4. Inhalational Agents: Sevoflurane

highly fluorinated hydrocarbon with the simple formula C4H3F7O. boiling point 59 °C; blood–gas partition coefficient 0.68; minimum alveolar concentration (MAC50) 2.0%; metabolism 3–5%.

sevoflurane is a hypnotic agent that can be used for the induction and maintenance of general anaesthesia. Theories about its mechanism of action are detailed in the following.

sevoflurane is a vasodilator which increases cerebral blood flow and may thereby affect intracranial pressure it also decreases the cerebral metabolic rate and oxygen consumption (CMRO2). t uncouples the relationship between cerebral blood flow and PaCO2 reduction in cerebral perfusion pressure secondary to its cardiodepressant effects degree of neuroprotection via a process analogous to ischaemic preconditioning.

the changes are dose-dependent. At low concentrations (at MAC less than 1.0), sevoflurane (and the other volatile agents) reduce power in the alpha range (waves of frequency 8–15) increase it in the beta range (16–30 Hz). There is thus a shift overall to greater frequencies As anaesthesia deepens, however, the activity in these frequencies decreases towards the theta (4–7 Hz) delta (<3 Hz) ranges. At MAC greater than 2.0, all the volatile agents induce EEG burst suppression.

reduces alveolar ventilation by reducing tidal volume accompanied by an increase in respiratory frequency rise in respiratory rate and resultant increase in dead-space ventilation leads to an increase in PaCO2, ->respiratory centres become less sensitive reduces bronchial tone not an airways irritant and is a forgiving agent inhalation induction because even high inspired concentrations rarely provoke coughing, laryngospasm or breath-holding

acts both as a vasodilator which decreases systemic vascular resistance as a myocardial depressant which reduces cardiac output mean arterial pressure minimally arrythmogenic but may prolong the QT interval and so is best avoided in patients with + congenital or acquired long QT syndrome.

: sevoflurane undergoes minimal metabolism (3–5%) and is not degraded to antigenic trifluroacetic acid-protein complexes (as happens with the metabolism of halothane). It leads to a dose-dependent reduction in hepatic blood flow secondary to its cardiovascular depressant actions.

negligible effects on renal physiology, but because it is a fluorinated hydrocarbon, it does produce inorganic fluoride ions sufficient to raise serum fluoride levels in some subjects to more than 50 μmol l−1. Although this is a level at which fluoride has been shown to cause polyuric renal failure (following prolonged anaesthesia with methoxyflurane, for example), it does not appear to be clinically significant when associated with sevoflurane administration, and the agent is not considered to cause renal toxicity.

: sevoflurane causes a dose-dependent reduction in uterine tone. Malignant hyperpyrexia: sevoflurane is a trigger agent

Compounds A and B: 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 compounds A (trifluoromethyl vinyl ether), B, D, E and G. Only compound A has been shown to have any toxicity, as it is degraded into a nephrotoxic metabolite. (The reaction with barium lime is about five times more rapid than with soda lime.) The dose-dependent renal damage noted in rats has never been seen in humans despite many millions of administrations, probably because of marked quantitative differences in rodent enzyme systems.

the volatile agents act at the central neuraxial level (brain as well as spinal cord); at axons and synapses; and at the molecular level, on pre- and post-synaptic membranes. As a generalization about their overall mechanism of action, however, it appears that these agents acts as potent agonists at the GABAA and glycine receptors and thereby inhibit the function of their post-synaptic ligand-gated ion channels of the GABAA receptor

agents also act pre-synaptically as antagonists to inhibit ion channel activity mediated by serotoninergic, glutaminergic and particularly the nicotinic acetylcholine receptors They act at spinal cord level by diminishing nociceptive afferents ascending to thalamo-cortical tracts. Hypnosis is mediated at supraspinal level, with the areas particularly influenced being the thalamus and the reticular formation in the midbrain.

Ischaemic preconditioning describes the protective evolutionary process whereby tissues that are exposed to recurrent ischaemic, hypoxic or metabolic insults that injure, but do not kill, the cells, are better able to tolerate a subsequent and much more severe event. The cascade results in the modulation of myocardial mitochondrial activity via activation of the ATP-sensitive potassium channels, which are found on the nuclear, mitochondrial and sarcolemmal membranes of cardiac myocytes, activation of the mitochondrial permeability transition pore leads finally to a reduction in intracellular calcium and a fall in myocardial contractility number of agents, particularly halogenated inhalation anaesthetics, but also opioids, appear to trigger an analogous process, now described as ‘anaesthetic preconditioning’. The effect is initiated at MAC values as low as 0.25 but is maximal at MAC 1.0–1.5. Sophisticated studies have confirmed that volatile agents prime some of these signalling pathways and initiate a cascade of reactions with alterations in cardiac gene and protein expression