Isoflurane

(BAN, USAN, rINN)
Isoflurane Chemical formula
Synonyms: Compound 469; Isofluraani; Isofluran; Isoflurano; Isofluranum; Izoflurán; Izofluran; Izofluranas. 1-Chloro-2,2,2-trifluoroethyl difluoromethyl ether; 2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane.
Cyrillic synonym: Изофлуран.

💊 Chemical information

Chemical formula: C3H2ClF5O = 184.5.
CAS — 26675-46-7.
ATC — N01AB06.
ATC Vet — QN01AB06.

Pharmacopoeias.

In Eur., Jpn, and US.

Ph. Eur. 6.2

(Isoflurane). A clear, colourless, mobile, heavy liquid. B.p. about 48°. It is non-flammable. Practically insoluble in water; miscible with dehydrated alcohol and with trichloroethylene. Store in airtight containers. Protect from light.

USP 31

(Isoflurane). A clear, colourless, volatile liquid having a slight odour. B.p. about 49°. Insoluble in water; miscible with common organic solvents and with fats and oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°.

💊 Adverse Effects and Precautions

As with other halogenated anaesthetics, respiratory depression, hypotension, arrhythmias, and malignant hyperthermia have been reported; patients with known or suspected susceptibility to malignant hyperthermia should not be anaesthetised with isoflurane. Isoflurane differs from halothane and enflurane in that it produces less cardiac depression than either drug and heart rate may be increased. Also isoflurane sensitises the myocardium to sympathomimetics to a lesser extent than halothane and enflurane. The incidence of cardiac arrhythmias is lower with isoflurane than with halothane. Shivering, nausea, and vomiting have been reported in the postoperative period. Induction with isoflurane is not as smooth as with halothane and this may be connected with its pungency; breath holding, coughing, and laryngospasm may occur. It has been reported to increase the cerebrospinal pressure and should be used with caution in patients with raised intracranial pressure. Isoflurane relaxes the uterine muscle; increased blood loss may occur after curettage or termination of pregnancy. In order to minimise the risk of developing elevated carboxyhaemoglobin levels, carbon dioxide absorbents in anaesthetic apparatus should not be allowed to dry out when delivering volatile anaesthetics such as isoflurane (see below). See also Adverse Effects and Precautions of General Anaesthetics.
Others2 also found a higher incidence of coughing, salivation, and laryngospasm with isoflurane than halothane, but felt that it could be used as an alternative. Further information on the adverse effects profile of isoflurane can be obtained from the report of and commentaries on an extensive multicentre study of patients undergoing anaesthesia with this agent.3,4
1. Cattermole RW, et al. Isoflurane and halothane for outpatient dental anaesthesia in children. Br J Anaesth 1986; 58: 385–9
2. McAteer PM, et al. Comparison of isoflurane and halothane in outpatient paediatric dental anaesthesia. Br J Anaesth 1986; 58: 390–3
3. Forrest JB, et al. A multi-centre clinical evaluation of isoflurane. Can Anaesth Soc J 1982; 29 (suppl): S1–S69
4. Levy WJ. Clinical anaesthesia with isoflurane: a review of the multicentre study. Br J Anaesth 1984; 56: 101S–112S.

Carbon dioxide absorbents.

Significant carboxyhaemoglobinaemia may develop rarely during anaesthesia with volatile anaesthetics given by circle breathing systems containing carbon dioxide absorbents.1 The effect is only seen when the absorbent has become excessively dried out. The use of barium hydroxide lime (which is not available in the UK) as an absorbent produces more carbon monoxide than soda lime, particularly at low water content. No cases of this complication had been reported to date in the UK.
1. Committee on Safety of Medicines/Medicines Control Agency. Safety issues in anaesthesia: volatile anesthetic agents and carboxyhaemoglobinaemia. Current Problems 1997; 23: 7. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023230&RevisionSelectionMethod= LatestReleased (accessed 16/05/06)

Effects on the cardiovascular system.

