Desflurane: Pharmacology and Clinical Use

Quick Answer

Desflurane is a fluorinated methyl ethyl ether with lowest blood/gas partition coefficient (0.42), providing most rapid emergence of volatile agents. Physical properties: High vapor pressure (669 mmHg at 20°C), requiring heated (23°C) pressurized vaporizer (Tec 6/7). Pharmacokinetics: Very low solubility → fastest induction and emergence (wash-in and wash-out), suitable for ambulatory surgery. Side effects: Pungent odor → airway irritation (cough, laryngospasm, breath-holding), contraindicated for inhalational induction; sympathetic stimulation (tachycardia, hypertension) on rapid increase in concentration. Clinical use: Maintenance only (not induction), MAC 6.0% (age-dependent), good for neurosurgery (rapid emergence for neuro assessment), bariatric surgery, outpatient procedures. Environmental: High atmospheric lifetime (14 years), significant greenhouse gas contribution. [1-10]

Pharmacology

Physical Properties

Molecular Characteristics:

• Structure: Fluorinated methyl ethyl ether (CF₃-CHF-O-CHF₂)
• Molecular weight: 168 Da
• Boiling point: 23.5°C (near room temperature)
• Vapor pressure: 669 mmHg at 20°C, 760 mmHg at 23°C
• Density: 1.47 g/mL (liquid)

Partition Coefficients:

• Blood/gas: 0.42 (lowest of all volatile agents)
  • cf. Nitrous oxide 0.46, sevoflurane 0.65, isoflurane 1.4, halothane 2.5
• Oil/gas: 18.7
• Oil/water: 29
• Brain/blood: 1.3
• Muscle/blood: 2.0
• Fat/blood: 27 (higher than sevoflurane)

Clinical Implications of Low Blood/Gas Solubility:

• Rapid wash-in: Fast alveolar concentration rise (induction)
• Rapid wash-out: Fast emergence, quick offset
• Sensitive to ventilation changes: Alterations in minute ventilation rapidly change depth
• Less dependent on cardiac output: Low solubility means less uptake per cardiac output unit

Vaporizer Requirements

Tec 6/7 Vaporizer (Desflurane-Specific):

• Heated: 23°C (above boiling point of desflurane)
• Pressurized: Electrically heated, pressurized to 1500 mmHg (2 atm)
• Dual-circuit: Fresh gas flows through heat exchanger, not through liquid
• Injection: Liquid desflurane injected into heated vaporization chamber, then mixed with fresh gas
• Safety: Will not deliver desflurane if power fails or overheats
• Interlocks: Desflurane vaporizer cannot be used simultaneously with other agent vaporizers
• Filling: Easy-fill system, agent-specific (purple color coding)

Why Standard Vaporizers Don't Work:

• Desflurane boiling point 23.5°C → at room temperature would boil (volatile)
• Variable output with temperature fluctuations
• Tec 6/7 maintains constant temperature and pressure for precise delivery

Pharmacokinetics

Uptake and Distribution:

• Rapid alveolar rise: Due to low blood/gas partition coefficient
• Induction: Faster than sevoflurane (theoretical), but airway irritation limits use
• Emergence: Fastest of all volatile agents (5-10 minutes to awakening after prolonged infusion)
• Context-sensitive decrement time: Half-life independent of duration (unlike propofol)
• Fat solubility: Moderate (27× blood) - prolonged exposure (>6 hours) may slow emergence slightly

Metabolism:

• Metabolized: 0.02% (minimal)
• Pathway: CYP2E1 oxidation → trifluoroacetic acid (TFA), inorganic fluoride, CO₂
• Fluoride levels: Negligible (peak <5 μmol/L)
• Cross-sensitivity: TFA similar to halothane metabolite (theoretical hepatitis risk, extremely rare)
• Renal/hepatic: No organ toxicity from metabolism

Elimination:

• Primary: Exhalation (unchanged drug)
• Metabolism: <0.1%
• Clearance: Very rapid due to low solubility

Pharmacodynamics

Central Nervous System:

• MAC: 6.0% (young adult), decreases with age
  • 20 years: 7.25%
  • 40 years: 6.0%
  • 60 years: 4.5%
  • 80 years: 3.5%
• Cerebral blood flow: Increases (vasodilation) dose-dependently
• CMRO₂: Decreases
• ICP: May increase at >1 MAC (cerebral vasodilation)
• EEG: Burst suppression at high concentrations
• Emergence: Rapid, clear-headed recovery (good for neurosurgery)

Cardiovascular System:

