Desflurane (DB01189): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Contemporary Role in Anesthesia

Introduction and Overview

Identity and Classification

Desflurane, identified chemically as (±)1,2,2,2-tetrafluoroethyl difluoromethyl ether, is a highly fluorinated methyl ethyl ether that functions as a volatile liquid general anesthetic.[1] It is classified as an organofluorine compound and is administered clinically as a racemic mixture of its (R) and (S) optical isomers, or enantiomers.[1] As a member of the halogenated ether class of anesthetics, it shares a structural lineage with agents like isoflurane and sevoflurane, but possesses a unique physicochemical profile that defines its distinct clinical behavior.[2]

Historical Context and Development

Desflurane was first synthesized in the 1970s by a team led by Ross Terrell as part of a broad search for non-combustible anesthetic agents.[4] Its development was pursued in the late 1980s by Anaquest (a division of BOC Healthcare) to address a clinical demand for an inhaled anesthetic with more rapid induction and, particularly, faster emergence than the agents available at the time, such as isoflurane and halothane.[3] However, the progression of Desflurane from laboratory synthesis to clinical application was significantly delayed. This was due to formidable challenges posed by its physical properties, namely a very high vapor pressure approaching that of the atmosphere at room temperature and an associated explosive risk during its synthesis process. These hurdles postponed clinical testing until 1988.[5] Following successful trials, Desflurane was granted approval by the U.S. Food and Drug Administration (FDA) on September 18, 1992, a full decade before the widespread adoption of its main competitor, sevoflurane.[3]

Core Clinical Thesis: An Agent of Contrasts

Desflurane occupies a paradoxical position in the landscape of modern anesthesiology. It is an agent defined by a series of sharp contrasts, where its greatest strengths are intrinsically linked to its most significant liabilities.

On one hand, its chemical structure confers a set of physicochemical properties, most notably an exceptionally low solubility in blood, that result in a near-ideal pharmacokinetic profile for a volatile anesthetic. This profile facilitates an unparalleled speed of onset and offset, granting the clinician precise, real-time control over the depth of anesthesia and enabling the most rapid emergence and recovery of any available inhaled agent.[1] These characteristics have established its value in specific clinical contexts where swift recovery is not merely a convenience but a clinical necessity, such as in lengthy neurosurgical or bariatric procedures, ambulatory surgery, and any case where a rapid return to consciousness is paramount for patient assessment.[4]

On the other hand, the very properties that make it unique also generate substantial practical, economic, and environmental burdens. Its high volatility mandates the use of a complex and expensive heated vaporizer, limiting its accessibility.[1] Its pronounced pungency and airway-irritant effects complicate or preclude its use for inhalational induction of anesthesia, particularly in the pediatric population.[1] Furthermore, its high acquisition cost and its status as an exceptionally potent greenhouse gas have rendered it economically and environmentally unsustainable for routine use, triggering a global movement within the medical community to restrict or eliminate its presence from clinical practice.[1]

The clinical story of Desflurane is therefore a case study in the evolving priorities of medicine. Developed to optimize a single, purely clinical parameter—speed of recovery—its continued utility is now judged against a much broader and more complex set of criteria that include cost-effectiveness, logistical feasibility, and environmental stewardship. The tension between its pharmacokinetic elegance and its practical and ecological shortcomings is the central theme that defines its past, present, and future role in anesthesia.

Physicochemical Properties and Clinical Relevance

The clinical behavior of Desflurane is a direct consequence of its unique molecular structure and the resulting physical properties. Its high degree of fluorination and its isomeric relationship to isoflurane are fundamental to understanding its advantages and limitations.