Isoflurane is considered to produce less cardiovascular depression than halothane. However, the results of a study1 suggest that while this may be true for young patients, in elderly patients isoflurane appears to have a cardiac depressant effect similar to that of halothane.
1. McKinney MS, et al. Cardiovascular effects of isoflurane and halothane in young and elderly adult patients. Br J Anaesth 1993; 71: 696–701.
CEREBRAL BLOOD FLOW. Autoregulation of cerebral blood flow appears to be impaired at higher concentrations of isoflurane. A study1 in healthy subjects found that increasing isoflurane anaesthesia from a concentration of 1 to 2 MAC increased cerebral blood flow and reduced cerebral oxygen metabolism.
1. Olsen KS, et al. Effect of 1 or 2 MAC isoflurane with or without ketanserin on cerebral blood flow autoregulation in man. Br J Anaesth 1994; 72: 66–71.
CORONARY CIRCULATION. Halothane, enflurane, and isoflurane decrease coronary perfusion pressure, coronary blood flow, ventricular function, and myocardial oxygen demand. Halothane and enflurane have a variable effect on coronary vascular resistance, but isoflurane dilates coronary vessels.1There has been concern over the potential of isoflurane to produce coronary steal and whether this effect is detrimental in patients with ischaemic heart disease.2 However, despite conflicting results of individual studies3-6 an early review7 concluded that isoflurane could be used safely even in high-risk patients with coronary artery disease provided that blood pressure and heart rate were maintained close to baseline concentrations. A subsequent review8 considered that more recent evidence supported the use of isoflurane as the anaesthetic agent of choice in patients with coronary heart disease.
1. Quail AW. Modern inhalational anaesthetic agents: a review of halothane, isoflurane and enflurane. Med J Aust 1989; 150: 95–102
2. Stoelting RK. Anesthesiology. JAMA 1991; 265: 3103–5
3. Buffington CW, et al. The prevalence of steal-prone coronary anatomy in patients with coronary artery disease: an analysis of the coronary artery surgery study registry. Anesthesiology 1988; 69: 721–7
4. Inoue K, et al. Does isoflurane lead to a higher incidence of myocardial infarction and perioperative death than enflurane in coronary artery surgery? A clinical study of 1178 patients. Anesth Analg 1990; 71: 469–74
5. Slogoff S, et al. Steal-prone coronary anatomy and myocardial ischemia associated with four primary anesthetic agents in humans. Anesth Analg 1991; 72: 22–7
6. Stühmeier KD, et al. Isoflurane does not increase the incidence of intraoperative myocardial ischaemia compared with halothane during vascular surgery. Br J Anaesth 1992; 69: 602–6
7. Hogue CW, et al. Anesthetic-induced myocardial ischemia: the isoflurane-coronary steal controversy. Coron Artery Dis 1993; 4: 413–19
8. Agnew NM, et al. Isoflurane and coronary heart disease. Anaesthesia 2002; 57: 338–47.

Effects on the kidneys.

See under Metabolism in Pharmacokinetics, below.

Effects on the liver.

Of 45 cases of isoflurane-associated hepatotoxicity reported to the FDA between 1981 and 1984 there was some other cause for the liver damage in 29. While isoflurane might have been one of the causes of the damage in the other 16 cases, there was not a reasonable likelihood of an association between isoflurane and postoperative liver impairment.1 Subsequent rare cases of hepatotoxicity,2-7 sometimes fatal,2,5,7 have suggested that isoflurane may induce hepatitis, though much less frequently than halothane, and that there may be cross-sensitisation with other halogenated anaesthetics. See also under the Adverse Effects of Halothane.
1. Stoelting RK, et al. Hepatic dysfunction after isoflurane anesthesia. Anesth Analg 1987; 66: 147–53
2. Carrigan TW, Straughen WJ. A report of hepatic necrosis and death following isoflurane anesthesia. Anesthesiology 1987; 67: 581–3
3. Sinha A, et al. Isoflurane hepatotoxicity: a case report and review of the literature. Am J Gastroenterol 1996; 91: 2406–9
4. Hasan F. Isoflurane hepatotoxicity in a patient with a previous history of halothane-induced hepatitis. Hepatogastroenterology 1998; 45: 518–22
5. Turner GB, et al. Fatal hepatotoxicity after re-exposure to isoflurane: a case report and review of the literature. Eur J Gastroenterol Hepatol 2000; 12: 955–9
6. Malnick SDH, et al. Acute cholestatic hepatitis after exposure to isoflurane. Ann Pharmacother 2002; 36: 261–3
7. Ihtiyar E, et al. Fatal isoflurane hepatotoxicity without re-exposure. Indian J Gastroenterol 2006; 25: 41–2.

Effects on the nervous system.

Seizures associated with induction of anaesthesia with isoflurane have been reported in patients without known neurological abnormalities and not undergoing neurosurgery.1,2 However, data from a retrospective analysis of patients undergoing intracranial surgery indicated that when convulsions occurred postoperatively in these conditions, it was the neurosurgical procedures rather than the anaesthetics that were responsible.3 See also under Status Epilepticus in Uses, below.
1. Poulton TJ, Ellingson RJ. Seizure associated with induction of anesthesia with isoflurane. Anesthesiology 1984; 61: 471–6
2. Hymes JA. Seizure activity during isoflurane anesthesia. Anesth Analg 1985; 64: 367–8
3. Christys AR, et al. Retrospective study of early postoperative convulsions after intracranial surgery with isoflurane or enflurane anaesthesia. Br J Anaesth 1989; 62: 624–7.

