Why this drug is interesting

Sevoflurane is not pungent, does not irritate the airway much, and has a blood/gas partition coefficient of 0.65.¹ Those three facts together are why a child can be anaesthetised through a mask without a cannula, why depth can be changed within a breath or two, and why a patient is often awake before the surgeon has finished the dressing. It replaced halothane in UK paediatric practice for reasons that are straightforwardly pharmacological.

Everything difficult about the drug follows from the same chemistry. It is a halogenated ether, so it triggers malignant hyperthermia. It degrades in the carbon dioxide absorber, which generates Compound A and — if the absorbent has dried out — heat, formaldehyde, carbon monoxide and in rare reports fire. Its rapid offset produces emergence agitation in small children. And it sensitises the myocardium to catecholamines, which is where it collides with ephedrine and adrenaline.

MAC by age

All three UK labels carry the same Table 1. The nitrous oxide column is the MAC-equivalent in 65% N₂O / 35% O₂ except in the 1 to under 3 year group, where 60% N₂O / 40% O₂ was used.¹²³

Age	In oxygen	In 65% N₂O / 35% O₂
0 – 1 month (full term)	3.3%	2.0%
1 – <6 months	3.0%	2.0%
6 months – <3 years	2.8%	2.0%
3 – 12 years	2.5%	2.0%
25 years	2.6%	1.4%
40 years	2.1%	1.1%
60 years	1.7%	0.9%
80 years	1.4%	0.7%

Dosing

Induction: 0.5–1.0% in O₂ ± N₂O, increasing in increments of 0.5–1.0%, to a maximum of 8% in adults and children¹³
Up to 5% usually produces surgical anaesthesia in under 2 minutes in adults; up to 7% in children¹²³
Maintenance: 0.5–3% in O₂ with or without N₂O¹³
Nitrous oxide reduces the MAC equivalent by approximately 50% in adults and approximately 25% in children¹
"Sevoflurane should be delivered via a vaporizer specifically calibrated for use with Sevoflurane"¹ — the physical properties differ between volatiles and an agent-specific vaporiser is not a formality
Licensed age range differs between labels: Piramal says "adult and paediatric patients of all ages, including full term neonates";¹ Baxter says "adults and children";³ AbbVie says "adult and paediatric patients for inpatient and outpatient surgery"²

The low-flow restriction, and the label that omits it

Sevoflurane degrades in contact with the carbon dioxide absorbent to Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFE). Compound A is nephrotoxic in rats. Formation increases as absorbent temperature rises, as sevoflurane concentration rises, and as fresh gas flow falls — which is precisely the direction modern low-flow anaesthesia pushes in, for cost and for environmental reasons.

So whether a UK anaesthetist is working under a stated numerical ceiling on low-flow sevoflurane depends on which manufacturer's product their trust happens to stock. That is a live question, not a historical one, because low-flow technique is actively encouraged.

The reassuring numbers are in the label that omits the restriction

The quantitative case that Compound A is not a clinical problem in humans is printed only in the AbbVie §5.3: Compound A was minimally nephrotoxic in rats at 50–114 ppm over 3 hours; "comparable human thresholds for Compound A-related nephrotoxicity would be predicted to be 150-200 ppm"; and "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."² Nineteen parts per million against a predicted threshold of 150–200. The two labels hold opposite halves of the picture: one imposes the restriction without the exposure data, the other gives the exposure data without the restriction. Neither is wrong; neither is complete. All three labels agree that "the mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established".¹²³

Desiccated absorbent — heat, degradants and fire

The mechanism is a second degradation pathway that operates only when the absorbent is dry. Sevoflurane dissociates to hexafluoroisopropanol and formaldehyde; formaldehyde degrades further to methanol and formate; formate contributes to carbon monoxide formation at high temperature; methanol reacts with Compound A to form Compounds B, C and D.² In an experimental machine with desiccated absorbent and 8% sevoflurane for two hours or more, formaldehyde concentrations in the circuit "were consistent with levels known to cause mild respiratory irritation", though "the clinical relevance of the degradants observed under this extreme experimental model is unknown".¹