Chemical Identity and Structure

• IUPAC Name: 2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane.[1]
• CAS Number: 57041-67-5.[1]
• Molecular Formula: C3​H2​F6​O.[1]
• Molecular Weight: 168.04 g/mol.[1]
• Structure: Desflurane is a structural isomer of isoflurane. The critical difference is the substitution of a single fluorine atom in Desflurane for the chlorine atom found on the α-ethyl carbon of isoflurane.[2] This seemingly minor change—replacing chlorine with fluorine—dramatically alters the molecule's intermolecular forces, reducing its solubility and increasing its volatility, which in turn dictates its entire clinical profile.[4]

Physical State and Appearance

At standard room temperature and pressure, Desflurane is a colorless, mobile, and heavy volatile liquid.[3] While some database entries describe its odor as "slight non-pungent," this description is contradicted by extensive clinical evidence.[3] In the context of anesthetic administration, Desflurane is overwhelmingly recognized as being highly pungent and a potent airway irritant.[1] This pungency is a defining clinical characteristic, frequently causing coughing, breath-holding, laryngospasm, and salivation, especially at the higher concentrations required for induction of anesthesia.[1] Therefore, for all practical purposes, its airway irritability is a major clinical limitation.

Volatility and Vapor Pressure

Desflurane is distinguished by its extreme volatility, a property that presents both advantages and significant technical challenges.

• Boiling Point: Its boiling point is very low and close to typical operating room temperatures, variously cited as 22.8°C or 23.5°C (74.3°F) at standard atmospheric pressure.[1]
• Vapor Pressure: Consequently, it has a very high saturated vapor pressure, reported as 669–681 mmHg (approximately 89 kPa) at 20°C.[1] This value is nearly equal to atmospheric pressure at sea level, meaning the liquid will readily boil if left open to the environment.

Solubility Characteristics

The solubility of an inhaled anesthetic in blood and tissues is the primary determinant of its speed of onset and recovery. Desflurane's solubility is exceptionally low, which is the basis for its primary clinical advantage.

• Blood:Gas Partition Coefficient: 0.42. This value is the lowest among all modern volatile anesthetics and indicates very poor solubility in blood. It is even less soluble than nitrous oxide (0.47).[1]
• Oil:Gas Partition Coefficient: 19. This value reflects its lipid solubility and is a key determinant of its anesthetic potency. A lower oil:gas coefficient generally corresponds to lower potency.[1]
• Water Solubility: Described as negligible or poor.[3]

Clinical Implications of Physicochemical Properties

The unique physical chemistry of Desflurane has profound and direct consequences for its clinical use, necessitating specialized equipment and defining its pharmacokinetic profile.

A critical consequence of Desflurane's low boiling point and high vapor pressure is the "vaporizer imperative." If used in a conventional variable-bypass vaporizer, which works by passing fresh gas over a liquid anesthetic, Desflurane would boil, leading to several problems. The output concentration would be dangerously high and unpredictable, and the rapid vaporization would cause significant cooling of the remaining liquid (due to the latent heat of vaporization), further altering its vapor pressure and making the delivered dose dangerously erratic.[1]

To overcome this, a fundamentally different technology was required. The Tec 6 vaporizer (and its successors) was specifically engineered for Desflurane. This device is electrically powered and functions by heating the liquid Desflurane to a constant temperature (approximately 39°C) and pressurizing it to approximately 2 atmospheres.[2] This converts the anesthetic into a pure gas at a known pressure. The vaporizer then injects this gas directly into the fresh gas flow using electronic controls, ensuring a precise and predictable final concentration delivered to the patient.[1] This technological dependency is a direct result of Desflurane's basic chemistry and leads to significant downstream consequences, including higher capital equipment costs and an added layer of complexity and potential failure, limiting its deployment in resource-constrained settings.[1]

The most important clinical advantage of Desflurane stems directly from the "solubility-kinetics link." The anesthetic effect is driven by the partial pressure of the agent in the brain, which equilibrates with its partial pressure in the blood and, ultimately, the alveoli. Because Desflurane has a very low blood:gas partition coefficient (0.42), it does not readily dissolve in the blood.[1] This means that only a very small amount of the anesthetic needs to transfer from the lungs to the blood to rapidly increase the blood's partial pressure. As a result, the arterial (and thus brain) partial pressure rises very quickly to match the concentration being delivered by the anesthesia machine, leading to a rapid wash-in and fast induction of anesthesia.[13] Conversely, when administration is ceased, the agent rapidly leaves the blood and is exhaled, causing a swift drop in brain concentration and a rapid washout, resulting in the fastest emergence and recovery among all volatile agents.[7] This direct, causal relationship between a fundamental physical constant and the drug's primary clinical benefit is the cornerstone of its value proposition.

