P1: PCX Printer: Yet To Come
9780521704632c08a CUFX213A/Peck 9780521618168 December 28, 2007 10:40
8 General anaesthetic agents
The chloro-fluoro method – here the basic molecular architecture is manufac-
tured but with chlorine attached. This is then substituted with flourine to produce
sevoflurane.Effects
Respiratory – sevoflurane is a useful agent for induction of anaesthesia due to
its pleasant odour and favourable physical properties. It does, however, depress
ventilation in a predictable fashion with a reduction in minute volume and a rise
in PaCO 2.
Cardiovascular – the systemic vascular resistance falls and, due to an unchanged
heart rate, the blood pressure falls. Cardiac contractility is unaffected and the heart
is not sensitized to catecholamines. Vascular resistance to both cerebral and coro-
nary circulations is decreased.
Central Nervous System – compared with halothane, there is evidence that children
exhibit a higher incidence of post-operative agitation and delirium, which may
extend beyond the initial recovery period.Metabolism
Sevoflurane undergoes hepatic metabolism by cytochrome P450 (isoform 2E1) to a
greater extent than all the other commonly used volatile agents except halothane
(Table8.6). Hexafluoroisopropanol and inorganic F−(known to cause renal toxic-
ity) are produced. The now obsolete volatile anaesthetic methoxyflurane was also
metabolized by hepatic P450 releasing F−, and when plasma levels rose above 50
μmol.l−^1 renal toxicity was observed. However, renal toxicity is not observed fol-
lowing sevoflurane administration even when plasma levels reach 50μmol.l−^1 .A
possible explanation lies in the additional metabolism of methoxyflurane by renal
P450 to F−, which generates a high local concentration while sevoflurane undergoes
little or no renal metabolism.Toxicity
Compounds A, B, C, D and E have all been identified when sevoflurane is used in
the pressence of carbon dioxide absorbents. Only compounds A and B (which is less
toxic) are present in sufficient amount to make analysis feasible. Their formation
is favoured in the presence of potassium hydroxide rather than sodium hydroxide
based absorbents particularly when dry. The reaction releases heat and consumes
sevoflurane both of which are readily detectible.
The lethal concentration of compound A in 50% of rats is 300–400 ppm after 3
hours exposure. Extrapolation of these and other animal studies suggest a human
nephrotoxic threshold of 150–200 ppm. Recent work suggests that even with flow
rates of 0.25 l.min−^1 for 5 hours the level of compound A peaks at less than 20 ppm
and is not associated with abnormal tests of renal function.