Effects on the respiratory tract.

A study1 conducted mainly in adults found that humidification of anaesthetic mixtures containing isoflurane could reduce respiratory complications such as coughing, laryngospasm, and breath-holding that were usually associated with the use of isoflurane for induction. However, a similar study2 in children failed to confirm these findings.
1. van Heerden PV, et al. Effect of humidification on inhalation induction with isoflurane. Br J Anaesth 1990; 64: 235–7
2. McAuliffe GL, et al. Effect of humidification on inhalation induction with isoflurane in children. Br J Anaesth 1994; 73: 587–9.

Effects on the skin.

There have been rare reports of contact dermatitis to isoflurane in anaesthetists.1,2
1. Caraffini S, et al. Isoflurane: an uncommon cause of occupational airborne contact dermatitis. Contact Dermatitis 1998; 38: 286
2. Muncaster A, et al. Allergic contact dermatitis to isoflurane. Br J Dermatol 1999; 141: (suppl 55): 96–7.

Porphyria.

Isoflurane is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

💊 Interactions

The effects of competitive neuromuscular blockers such as atracurium are enhanced by isoflurane. Care is advised if adrenaline and other sympathomimetics are given during isoflurane anaesthesia. See also Interactions of General Anaesthetics.

General anaesthetics.

For a report that isoflurane increases serum concentrations of propofol.

💊 Pharmacokinetics

Isoflurane is absorbed on inhalation. The blood/gas partition coefficient is lower than that of enflurane or halothane. It is mostly excreted unchanged through the lungs. About 0.2% of inhaled isoflurane is metabolised, mainly to inorganic fluoride.

Metabolism.

In 26 patients sedated with isoflurane for 24 hours, plasma fluoride ion concentration increased from a mean of 4.03 nanomol/mL to 13.57 nanomol/mL in 12 hours after stopping sedation.1 These fluoride concentrations were considered to be too low to cause clinical renal dysfunction. In 30 patients sedated with isoflurane for up to 127 hours (mean duration was 36 hours), mean plasma fluoride ion concentration increased2 to 20.01 nanomol/mL during sedation and continued rising for 16 hours after stopping isoflurane to a maximum mean concentration of 25.34 nanomol/mL; thereafter, levels gradually declined to normal values by the fifth day. Despite the increased plasma fluoride ion concentrations, no biochemical or clinical evidence of deterioration in renal function was found. Giving isoflurane for 34 days to a patient with tetanus who required sedation to facilitate mechanical ventilation resulted3 in sustained fluoride ion concentrations of 50 nanomol/mL and a peak concentration of 87 nanomol/mL. Although such concentrations are considered to be potentially nephrotoxic no clinical effect on renal function was found.
1. Kong KL, et al. Isoflurane sedation for patients undergoing mechanical ventilation: metabolism to inorganic fluoride and renal effects. Br J Anaesth 1990; 64: 159–62
2. Spencer EM, et al. Plasma inorganic fluoride concentrations during and after prolonged (>24h) isoflurane sedation: effect on renal function. Anesth Analg 1991; 73: 731–7
3. Stevens JJWM, et al. Prolonged use of isoflurane in a patient with tetanus. Br J Anaesth 1993; 70: 107–109.

💊 Uses and Administration

Isoflurane is a volatile halogenated anaesthetic given by inhalation. It is an isomer of enflurane and has anaesthetic actions similar to those of halothane. Isoflurane has a minimum alveolar concentration (MAC) value ranging from 1.05% in the elderly to 1.87% in infants. It is used in the induction and maintenance of general anaesthesia although induction is more often carried out using an intravenous anaesthetic. Isoflurane is also used in subanaesthetic doses to provide analgesia in obstetrics and other painful procedures. Isoflurane is given using a calibrated vaporiser. If it is used for induction then it is given with oxygen or oxygen and nitrous oxide mixtures and induction should start with an isoflurane concentration of 0.5% v/v increased to 1.5 to 3% v/v which generally produces surgical anaesthesia within 10 minutes. Its pungency may limit the rate of induction. Anaesthesia may be maintained with a concentration of 1 to 2.5% v/v with oxygen and nitrous oxide mixtures; 1.5 to 3.5% v/v may be required if used only with oxygen. Isoflurane 0.5 to 0.75% v/v with oxygen and nitrous oxide mixtures is suitable to maintain anaesthesia for caesarean section. Although isoflurane is reported to possess muscle relaxant properties, neuromuscular blockers may nevertheless be required. Recovery is rapid.

Anaesthesia.