Malignant hyperthermia and perioperative hyperkalaemia

The labelled description of the syndrome is worth reading as written, because it names the problem of specificity: it is "signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnoea, cyanosis, arrhythmias, and/or unstable blood pressure", but "some of these nonspecific signs may also appear during light anaesthesia, acute hypoxia, hypercapnia and hypovolaemia".¹

Treatment is "discontinuation of triggering agents (e.g. sevoflurane), administration of intravenous dantrolene sodium … and application of supportive therapy"¹ (see the dantrolene monograph), with active cooling, respiratory and circulatory support, correction of electrolyte and acid–base abnormalities, and monitoring of urine output because "renal failure may appear later".¹ In clinical trials one case of malignant hyperthermia was reported; there have been postmarketing reports, some of them fatal.¹

Perioperative hyperkalaemia is a separate syndrome that looks similar

"Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases."¹ These patients had raised creatine kinase and sometimes myoglobinuria, but — crucially — "none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state".¹ So this is not malignant hyperthermia, and the label's instruction for it is "early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias" followed by evaluation for latent neuromuscular disease — not the dantrolene pathway. That is a distinction to make on the findings in front of you, not a reason to withhold dantrolene from a case you cannot yet separate: the label describes these two presentations as distinguishable in retrospect, and says nothing about how to tell them apart in the first few minutes. See suxamethonium and calcium salts.

Cardiovascular and neurological effects

Catecholamine sensitisation

Haemodynamics

Dose-dependent fall in blood pressure. "Excessive decrease in blood pressure may be related to depth of anaesthesia and in such instances may be corrected by decreasing the inspired concentration of sevoflurane."¹ The first intervention is the dial, not a pressor.
It happens faster than with other volatiles. "Due to sevoflurane's insolubility in blood, hemodynamic changes may occur more rapidly than with some other volatile anaesthetics."¹ Low solubility cuts both ways.
In one volunteer study mean arterial pressure fell with no change in heart rate, and plasma noradrenaline concentrations were unaltered.¹ So the hypotension is not accompanied by a compensatory tachycardia you can use as a warning sign.
Arterial dilatation, including coronary. Caution in coronary disease, "and it is important to maintain normal haemodynamics to avoid myocardial ischemia in these patients".¹
AV junctional rhythm may develop "especially when a vagolytic drug such as atropine has been given beforehand"¹ — see atropine.
QTc prolongation with very rare, occasionally fatal, torsades de pointes — caution in the elderly and in congenital long QT.¹
Marked hypotension with calcium antagonists, particularly dihydropyridines, and additive negative inotropy; impaired AV conduction with verapamil; and potentiation of the negative inotropic, chronotropic and dromotropic effects of beta blockers — which should nonetheless not be stopped abruptly.¹

Central nervous system

In patients with normal intracranial pressure, minimal effect on ICP with preserved CO₂ responsiveness. "The safety of sevoflurane has not been investigated in patients with a raised ICP"¹ — so the reassuring statement does not extend to the patients who need it. Administer cautiously with ICP-reducing manoeuvres such as hyperventilation.
Seizures. "Many have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors."¹ In children "the depth of anaesthesia should be limited", and EEG may help optimise the dose in those predisposed.
Dystonic movements in children have been observed.¹
Isolated ventricular arrhythmia reported in paediatric patients with Pompe's disease; caution in mitochondrial disorders and in myasthenia gravis.¹
Down syndrome: "A significantly higher prevalence and degree of bradycardia has been reported in children with Down syndrome during and following sevoflurane induction."¹³ This statement is absent from the AbbVie label.²

Emergence agitation in children

The trial dataset puts a comparable number on it from a different angle: across more than 3,200 patients in US and European controlled trials, the most frequent adverse events overall were nausea 24% and vomiting 17%, and agitation occurred frequently in children at 23%.¹ Agitation is classified very common in the §4.8 table.¹