• Heart rate: Dose-dependent increase (sympathetic stimulation)
• Blood pressure: Dose-dependent decrease (vasodilation), but may increase on rapid concentration change
• Contractility: Mild depression at high concentrations
• SVR: Decreased (vasodilation)
• Coronary blood flow: Increased (vasodilation)
• Coronary steal: Theoretical concern (vasodilation may divert flow from stenotic vessels), but clinical significance unclear
• Arrhythmias: Rare, less than halothane
• Catecholamine sensitivity: Less than halothane

Respiratory System:

• Ventilation: Dose-dependent decrease (tidal volume and minute ventilation)
• Response to CO₂: Decreased slope (less responsive)
• Airway resistance: May increase (bronchodilation less than sevoflurane, airway irritation)
• Irritation: Pungent → cough, laryngospasm, breath-holding, salivation
• Contraindication: Inhalational induction (especially children)

Airway Effects (Unique to Desflurane):

• Pungency: Most irritating of modern volatiles
• Concentration-related: Worse at higher concentrations
• Mechanism: Trigeminal nerve irritation (nasal, pharyngeal mucosa)
• Clinical: Coughing, breath-holding, laryngospasm, increased secretions
• Avoidance: Not for mask induction; use IV induction first

Musculoskeletal System:

• Muscle relaxation: Synergistic with neuromuscular blockers
• Contracture: Normal muscle, not MH-susceptible muscle (unlike halothane in MH)
• Malignant hyperthermia: Trigger (like all volatile agents)

Renal System:

• Blood flow: Decreased (vasodilation of afferent/efferent arterioles)
• GFR: Mild decrease
• Urine output: May decrease
• Nephrotoxicity: None (no fluoride release)

Hepatic System:

• Blood flow: Decreased (arterial vasodilation, reduced MAP)
• Hepatotoxicity: Extremely rare (not associated like halothane)
• Metabolism: Minimal (0.02%)

Uterus:

• Uterine relaxation: Similar to other volatiles (dose-dependent)
• Contraindicated: Not for inhalational induction in obstetrics (airway irritation)

Clinical Effects

Sympathetic Stimulation:

• On rapid increase: Tachycardia, hypertension
• Mechanism: Airway irritation triggers sympathetic reflex
• Prevention: Gradual increases in concentration (avoid "overpressurizing")
• Treatment: Beta-blockers (esmolol), opioids (blunt response)

Carbon Monoxide Production:

• Occurs with: Desiccated CO₂ absorber (dry baralyme or soda lime)
• Mechanism: Base-catalyzed degradation of desflurane
• Risk: Closed circuit with fresh gas flow <1 L/min, allowing desiccation
• Prevention: Ensure absorber not desiccated, use sevoflurane if low-flow technique
• Monitoring: CO-oximetry (measures carboxyhemoglobin)
• Clinical significance: Rare but potentially dangerous

Clinical Use

Indications

Primary Indications:

1. Maintenance after IV induction: Main use (cannot be used for induction)
2. Neurosurgery: Rapid emergence allows quick neuro assessment
3. Outpatient/ambulatory surgery: Fast recovery, minimal residual effects
4. Bariatric surgery: Rapid emergence reduces aspiration risk
5. Thoracic surgery: Allows rapid wake-up for bronchoscopy/extubation
6. Cardiac surgery: Rapid emergence (controversial - sympathetic stimulation)

Specific Advantages:

• Fastest emergence: Time to eye opening 5-10 minutes after 2-hour surgery
• Rapid titratability: Due to low solubility, depth changes quickly
• Cost: Less expensive than sevoflurane (agent cost)
• No hepatic metabolism: No toxicity concerns
• No nephrotoxicity: Unlike methoxyflurane (obsolete)

Contraindications

Absolute:

• Inhalational induction: Especially in children (airway irritation)
• Susceptibility to MH: Like all volatiles

Relative:

• Ischemic heart disease: Theoretical coronary steal (controversial)
• Severe airway disease: May worsen bronchospasm
• Pheochromocytoma: Sympathetic stimulation may trigger catecholamine release
• Neurosurgery with ICP concern: Vasodilation may increase ICP (use <0.5 MAC if possible)

Administration Technique

Induction:

• Not used: IV induction required (propofol, thiopental, etc.)
• After intubation: Can commence desflurane

Maintenance:

• Concentration: 4-8% (1-1.5 MAC for adults)
• Fresh gas flow: 1-3 L/min (higher initially for wash-in)
• Titration: Adjust to hemodynamic parameters (avoid rapid increases)
• Adjuncts: Opioids (reduce MAC, blunt sympathetic response), N₂O (reduces MAC, less desflurane used)

