# Sevoflurane

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.
It is on the World Health Organization's List of Essential Medicines.

## Medical uses

It is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia, across all ages, but particularly in pediatric anesthesia, as well as in veterinary medicine. Together with desflurane, sevoflurane is replacing isoflurane and halothane in modern anesthesia practice. It is often administered in a mixture of nitrous oxide and oxygen.

## Physiological effects

Sevoflurane is a potent vasodilator. As such, it induces a dose dependent reduction in blood pressure and cardiac output. It is a bronchodilator, however, in patients with pre-existing lung pathology, it may precipitate coughing and laryngospasm. It reduces the ventilatory response to hypoxia and hypercapnia, and impedes hypoxic pulmonary vasoconstriction. Sevoflurane vasodilatory properties also cause it to increase intracranial pressure and cerebral blood flow. However, it reduces cerebral metabolic rate.

## Adverse effects

Sevoflurane has an excellent safety record, but is under review for potential hepatotoxicity, and may accelerate Alzheimer's. There were rare reports involving adults with symptoms similar to halothane hepatotoxicity. Sevoflurane is the preferred agent for mask induction due to its lesser irritation to mucous membranes.
Sevoflurane is an inhaled anesthetic that is often used to induce and maintain anesthesia in children for surgery. During the process of awakening from the medication, it has been associated with a high incidence (>30%) of agitation and delirium in preschool children undergoing minor noninvasive surgery. It is not clear if this can be prevented.
Studies examining a current significant health concern, anesthetic-induced neurotoxicity (including with sevoflurane, and especially with children and infants) are "fraught with confounders, and many are underpowered statistically", and so are argued to need "further data... to either support or refute the potential connection".
Concern regarding the safety of anaesthesia is especially acute with regard to children and infants, where preclinical evidence from relevant animal models suggest that common clinically important agents, including sevoflurane, may be neurotoxic to the developing brain, and so cause neurobehavioural abnormalities in the long term; two large-scale clinical studies (PANDA and GAS) were ongoing as of 2010, in hope of supplying "significant [further] information" on neurodevelopmental effects of general anaesthesia in infants and young children, including where sevoflurane is used.
In 2021, researchers at Massachusetts General Hospital published in Communications Biology research that sevoflurane may accelerate existing Alzheimer's or existing tau protein to spread: "These data demonstrate anesthesia-associated tau spreading and its consequences. [...] This tau spreading could be prevented by inhibitors of tau phosphorylation or extracellular vesicle generation." According to Neuroscience News, "Their previous work showed that sevoflurane can cause a change (specifically, phosphorylation, or the addition of phosphate) to tau that leads to cognitive impairment in mice. Other researchers have also found that sevoflurane and certain other anesthetics may affect cognitive function."
Additionally, there has been some investigation into potential correlation of sevoflurane use and renal damage (nephrotoxicity). However, this should be subject to further investigation, as a recent study shows no correlation between sevoflurane use and renal damage as compared to other control anesthetic agents. There is also evidence that renal damage may be caused by compound A, a product of the degradation of sevoflurane.

## Pharmacology

The exact mechanism of the action of general anaesthetics has not been delineated. Sevoflurane acts as a positive allosteric modulator of the GABA$_A$ receptor in electrophysiology studies of neurons and recombinant receptors. However, it also acts as an NMDA receptor antagonist, potentiates glycine receptor currents, and inhibits nAChR and 5-HT$_3$ receptor currents.

## History

Sevoflurane was discovered by Ross Terrell alongside Louise Speers in the early 1960s researching at Airco Industrial Gases. Sevoflurane was concurrently synthesized by Richard Wallen. The rights for sevoflurane worldwide were held by AbbVie. It is available as a generic drug.

## Global-warming potential

Sevoflurane is a greenhouse gas. The twenty-year global-warming potential, GWP(20), for sevoflurane is 349, however this is significantly lower than isoflurane or desflurane.

## Degradation

Sevoflurane will degrade into what is most commonly referred to as compound A (fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether) when in contact with CO$_2$ absorbents, and this degradation tends to enhance with decreased fresh gas flow rates, increased temperatures, and increased sevoflurane concentration. Compound A may be correlated with renal damage.