Pharmacokinetics, metabolism and interactions

Blood/gas partition coefficient: 0.65¹³
Wash-in (F_A/F_I at 30 min): 0.85¹
Wash-out (F_A/F_A0 at 5 min): 0.15¹
Fraction metabolised: <5%¹
Route of metabolism: Defluorination by CYP2E1 to hexafluoroisopropanol, with release of inorganic fluoride; HFIP glucuronidated and excreted in urine¹
Inorganic fluoride: Peaks within 2 hours of the end of anaesthesia, back to pre-operative levels within 48 hours¹

In the AbbVie label the same fluoride paragraph adds that "in clinical trials, elevated fluoride concentrations were not associated with impairment of renal function".²

Interactions worth knowing

CYP2E1 inducers — isoniazid and alcohol — increase sevoflurane metabolism and plasma fluoride. "Concomitant use of sevoflurane and isoniazid can potentiate the hepatotoxic effects of isoniazid. Due to possible induction of metabolism, isoniazid treatment should be discontinued 1 week before surgery and not restarted until 15 days after surgery."¹ That is an unusually specific instruction and it is easy to miss in a tuberculosis patient coming to theatre.
St John's wort — "severe hypotension and delayed emergence from anaesthesia with halogenated inhalational anaesthetics have been reported in patients treated long-term".¹
Non-selective MAO inhibitors — risk of intraoperative collapse cannot be excluded; stop two weeks before surgery.¹
Indirect-acting sympathomimetics, including ephedrine and amphetamines — risk of acute hypertensive episode; the label advises interrupting such treatment "some days before surgery".¹ See the ephedrine monograph for why this warning sits awkwardly beside the routine intraoperative use of ephedrine as a pressor.
Non-depolarising neuromuscular blockers are potentiated in both intensity and duration, with adjustments similar to isoflurane. For intubation, do not reduce the dose; during maintenance, expect to need less than with N₂O/opioid anaesthesia, guided by nerve stimulation.¹ The effect on suxamethonium and depolarising block "has not been studied". See rocuronium and sugammadex.
Benzodiazepines and opioids reduce MAC as expected; alfentanil and sufentanil with sevoflurane "may lead to a synergistic fall in heart rate, blood pressure and respiratory rate".¹ See midazolam and fentanyl.
Potentiation of neuromuscular block appears within a few minutes of starting sevoflurane, so reducing the relaxant dose at induction "may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation".¹

Hepatic

"Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences."¹ Patients with repeated exposure to halogenated hydrocarbons within a relatively short interval may have an increased risk of hepatic injury, and in anyone who has had jaundice, unexplained fever or eosinophilia after a previous inhalational anaesthetic, "it is recommended to avoid administration of sevoflurane if anaesthesia with intravenous medicinal products or regional anaesthesia is possible".¹

Obstetrics

Safety was demonstrated for mothers and infants in a clinical trial of anaesthesia for Caesarean section; safety in labour and vaginal delivery "has not been demonstrated".¹ The operative caution is uterine, and the label states it twice in slightly different words: §4.4 warns that "the relaxant effect on the uterus could increase the risk of uterine bleeding", and §4.6 gives as the reason for caution in obstetric anaesthesia "the relaxant effect of sevoflurane on the uterus and increase in uterine haemorrhage".¹ That matters when a volatile is deepened during a difficult delivery.

Practical use

Use an agent-specific vaporiser and know the delivered concentration exactly. The label says so twice, in §4.2 and §4.4.¹
Monitor ECG, blood pressure, oxygen saturation and end-tidal CO₂ throughout — a labelled requirement, not a local policy.¹
Check the absorbent, and replace it routinely rather than on the colour indicator. If inspired concentration and vaporiser setting disagree, suspect a hot, dry canister.¹
Treat hypotension by turning the vaporiser down first. Then consider whether the patient was hypovolaemic before you started.
Ask about neuromuscular disease in every child — the hyperkalaemia syndrome targets latent as well as overt disease, especially Duchenne.¹
Ask about malignant hyperthermia in the family, and know where your dantrolene is and which product it is.
Warn parents about emergence agitation before the anaesthetic, and have analgesia running before the volatile goes off.
For a long case at low flow, know which label your trust's product carries — two of the three impose a 2 MAC hour ceiling at 1 to <2 L/min and do not recommend flows below 1 L/min.¹³
Isoniazid is a one-week-before, fifteen-days-after instruction, not a routine caution.¹

