Inhalation/Respiratory Induction and maintenance of general anaesthesia
Adult: Induction: Premedicated patient: Up to 5% v/v with oxygen (or mixture of oxygen and nitrous oxide), individualised and titrated to the desired effect according to age and clinical status. Unpremedicated patient: Up to 8% v/v. Maintenance: 0.5-3% v/v with or without nitrous oxide. Doses are administered via calibrated vaporiser. Individualise dose according to patient response. Elderly: Dose reduction may be necessary. Child: Induction: Premedicated patient: Up to 7% v/v with oxygen (or mixture of oxygen and nitrous oxide) given via calibrated vaporiser.
Special Patient Group
Pharmacogenomics:
Sevoflurane is identified as a triggering agent of malignant hyperthermia. Individuals who are susceptible to malignant hyperthermia or those who carry certain genetic variants of ryanodine receptor isoform 1 gene (RYR1) and CACNA1S gene are predisposed to possible fatal hypermetabolic reactions triggered by potent volatile anaesthetics like sevoflurane. Approx 70% of individuals who have susceptibility to malignant hyperthermia have the RYR1 pathogenic variants as the primary pharmacogenetic trait, while approx 1% of patients with malignant hyperthermia susceptibility have the CACNA1S pathogenic variants.
Clinical Pharmacogenetics Implementation Consortium (CPIC) supplemented the evaluations of the European Malignant Hyperthermia Group (EMHG) consortium which identified the 50 causative variants considered as diagnostic mutations. CPIC recommends performing genetic testing prior to initiation and consider the personal family history of individuals in relation to malignant hyperthermia and their susceptibility. The recommendations are directed at a scenario of patients without known personal or family history of susceptibility to malignant hyperthermia, without myopathy, and determined positive to at least 1 of the 50 identified pathogenic variants.
Recommendations for sevoflurane in relation to RYR1 and CACNA1S phenotype according to genotype:
Malignant hyperthermia susceptible
An individual heterozygous for an RYR1 or CACNA1S malignant hyperthermia causative variant assigned by EMHG [e.g. RYR1 c.103T>C; p.(Cys35Arg), RYR1 c.488G>T; p.(Arg163Leu), RYR1 c.742G>A>C; p.(Gly248Arg), RYR1 c.1209C>G; p.(Ile403Met), RYR1 c.1565A>C; p.(Try522Ser), RYR1 c.14545G>A; p.(Val4849Ile), and CACNA1S c.520C>T; p.(Arg174Trp), CACNA1S c.3257G>A; p.(Arg1086His)] (refer to detailed CPIC guideline for complete list of causative variants), are at increased risk of developing malignant hyperthermia if administered with sevoflurane. Avoid using sevoflurane, except in cases where the benefits outweigh the risks. Regional anaesthesia (e.g. neuraxial, peripheral nerve block or local anaesthesia), nondepolarizing muscle relaxants, prolonged inhalational anaesthesia with non-triggering agents, and IV inducing agents may be used as alternatives in individuals who are susceptible to malignant hyperthermia.
Uncertain susceptibility
Patients who are negative for RYR1 or CACNA1S malignant hyperthermia causative variant based from EMHG. Negative or inconclusive results do not eliminate the risk of susceptibility to malignant hyperthermia. CPIC recommends monitoring the individual’s clinical findings, family history, and other laboratory data, and perform further genetic testing to guide the use of sevoflurane.
Contraindications
Known or suspected genetic susceptibility to malignant hyperthermia (e.g. presence of RYR1 or CACNA1S pathogenic variants). History of hepatic impairment, fever or leucocytosis of unknown cause associated with halogenated anaesthetics. Concomitant administration with succinylcholine.
