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Sevoflurane - Complete Anaesthesia Exam Review

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1. BASIC PHARMACOLOGY & PHYSICAL PROPERTIES

• Morgan & Mikhail's Clinical Anesthesiology, 7e - p. 312
• Katzung's Basic & Clinical Pharmacology, 16e - Table 25-1

• MAC is reduced by: increasing age, hypothermia, hypotension (MAP <50), pregnancy, prior opioids, N2O (additive), benzodiazepines, alpha-2 agonists, hypoxia, metabolic acidosis
• MAC is increased by: infants (peak ~6 months), hyperthermia, chronic alcohol use, chronic opioid use, red hair (possibly)

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2. MECHANISM OF ACTION

1. Potentiation of GABA-A receptors - enhances inhibitory Cl- conductance
2. Inhibition of NMDA receptors - reduces excitatory glutamate signaling
3. Activation of 2-pore domain K+ channels (TREK/TASK) - hyperpolarizes neurons
4. Inhibition of voltage-gated Na+ and Ca2+ channels
5. Potassium channel (Shaker-family Kv1.2) interactions have also been demonstrated

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3. PHARMACOKINETICS

• Induction: 2-4% inhaled concentration (can use 4-8% with N2O for 1-min induction)

• Major metabolite: hexafluoroisopropanol (HFIP) - conjugated to glucuronide
• Also produces inorganic fluoride (F-): serum levels average 22-31 µmol/L (exceed 50 µmol/L in ~7% of patients, but no clinical renal toxicity)
• NOT metabolized to trifluoroacetate - so no immune-mediated hepatitis

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4. EFFECTS ON ORGAN SYSTEMS

A. Cardiovascular System

• Concentration-dependent decrease in arterial BP - due to decreased systemic vascular resistance (SVR) and mild myocardial depression
• No tachycardia (unlike isoflurane/desflurane) - cardiac output less well maintained
• Mild myocardial contractility depression - less than halothane
• BP falls slightly less than with isoflurane or desflurane
• QT interval prolongation - clinical significance uncertain; can persist 60 min post-emergence in infants
• Does NOT sensitize myocardium to catecholamine-induced arrhythmias (unlike halothane)
• Coronary vasodilation - half as potent as isoflurane (less "coronary steal" risk)
• Ischemic preconditioning - provides myocardial protection (may reduce ischemia-reperfusion injury)

B. Respiratory System

• Concentration-dependent respiratory depression: decreased tidal volume, increased respiratory rate in spontaneous breathing - net effect: reduced minute ventilation, raised PaCO2
• Non-irritating to airway - no coughing, breath-holding, or laryngospasm on induction
• Most potent bronchodilator of all volatile anesthetics (best for asthma patients)
• Does not increase secretions
• Decreases hypoxic pulmonary vasoconstriction (HPV) - can worsen V/Q mismatch

C. Central Nervous System

• Decreases CMRO2 (cerebral metabolic rate) - dose-dependent
• Decreases cerebrovascular resistance (CVR), can mildly increase CBF and ICP at normocarbia (>1.5 MAC more pronounced)
• The response to hypocapnia is preserved - hyperventilation can counteract ICP rise
• Does NOT cause seizure activity (unlike enflurane) - seizures not reported with sevoflurane
• Emergence delirium (agitation) - especially in children; short-lived, no long-term sequelae
  • Strategies to prevent: fentanyl 1 µg/kg, propofol, ketamine, or alpha-2 agonists (dexmedetomidine)

D. Neuromuscular System

• Potentiates non-depolarizing neuromuscular blockers (NMBAs) - dose-dependent enhancement
• Produces adequate muscle relaxation for intubation at high concentrations after inhalational induction
• Trigger for malignant hyperthermia (MH) in susceptible individuals

E. Renal System

• Slight decrease in renal blood flow
• Compound A (fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether) - formed by degradation in CO2 absorbents:
  • Nephrotoxic in rats (proximal tubular necrosis at >150 ppm-hours)
  • NOT clinically nephrotoxic in humans (human kidneys have far lower renal beta-lyase activity)
  • Peak compound A: ~20 ppm with soda lime, ~30 ppm with Baralyme at 1 L/min FGF
  • FDA recommendation: FGF ≥1-2 L/min; limit exposure to ≤2 MAC-hours
• Serum fluoride rise: peaks around 22-31 µmol/L - no renal concentrating defect

F. Hepatic System

• Decreases portal vein blood flow but increases hepatic artery blood flow - total hepatic blood flow maintained
• NOT hepatotoxic - not metabolized to trifluoroacetate, so no immune hepatitis (unlike halothane)
• No reported hepatic toxicity in clinical use