Critical appraisal

The low-flow restriction is the finding on this page. Two of three UK labels cap exposure at 2 MAC hours between 1 and 2 L/min and advise against flows below 1 L/min; the third says nothing about flow at all. Low-flow anaesthesia is actively promoted on cost and environmental grounds, so this is not an academic gap — and it is resolved for an individual anaesthetist only by reading the specific product's SmPC.
Compound A is better characterised than the restriction implies, and that characterisation is in the wrong label. A predicted human threshold of 150–200 ppm against measured clinical exposures averaging 19 ppm is reassuring arithmetic. It appears only in the AbbVie document, under §5.3 preclinical safety, where an anaesthetist is least likely to look.
The rat nephrotoxicity data are rat data and all three labels say so. "The mechanism of this renal toxicity in rats is unknown and its relevance to man has not been established." That sentence is frequently dropped when Compound A is discussed, which turns a declared uncertainty into an implied human hazard.
The §4.5 adrenaline entries contradict each other. "Safe with cardiovascular drugs, including epinephrine" and "parenteral administration of adrenaline and noradrenaline is not recommended" cannot both be acted on literally. A reader needs the dose-and-purpose distinction the label does not supply.
The fire warning is real, rare, and device-dependent rather than drug-dependent. It concerns desiccated potassium-hydroxide absorbents, a material largely retired from UK practice. It belongs on the page because the label's instruction — do not trust the colour indicator — remains good advice with any absorbent.
Emergence agitation is quantified (about 25%, and 23% in the trial dataset) and still routinely described to families as unexpected. That is a communication failure rather than a pharmacological one.

References

1
Sevoflurane 100% Inhalation Vapour, liquid — Summary of Product Characteristics, Piramal Critical Care Ltd. electronic Medicines Compendium, product 9780. Sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 5.1, 5.2. Text updated 12 Aug 2026; verified 6 Oct 2026. This is the most recently revised of the three UK labels and is the primary source for this page unless stated otherwise.
2
Sevoflurane — Summary of Product Characteristics, AbbVie Ltd. emc, product 833. Sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.8, 5.2, 5.3. Text updated 15 Jun 2020; verified 6 Oct 2026. The only one of the three carrying the Compound A ppm figures, and the only one with no fresh-gas-flow restriction.
3
Sevoflurane Baxter, 100%, Inhalation vapour, liquid — Summary of Product Characteristics, Baxter Healthcare Ltd. emc, product 1866. Sections 4.1, 4.2, 4.3, 4.4, 4.5, 5.1, 5.3. Text updated 18 Jan 2024; verified 6 Oct 2026.
4
Ephedrine Hydrochloride 3 mg/ml Solution for Injection in Pre-filled Syringe — Summary of Product Characteristics, Laboratoire Aguettant. emc, product 5354. Sections 4.1, 4.4, 4.5. Verified 6 Oct 2026. See the ephedrine monograph.
5
Agilus 120 mg powder for solution for injection (dantrolene sodium) — Summary of Product Characteristics, Norgine Pharmaceuticals Limited. emc, product 15912. Section 4.2: 2.5 mg/kg, repeat every 10 min, not to exceed 300 mg (2.5 vials) per dose; re-examine the diagnosis at a cumulative 10 mg/kg; reconstitute with 20 mL water for injections. Text updated 16 Apr 2025; verified 6 Oct 2026. See the dantrolene monograph.
6
Sevoflurane — dosing and safety monograph. BNF, NICE. bnf.nice.org.uk

Sevoflurane

At a glance