4. Inhalational Agents vs Ideal

: the ideal agent would be safe by virtue of its specificity for the nervous system. It would, in other words, allow a controlled state of insensibility in which all other physiological indices such as cerebral and myocardial blood flow remained unchanged. It would also be advantageous were it to be analgesic. No such agent exists, and so patients receiving inhalational agents may be at potential risk from the secondary, undesirable effects of an agent, from direct toxic effects, or from toxic products of metabolism.

effects: the potential to cause airways irritation is discussed in more detail later in this section. All the drugs are respiratory depressants and cause a decrease in tidal volume with an increase in respiratory rate. They are effective bronchodilators. The ideal agent might be one that relaxes bronchial smooth muscle but which has no other effects on respiratory physiology.

: the ideal agent would exhibit complete cardiovascular stability; however, all the halogenated agents have cardiovascular effects, but none so marked as to preclude their clinical use. All the agents in current use are cardioprotective via a mechanism similar to that seen in ischaemic preconditioning. Halothane is the most arrhythmogenic. It causes a dose-related fall in mean arterial pressure (MAP) and may also cause bradycardia, junctional rhythms and ventricular premature beats. It sensitizes the myocardium to catecholamines, particularly in the presence of hypercapnia and acidosis, and under such circumstances may provoke much more malignant arrhythmias such as ventricular tachycardia. Experience with this agent in the UK has all but disappeared, but it is still used widely in the developing world. Enflurane similarly causes dose-related cardiovascular depression, but is not arrhythmogenic. This agent similarly is almost obsolete in the UK. Isoflurane leads to a dose-dependent reduction in systemic vascular resistance (SVR) and coronary vascular vasodilatation. Heart rate increases and cardiac output and contractility are maintained. Isoflurane was believed to cause a coronary steal syndrome in which coronary vasodilatation diverted blood away from stenotic vessels. Controlled trials have suggested that it is no worse than any other volatile in this regard. Desflurane causes a similar fall in SVR and MAP, while heart rate rises and cardiac output is maintained. Sevoflurane also leads to dose-dependent cardiovascular depression, with decreases in MAP, SVR and contractility. The heart rate does not increase and the agent causes less coronary vasodilatation than isoflurane. Xenon is cardiostable

all the halogenated agents increase cerebral blood flow which can cause a rise in intracranial pressure that in some circumstances may be deleterious. Sevoflurane preserves cerebral autoregulation better than the other agents. Desflurane, in contrast, abolishes autoregulation at 1.5 MAC. Alone amongst the agents, it increases cerebrospinal fluid production. At 1.0 MAC, isoflurane and sevoflurane are associated with minimal changes in CBF and ICP. — Enflurane is associated with abnormal epileptiform activity in the EEG, particularly if its administration is accompanied by hypocapnia. — Xenon increases cerebral blood flow and increases intracranial pressure.

: by definition, the agent has to be able to induce and maintain a state of anaesthesia, and all the halogenated agents produce dose-dependent narcosis Some are more ‘potent’ than others in the sense that their effects are produced at lower concentrations, but clinically this is of little relevance A much more significant property is the blood solubility, as quantified by the blood–gas partition coefficient. The less soluble the agent, the lower the amount required to produce a given partial pressure and the more rapid the onset of action. xenon (whose blood–gas partition coefficient is only 0.12), desflurane (0.42), nitrous oxide (0.47), sevoflurane (0.68), isoflurane (1.4), enflurane (1.9) and halothane (2.3).

MAC at which 50% of the population will not display reflex movement in response to a standard surgical stimulus. This is the MAC50, but the MAC95 (the prevention of movement in 95% of subjects) is more useful. MAC50 values are halothane (0.75%), isoflurane (1.17%), enflurane (1.63%), sevoflurane (1.8%), desflurane (6.6%), xenon (71%) and nitrous oxide (105%)

Sevoflurane is non-irritant to the upper airway and bronchi, and inhalational induction can be swift and effective in the most testing of circumstances. — Halothane shares the same characteristics, but is slightly more pungent. — Enflurane is not dissimilar, although inhalation induction is more prolonged. — Isoflurane is more irritant to airways and is associated with a higher incidence of coughing and breath-holding. — Desflurane is said to be the most inferior agent in this respect, its other benefits being offset by its effective capacity to provoke laryngospasm, excessive secretions and apnoea. This is not a problem at end-tidal concentrations up to 6%.