Special Precautions
Patient with neuromuscular disease (e.g. Duchenne muscular dystrophy); heart failure, coronary artery disease, seizure disorder, mitochondrial disorders. Patients who are hypovolaemic, hypotensive, haemodynamically compromised, and at risk of QT prolongation or increased intracranial pressure. Obstetric anaesthesia. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Respiratory depression, hypotension, agitation or delirium, increased intracranial pressure, dystonic movements (children). Rarely, hepatic effects (e.g. postoperative hepatic dysfunction, hepatitis with or without jaundice), seizures. Cardiac disorders: Bradycardia, tachycardia. Gastrointestinal disorders: Nausea, vomiting, salivary hypersecretion. General disorders and administration site conditions: Chills, hypothermia. Immune system disorders: Rarely, hypersensitivity. Investigations: Abnormal blood glucose, LFTs, WBC count; increased blood fluoride, AST/ALT. Nervous system disorders: Drowsiness, dizziness, headache. Renal and urinary disorders: Urinary retention, acute renal failure. Respiratory, thoracic and mediastinal disorders: Cough, laryngospasm, airway obstruction, apnoea, breath-holding. Vascular disorders: Hypertension. Potentially Fatal: Malignant hyperthermia. Rarely, perioperative hyperkalaemia resulting in cardiac arrhythmias; QT prolongation associated with torsade de pointes; hepatic necrosis and failure.
Patient Counseling Information
This drug may impair mental alertness for some time after administration, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor blood pressure, temperature, heart rate and rhythm, oxygen saturation, end-tidal CO2, and end-tidal sevoflurane levels prior to and throughout anaesthesia; temperature of CO2 absorbent canister. Monitor for emergence of agitation and delirium.
Overdosage
Symptoms: Respiratory depression and circulatory insufficiency. Management: Discontinue administration, establish clear airway, initiate assisted or controlled ventilation with oxygen and maintain adequate CV function.
Drug Interactions
Increased risk of QT prolongation with class Ia and III antiarrhythmics. May increase risk of ventricular arrhythmia with β-sympathomimetic agents (e.g. isoprenaline), and α- and β-sympathomimetic drugs (e.g. noradrenaline, adrenaline). Impaired atrioventricular conduction with verapamil. May increase the negative inotropic, chronotropic and dromotropic effects of β-blockers. Increased metabolism and toxicity with CYP2E1 inducers (e.g. isoniazid). May increase risk of acute hypertensive episode with indirect-acting sympathomimetics (e.g. ephedrine, amphetamines). Potentiates hepatotoxic effects of isoniazid. May decrease MAC with benzodiazepines, opioids, nitrous oxide. May cause synergistic fall in heart rate, blood pressure and respiratory rate with opioids (e.g. alfentanil, sufentanil). Potentiates neuromuscular blocking effects of pancuronium, vecuronium, atracurium. Potentially Fatal: Rarely, hyperkalaemia resulting to cardiac arrythmias with succinylcholine.
Food Interaction
Increased metabolism and toxicity of sevoflurane with alcohol. Increased risk of severe hypotension and delayed emergence from anaesthesia with St. John’s wort.
Action
Description: Mechanism of Action: Sevoflurane is a volatile, halogenated, and inhaled general anaesthetic which alters the activity of fast synaptic neurotransmitter receptors such as nicotinic acetylcholine, GABA, and glutamate receptors. It may depress myocardial contractility, decrease blood pressure by reducing the systemic vascular resistance, and decrease systemic sympathetic nervous activity. Onset: Induction time: Within 2-3 minutes. Pharmacokinetics: Absorption: Absorbed on inhalation. Blood/gas partition coefficient: Low. Distribution: Crosses the placenta. Metabolism: Metabolised in the liver (approx 5%) by CYP2E1 and undergoes defluorination to form its major metabolites, hexafluoroisopropanol (HFIP), inorganic fluoride, and CO2. Excretion: Via urine (up to 3.5% as inorganic fluoride); exhaled gases.
Chemical Structure
Sevoflurane Source: National Center for Biotechnology Information. PubChem Database. Sevoflurane, CID=5206, https://pubchem.ncbi.nlm.nih.gov/compound/Sevoflurane (accessed on Jan. 23, 2020)
N01AB08 - sevoflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.
References
Gonsalves SG, Dirksen RT, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or
CACNA1S Genotypes. CPIC Guideline. 2019 Jun;105(6):1338-1344. doi: 10.1002/cpt.1319. Accessed 04/12/2019Annotation of CPIC Guideline for Desflurane, Enflurane, Halothane, Isoflurane, Methoxyflurane, Sevoflurane, Succinylcholine and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/12/2019.Annotation of FDA Label for Sevoflurane and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 04/12/2019.Anon. CACNA1S - Sevoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 25/12/2019.Anon. RYR1 - Sevoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 25/12/2019.Anon. Sevoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 04/12/2019.Buckingham R (ed). Sevoflurane. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/12/2019.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 04/12/2019.Ultane (AbbVie Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/12/2019.
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