti-bodies against the halide/protein combination are produced. A second halothane exposure then may result in immune mediated hepatitis. The same metabolite is produced by breakdown of both isoflurane and desflurane, but as metabolism of these agents is low (1% for isoflurane, 0.2% for desflurane), the chance of hepatitis reduced accordingly. This form of immune mediated liver failure has never been proven to occur in animals.

Approximately 5% of sevoflurane is metabolised, but to different metabolites and is unlikely to trigger auto-immune hepatitis. Sevoflurane's metabolic pathway results in free inorganic fluoride ions. Theoretically they can cause renal damage, but direct toxicity has not been seen clinically in humans or in animals. Although the three agents do not cause direct toxicity, they can react with 'soda lime' to produce potentially toxic compounds, as described below.

Problems with Carbon-Dioxide Absorbents

In re-breathing systems expired carbon dioxide from the patient is absorbed, classically by strongly basic mixtures, such as 'soda lime'. Sevoflurane will react with soda-lime to produce 'Compound A' - which can cause renal toxicity. Breakdown (therefore concentration of Compound A) increases with increased temperature of the absorbent. Use of low flow breathing systems (essential for economic reasons) increases production by increasing temperature, and by allowing Compound A to accumulate. In normal clinical use, concentrations of Compound A do not reach toxic levels although there is experimental evidence of species differences.

In the 1990s, it was discovered that desflurane, and to a lesser extent, isoflurane broke down in the presence of dry soda-lime to produce carbon monoxide and formaldehyde. Under normal clinical conditions sevoflurane does not do so, but at very high temperatures (80°C)⁴ rapid breakdown both to Compound A and to carbon monoxide can occur. The pharmaceutical company issued a warning, now incorporated into the product characteristics, that there have been cases of spontaneous fire in the anaesthetic circuit when sevoflurane has been used with desiccated Baralyme and that theoretically these could also occur with any of absorbent containing strong bases such as sodium hydroxide (NaOH) and/or potassium hydroxide (KOH).

There are some ways to avoid or reduce the problem:

 Avoid the absorbent form becoming desiccated. This is easier said than done.

 Use of high flow methods of administering the anaesthetic. This becomes expensive.

 Use of the new generation of carbon-dioxide absorbents.⁵ Carbon dioxide absorbents consist primarily of calcium hydroxide, but the addition of strong bases such as KOH, NaOH or barium hydroxide speeds absorption. The new generation absorbents, of which there are a number of brands and formulations (e.g., LoFloSorb, Amsorb Plus), do not contain these and there is no risk of anaesthetic breakdown, or of Compound A and carbon monoxide production. Some less expensive products (e.g., Spherasorb,) contain no KOH and reduced NaOH, so although breakdown of the anaesthetic can occur, it will be less. Details of the content of different brands can be found in Anesthesia Patient Safety Foundation (APSF) (2005).⁵

Specific Similarities and Differences between Isoflurane, Sevoflurane and Desflurane

Cardiovascular and Respiratory Effects

All three cause dose-dependent cardiovascular and respiratory depression. However, although at MAC blood pressure falls through vasodilation, cardiac output is well maintained and tissue blood flow is good. Differences between the three seem clinically insignificant, other than heart rates are slower with sevoflurane. There is evidence that sevoflurane is more respiratory depressant than the other two agents.

Both isoflurane and desflurane are irritants to the respiratory tract; in humans neither can be used for mask induction of anaesthesia. In contrast, sevoflurane is non-irritant and is acceptable for mask induction in humans, and in animals induction of anaesthesia with it is accomplished with minimal struggling.

Boiling Points and Vaporizers

Desflurane boils at room temperature, so cannot be used in simple glass bottles. It must be given from a very specific (and expensive) vaporiser which works by heating the liquid so it all becomes gas, which is then mixed with the carrier gas. It is the need for this vaporiser that has limited the use of desflurane. The vaporiser is designed so that the bottle fits the filling port of the vaporiser, preventing spillage (essential in this case because of desflurane's low boiling point) - this technology has now been adapted for new sevoflurane and isoflurane vaporisers.

Both sevoflurane and isoflurane can be delivered by simple 'plenum' glass bottles, but calibrated temperature compensated vaporisers are more usually used. As the boiling point of isoflurane is so close to that of halothane, many old halothane vaporizers have been re-furbished and re-calibrated for use with isoflurane. Most sevoflurane vaporizers have been specifically made for purpose.

Which Anaesthetic, When?

All three agents give a rapid induction of and relatively rapid recovery from anaesthesia, and in small animals, cardiopulmonary differences are not sufficiently great to influence choice. Where a very rapid and very complete recovery is needed (for example, a dog with poor control of its airway) desflurane is the agent of choice. Sevoflurane is the choice for mask (or chamber) induction. Within the European Union, there are legal limitations in relation to the marketing authorisations (desflurane has none - sevoflurane only for the dog), but excepting these, all three are suitable for use in small animal practice.

References

1.  Hall LW. Bromochlorotrifluoroethane (Fluothane): a new volatile anaesthetic agent. Vet Rec 1957;69:615–618.

2.  Clarke KW. Options for inhalation anaesthesia. In Practice 2008;30:513–518.

3.  Kharasch ED. Adverse drug reactions with halogenated anesthetics. A review. Clin Pharmacol Ther 2008;84:158–162.

4.  Holak EJ, Mei DA, Dunning MB, Gundamraj R, Nosier R, Zhang L, Woehick HJ. Carbon monoxide production from sevoflurane breakdown: modelling of exposures under clinical conditions. Anesthesia and Analgesia. 2003;96:757–764.

5.  APSF. Carbon dioxide absorbent desiccation safety conference convened by APSF. 2005 viewed April 2011 at www.sodasorb.com/English/downloads/apsf_newsletter.pdf