Toxicity — Nitrous oxide depresses bone marrow function via its oxidation of the cobalt atom in the vitamin B12 complex as described previously. — Sevoflurane may produce the potentially, but not demonstrably toxic compound A, as well as free fluoride ions Enflurane also produces fluoride ions, while halothane is implicated in postexposure hepatic dysfunction

inhaled agents are eliminated through the lungs, but metabolism still occurs, principally by cytochrome P450 oxidation in the liver. None of the agents has active metabolites, but clearly the greater the proportion that undergoes hepatic metabolism the greater is the excretory load minimak Xenon is an inert gas which undergoes no biotransformation. — Nitrous oxide undergoes minimal metabolism (0.004%), mainly by gut microorganisms. — Desflurane is resistant to metabolism (0.02%), and serum fluoride levels do not rise even after prolonged administration. Isoflurane metabolism is around 0.2%, which can lead to a small rise in fluoride concentrations.

Enflurane metabolism is higher, at around 3%, and serum fluoride levels may reach 25 μmol l−1, which may be of theoretical importance in patients with pre-existing renal impairment. (Fluoride is nephrotoxic at levels of 50 μmol l−1 and above.) — Sevoflurane undergoes 3–5% metabolism and produces more fluoride ions than enflurane. Serum fluoride concentrations may reach 15–25 μmol l−1 after 1 MAC hour of administration. In theory, it should be used with caution in patients with renal dysfunction, but this is not regarded universally as a contraindication for its use. The chemical structure of sevoflurane is such that it cannot undergo biotransformation to an acyl halide, and so, unlike halothane, enflurane, isoflurane and desflurane, its metabolism does not result in the formation of trifluoroacetylated liver proteins and subsequent production of anti-trifluoroacetylated protein antibodies. — Halothane is the most extensively metabolized of the inhalational agents, with 20–40% being degraded by both reductive and oxidative pathways. A trifluoroacetylated compound produced by oxidation can bind to liver proteins, triggering in susceptible patients an immune reaction which may precipitate hepatic necrosis. This is a separate problem from the transient postoperative rise in liver enzymes, which may be seen in up to 20% of patients.

this refers to the molecular stability of the compound when exposed to the normal range of environmental conditions, and to the specific circumstances of its use in an anaesthetic breathing system. Ideally, it should be stable to light and to temperature, it should undergo no spontaneous degradation and require no preservatives, it should be non-flammable and non-corrosive and should be safe in the presence of soda lime and alkali. Most of the agents perform well against these criteria; some specific exceptions include the following Nitrous oxide supports combustion. — Desflurane has a low boiling point that is close to room temperature (23.5 °C). — Sevoflurane reacts with strong monovalent hydroxide bases, such as those which are used in soda lime and barium lime CO2 absorbers, to produce a number of substances, including compound A. (The reaction with barium lime is about five times more rapid than with soda lime.) Of the degradation products (compounds A, B, D, E and G), only A, which is a vinyl ether, has been shown to have any Halothane may degrade when exposed to light and so is presented in amber bottles in thymol 0.01% as a preservative. Accumulated thymol can affect vaporizer function.

this gas most closely approaches the ideal agent. It provides effective hypnosis and analgesia together with some muscle relaxation. It is non-irritant and, although it can depress respiration to the point of apnoea, it is cardiostable. It undergoes no metabolism, is not toxic and does not cause allergic reactions. It is stable in storage, is non-flammable and is environmentally neutral. At present its cost is prohibitive, and so until an efficient xenon recycling system can be developed, this almost ideal inhalational agent will not find widespread use.

his is a fluorinated ether (C3H4Cl2F2O) whose use as a mainstream volatile anaesthetic agent was discontinued following recognition of its nephrotoxicity. This was associated with its metabolic degradation to inorganic fluoride and other compounds, particularly dichloroacetic acid. It is an agent with high-lipid solubility and a slow onset and offset of action. It is also, however, a potent analgesic, including at sub-hypnotic doses, and so it has been reintroduced particularly for the out-of-hospital management of acute pain secondary to trauma (It is vaporized via a small handheld inhaler which contains only 3 ml of agent). When it was used as a general anaesthetic, methoxyflurane could be delivered at 1.0 MAC for up to 8 hours before nephrotoxicity would occur, and so it is likely that interest in potential of the agent as a useful rescue analgesic in a much wider context is likely to increase.