G. Uterine/Obstetric

• Uterine relaxation (tocolytic effect) in a dose-dependent manner - can increase bleeding during Caesarean section at >1 MAC
• Crosses placenta - fetal exposure possible; safe in low doses for obstetric procedures

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5. INDICATIONS

1. Inhalational induction of anaesthesia - especially in children and needle-phobic adults (preferred over all other volatile agents due to non-pungency)
2. Maintenance of anaesthesia - after IV or inhalational induction
3. Ambulatory/day-case surgery - rapid emergence, early discharge
4. Paediatric anaesthesia - agent of choice
5. Asthma patients - best bronchodilator among volatiles
6. Patients at risk for myocardial ischemia - less tachycardia than isoflurane/desflurane
7. Volatile Induction and Maintenance Anaesthesia (VIMA)
8. Rapid sequence inhalational induction - 4-8% with 50% N2O achieves unconsciousness in ~1 min

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6. CONTRAINDICATIONS

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7. SPECIAL PRECAUTIONS & CARE TO BE TAKEN

Malignant Hyperthermia (MH)

• Sevoflurane is a potent MH trigger - ABSOLUTELY CONTRAINDICATED in MH-susceptible patients
• In MH-susceptible patients: use a vapour-free/clean anaesthesia machine (flush with high-flow O2 for 10-20 min to wash out residual vapour)
• Have dantrolene immediately available

CO2 Absorbent / Compound A

• Desiccated soda lime or Baralyme dramatically increases compound A production
• Avoid running dry O2/N2O through circuit overnight
• Use calcium hydroxide-only absorbents (Amsorb, Dragersorb free) to minimize compound A
• Maintain FGF ≥ 2 L/min for anaesthetics lasting >2-3 hours
• Risk of fire/explosion in circuit if desiccated CO2 absorbent is present (exothermic reaction); also produces CO

Renal Precaution

• Fluoride-mediated nephrotoxicity: no clinical significance seen, but avoid prolonged low-flow anaesthesia in pre-existing renal impairment
• FDA: limit exposure to <2 MAC-hours at low FGF

Paediatric - Emergence Delirium

• Warn parents; not long-lasting
• Prevention: adequate analgesia + consider fentanyl, dexmedetomidine, or propofol at end of case

Obstetric

• Use at ≤1 MAC to minimize uterine relaxation and excessive blood loss

Cardiac

• QTc prolongation risk - caution in patients on drugs that prolong QT interval (Class Ia/III antiarrhythmics, tricyclics)
• Use with care in severe aortic stenosis (BP-dependent states)

Epilepsy

• Sevoflurane does not cause epileptiform activity - generally safe, but high-dose (>1.5 MAC) spike-wave activity has been reported

Endocrinology

• Avoid in suspected phaeochromocytoma only if combined with epinephrine (though sevoflurane itself does not sensitize - contrast with halothane)

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8. DRUG INTERACTIONS

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9. CLINICAL USE SUMMARY

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10. COMPARISON SNAPSHOT (Exam Table)

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11. HIGH-YIELD EXAM POINTS

• Non-pungent = preferred for inhalational induction (especially paediatrics)
• Most potent bronchodilator of volatile anaesthetics
• No tachycardia = preferred in patients with IHD/tachyarrhythmias
• Does NOT sensitize myocardium to catecholamines - can safely use epinephrine
• Compound A: nephrotoxic in rats, NOT in humans; use FGF >2 L/min with soda lime
• Emergence delirium in children - treat with analgesia, dexmedetomidine, propofol
• QT prolongation - clinical significance uncertain
• No halothane hepatitis - not metabolized to trifluoroacetate
• Metabolized by CYP2E1 - 5%; induced by alcohol and phenobarbital
• Malignant hyperthermia trigger - contraindicated in susceptible patients
• Uterine relaxation at >1 MAC - relevant in obstetric practice
• Desiccated CO2 absorbent → fire risk (circuit ignition) + CO production

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• Morgan & Mikhail's Clinical Anesthesiology, 7e, pp. 312-314
• Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 498-499
• Miller's Anesthesia, 10e, blocks 6, 27, 29
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e, pp. 1403-1404
• Katzung's Basic & Clinical Pharmacology, 16e, Table 25-1
• Lippincott Illustrated Reviews: Pharmacology - p. 677

Recent evidence note: A 2026 meta-analysis (PMID: 41217504) found EEG-guided sevoflurane dosing reduces emergence delirium in children compared to standard care. A 2025 meta-analysis (PMID: 41062401) suggests remimazolam has hemodynamic advantages over sevoflurane in select populations. These do not overturn current clinical practice recommendations.

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