CAESAREAN SECTION. Isoflurane 0.8% v/v has been found to be a suitable supplement to nitrous oxide-oxygen anaesthesia for patients undergoing caesarean section.1 It has been suggested2 that an overpressure technique might be of use to further reduce awareness in such patients. Giving isoflurane at a concentration of 2% v/v for 5 minutes followed by concentrations of 1.5% v/v for the next 5 minutes and 0.8% v/v thereafter produced higher arterial concentrations of isoflurane in patients undergoing caesarean section than when it was given at a concentration of 1% v/v throughout.2
1. Dwyer R, et al. Uptake of halothane and isoflurane by mother and baby during Caesarean section. Br J Anaesth 1995; 74: 379–83
2. McCrirrick A, et al. Overpressure isoflurane at Caesarean section: a study of arterial isoflurane concentrations. Br J Anaesth 1994; 72: 122–4.

Pain.

Isoflurane is used in subanaesthetic doses to provide analgesia in obstetrics and other painful procedures but studies1,2have been unable to confirm that it had an analgesic effect at subanaesthetic concentrations. The use of isoflurane 0.2 or 0.25% v/v in a mixture of nitrous oxide 50% v/v and oxygen 50% v/v has been studied.3,4
1. Tomi K, et al. Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth 1993; 70: 684–6
2. Roth D, et al. Analgesic effect in humans of subanaesthetic isoflurane concentrations evaluated by evoked potentials. Br J Anaesth 1996; 76: 38–42
3. Wee MYK, et al. Isoflurane in labour. Anaesthesia 1993; 48: 369–72
4. Bryden FM, et al. Isoflurane for removal of chest drains after cardiac surgery. Br J Anaesth 1994; 73: 712P–713P.

Sedation.

INTENSIVE CARE. Isoflurane is not usually considered for such a purpose but in a comparative 24-hour study1 in 60 patients requiring mechanical ventilation, isoflurane 0.1 to 0.6% v/v in an air-oxygen mixture produced satisfactory sedation for a greater proportion of time than did the continuous infusion of midazolam 10 to 200 micrograms/kg per hour. Patients given isoflurane also recovered more rapidly. Isoflurane has also been used successfully for sedation over 5 days in a 3-year-old infant who required ventilation for pneumonia, a complication of the child’s myasthenia gravis.2 However, there has been some concern over high plasma fluoride concentrations after prolonged use of isoflurane (see under Metabolism in Pharmacokinetics, above).
1. Kong KL, et al. Isoflurane compared with midazolam for sedation in the intensive care unit. BMJ 1989; 298: 1277–80
2. McBeth C, Watkins TGL. Isoflurane for sedation in a case of congenital myasthenia gravis. Br J Anaesth 1996; 77: 672–4.

Status epilepticus.

General anaesthesia may be used to control refractory tonic-clonic status epilepticus. A short-acting barbiturate such as thiopental is usually used. Despite rare reports of seizures associated with the use of isoflurane in anaesthetic procedures (see Effects on the Nervous System, above) it has been used successfully,1-3 typically in concentrations of 0.5 to 1% v/v, to control refractory convulsive status epilepticus. Although some4 consider that isoflurane-induced coma may be more easy to control than barbiturate-induced coma, the use of isoflurane may be limited by the need for special anaesthetic equipment and continuous EEG monitoring.
1. Meeke RI, et al. Isoflurane for the management of status epilepticus. DICP Ann Pharmacother 1989; 23: 579–81
2. Hilz MJ, et al. Isoflurane anaesthesia in the treatment of convulsive status epilepticus. J Neurol 1992; 239: 135–7
3. Mirsattari SM, et al. Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 2004; 61: 1254–9
4. Bauer J, Elger CE. Management of status epilepticus in adults. CNS Drugs 1994; 1: 26–44.

💊 Preparations

Proprietary Preparations

Arg.: Forane; Zuflax; Austral.: AErrane; Forthane; Austria: Forane; Belg.: Forene†; Braz.: Forane; Isoforine; Isothane†; Canad.: Forane; Chile: Forene; Cz.: AErrane; Forane; Denm.: Forene; Fin.: Forene; Ger.: Forene; Gr.: Forenium; Hong Kong: Forane; Hung.: AErrane; Forane; Indon.: AErrane; Forane; Irl.: Forane; Israel: AErrane; Forane; Ital.: AErrane; Forane; Malaysia: Forane; Mex.: Forane; Lisorane†; Sofloran; Neth.: AErrane; Forene; Norw.: Forene; NZ: AErrane; Forane; Philipp.: AErrane; Forane; Pol.: AErrane; Forane; Port.: Forene; Rus.: Forane (Форан)†; S.Afr.: AErrane; Forane; Singapore: Forane; Spain: AErrane; Forane; Swed.: Forene; Switz.: Forene; Thai.: AErrane; Forane; Turk.: AErrane; Forane; UK: AErrane; USA: Forane; Terrell; Venez.: Forene.
Published October 24, 2018.