Sevoflurane

Changes in the clinical effects of sevoflurane rapidly follow changes in the inspired concentration.

Cardiovascular Effects

As with all other inhalation agents sevoflurane depresses cardiovascular function in a dose related fashion. In one volunteer study, increases in sevoflurane concentration resulted in decrease in mean arterial pressure, but there was no change in heart rate. Sevoflurane did not alter plasma noradrenaline concentrations in this study.

Nervous System Effects

No evidence of seizure was observed during the clinical development programme.

In patients with normal intracranial pressure (ICP), sevoflurane had minimal effect on ICP and preserved CO₂ responsiveness. The safety of sevoflurane has not been investigated in patients with a raised ICP. In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing manoeuvres such as hyperventilation.

Paediatric

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/sedation drug administration or other factors such as the surgery or underlying illness. In addition, more recent published registry studies did not confirm these findings.

Published animal studies of some anaesthetic/sedation drugs have reported adverse effects on brain development in early life.

The low solubility of sevoflurane in blood should result in alveolar concentrations which rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent.

In humans <5% of the absorbed sevoflurane is metabolised. The rapid and extensive pulmonary elimination of sevoflurane minimises the amount of anaesthetic available for metabolism. Sevoflurane is defluorinated via cytochrome p450(CYP)2E1 resulting in the production of hexafluoroisopropanol (HFIP) with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). HFIP is then rapidly conjugated with glucuronic acid and excreted in the urine.

The metabolism of sevoflurane may be increased by known inducers of CYP2E1 (e.g. isoniazid and alcohol), but it is not inducible by barbiturates.

Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anaesthesia. Generally, concentrations of inorganic fluoride peak within 2 hours of the end of sevoflurane anaesthesia and return within 48 hours to pre-operative levels.

Animal studies have shown that hepatic and renal circulation are well maintained with sevoflurane.

Sevoflurane decreases the cerebral metabolic rate for oxygen (CMRO2) in a fashion analogous to that seen with isoflurane. An approximately 50% reduction of CMRO2 is observed at concentrations approaching 2.0 MAC. Animal studies have demonstrated that sevoflurane does not have a significant effect on cerebral blood flow.

In animals, sevoflurane significantly suppresses electroencephalographic (EEG) activity comparable to equipotent doses of isoflurane. There is no evidence that sevoflurane is associated with epileptiform activity during normocapnia or hypocapnia. In contrast to enflurane, attempts to elicit seizure-like EEG activity during hypocapnia with rhythmic auditory stimuli have been negative.

Compound A was minimally nephrotoxic at concentrations of 50-114 ppm for 3 hours in a range of studies in rats. The toxicity was characterised by sporadic single cell necrosis of the proximal tubule cells. The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established. Comparable human thresholds for Compound A-related nephrotoxicity would be predicted to be 150-200 ppm. The concentrations of Compound A found in routine clinical practice are on average 19 ppm in adults (maximum 32 ppm) with use of Soda lime as the CO₂ absorbent.

Developmental toxicity studies have been performed in pregnant rats and rabbits at doses up to 1 MAC for three hours per day. Reduced foetal body weights concomitant with increased skeletal variations were noted in rats only at maternally toxic concentrations. No adverse foetal effects were observed in rabbits. In fertility studies in rats at doses up to 1 MAC no effects on male and female reproductive capabilities were observed.

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.