Emergence:

• Discontinue: At end of surgery (or reduce to 0.5 MAC during closure)
• Hyperventilation: Speeds wash-out
• Fast emergence: May increase coughing on tube (ensure adequate analgesia)

Drug Interactions

Opioids:

• MAC reduction: 30-50% with high-dose opioids
• Cardiovascular: Opioids blunt sympathetic response to desflurane

Benzodiazepines:

• Synergistic: CNS depression

Nitrous Oxide:

• MAC reduction: 60% N₂O reduces desflurane MAC proportionally
• Cost saving: Less desflurane used

Neuromuscular Blockers:

• Synergistic: Enhanced muscle relaxation

Beta-blockers:

• Useful: Control tachycardia from sympathetic stimulation

Ephedrine/Phenylephrine:

• As needed: Treat hypotension (vasodilation from desflurane)

Comparison with Other Volatile Agents

Special Populations

Pediatrics:

• Age >5 years: Can be used (after IV induction)
• Young children: Avoid (airway irritation worse)
• MAC: Higher in children (7-8% for 1-5 years)

Elderly:

• Reduced MAC: 4-5% for 70-year-old
• Faster emergence: Still fastest agent despite age-related changes
• Hemodynamics: More sensitive to vasodilation

Obesity:

• Favorable: Rapid emergence despite increased fat mass (low fat solubility prevents accumulation)
• Preferred agent: For bariatric surgery

Pregnancy:

• Use: Maintenance only (not for inhalational induction)
• Uterine relaxation: Similar to other volatiles

Neonates:

• Not routinely used: Airway concerns, better alternatives (sevoflurane, isoflurane)

ANZCA Primary Exam Focus

Key Concepts

Physical Properties:

• Lowest blood/gas partition coefficient (0.42)
• Boiling point 23.5°C (requires heated vaporizer Tec 6/7)
• Vapor pressure 669 mmHg at 20°C
• Poorly soluble → fastest emergence

Pharmacokinetics:

• Minimal metabolism (0.02%)
• No fluoride release
• No organ toxicity
• Rapid wash-in and wash-out

Pharmacodynamics:

• MAC 6.0% (highest of modern agents)
• Airway irritation (pungent) - contraindicated for inhalational induction
• Sympathetic stimulation on rapid increase (tachycardia, hypertension)
• Coronary vasodilation (theoretical steal)

Clinical:

• Maintenance only
• Good for neurosurgery, ambulatory surgery, bariatric surgery
• Contraindicated for mask induction

Vaporizer:

• Tec 6/7 specifically for desflurane
• Heated to 23°C, pressurized
• Electrically powered

Common Exam Questions

Why can't desflurane be used for inhalational induction?

• Pungent odor → airway irritation → coughing, laryngospasm, breath-holding, secretions
• Especially problematic in children

Why does desflurane require a special vaporizer?

• Boiling point 23.5°C (near room temperature)
• Would boil at room temperature in standard vaporizer
• Tec 6/7 heats to 23°C and pressurizes to maintain liquid state

Compare desflurane and sevoflurane:

• Desflurane: Lower blood/gas (0.42 vs 0.65), faster emergence, irritating airway, no metabolism, lower cost
• Sevoflurane: Higher blood/gas, slower emergence, smooth airway, 2-5% metabolism (fluoride), higher cost, suitable for induction

What happens with rapid increase in desflurane concentration?

• Sympathetic stimulation → tachycardia, hypertension
• Airway irritation → coughing
• Prevent with gradual increases, opioids, beta-blockers

Environmental concerns:

• High global warming potential
• Long atmospheric lifetime (14 years)
• Significant greenhouse gas

References

1. ANZCA. Primary Examination Syllabus. Pharmacology Section.
2. Eger EI II. The pharmacology of desflurane. Anesthesiol Rev. 1993;20(5):156-163.
3. Weiskopf RB et al. Cardiovascular actions of desflurane in normocarbic volunteers. Anesth Analg. 1991;73(2):143-150.
4. Eger EI II. New inhaled anesthetics. Anesthesiology. 1994;80(4):906-909.
5. Gonsowski CT et al. Effect of temperature on the stability of desflurane. Anesthesiology. 1994;81(1):111-116.
6. Eger EI II. Uptake and distribution of desflurane. Anesthesiology. 1992;76(2):225-229.
7. Caldwell JE et al. The influence of renal function on the pharmacokinetics of desflurane. Anesth Analg. 1991;73(2):168-171.
8. Ryan SM, Nielsen CJ. Global warming potential of inhaled anaesthetics. BJA. 2010;105(6):760-766.