Chemical Stability and Degradation

Desflurane is chemically very stable and resistant to biodegradation.[4] It does not degrade in the presence of strong acids.[13] However, it can undergo two clinically relevant degradation reactions:

1. Carbon Monoxide Production: In the presence of desiccated (dry) carbon dioxide absorbents, particularly those containing strong bases like Baralyme (no longer in common use) but also soda lime, Desflurane can be degraded to form carbon monoxide (CO).[1] This can lead to the formation of carboxyhemoglobin in the patient's blood. This reaction is more pronounced with Desflurane than with other volatile agents.[18] This risk underscores the importance of regularly changing CO₂ absorbents and avoiding high fresh gas flows for prolonged periods, which can dry out the absorbent canister.[1]
2. Fluoroform Production: Prolonged direct contact with soda lime can also lead to the production of low levels of fluoroform (CHF3​).[13]

Table 1: Key Physicochemical and Pharmacokinetic Properties of Desflurane

Property	Value	Clinical Significance/Implication
Chemical Formula	C3​H2​F6​O	Highly fluorinated structure contributes to stability and low solubility.
Molecular Weight	168.04 g/mol	Influences density and diffusion characteristics.
Boiling Point	22.8°C	Extremely low; necessitates a specialized heated and pressurized vaporizer for safe delivery.2
Vapor Pressure (@ 20°C)	669-681 mmHg	High volatility; contributes to the need for a special vaporizer and risk of overdose with conventional equipment.1
Blood:Gas Partition Coefficient	0.42	Very low blood solubility; the fundamental basis for its rapid onset and rapid recovery from anesthesia.1
Oil:Gas Partition Coefficient	19	Lower lipid solubility compared to isoflurane; corresponds to lower anesthetic potency.1
Metabolism	<0.02%	Negligible biotransformation; results in a very low risk of hepatic and renal toxicity from metabolites.6
MAC (in O₂, 45 y/o)	6.0%	Defines anesthetic potency; it is less potent than other common volatile agents, requiring higher inspired concentrations.2

Comprehensive Pharmacology

The pharmacological profile of Desflurane is characterized by a multi-modal mechanism of action at the molecular level, which translates into dose-dependent effects across all major organ systems. Its pharmacokinetic profile is dominated by its low solubility, leading to rapid uptake and elimination.

Mechanism of Anesthetic Action

The precise mechanism by which Desflurane and other volatile anesthetics produce the state of general anesthesia remains an area of active research, but it is understood to be a multifactorial process involving modulation of synaptic transmission at multiple sites within the central nervous system.[2]

• Primary Theory - Ion Channel Modulation: The leading theory posits that Desflurane exerts its effects by binding to and altering the function of various ligand-gated ion channels.[2]
• Enhancement of Inhibition: A key action is the potentiation of inhibitory neurotransmission. Desflurane acts as a positive allosteric modulator of inhibitory receptors, most notably the gamma-aminobutyric acid type A (GABAA​) and glycine receptors. By binding to a site on these receptors distinct from the neurotransmitter binding site, it enhances the effect of endogenous GABA and glycine. This leads to an increased influx of chloride ions (Cl−) into the neuron, causing hyperpolarization of the cell membrane and making it more resistant to firing an action potential. This widespread neuronal inhibition contributes significantly to the sedative and hypnotic effects of the drug.[1]
• Suppression of Excitation: Concurrently, Desflurane suppresses excitatory neurotransmission. It acts as a negative allosteric modulator, or antagonist, of key excitatory receptors, including neuronal nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartate (NMDA) type glutamate receptors.[1] By inhibiting these channels, it reduces the flow of excitatory signals in the brain and spinal cord, contributing to amnesia and analgesia.
• Other Molecular Targets: The anesthetic state is further supported by Desflurane's action on other channels. It activates two-pore domain potassium (K2P​) channels, which increases potassium ion (K+) efflux from neurons, also leading to hyperpolarization and reduced excitability.[6] Additionally, it has been shown to inhibit components of the mitochondrial electron transport chain (NADH-ubiquinone oxidoreductase) and calcium-transporting ATPases, which may affect neuronal energy metabolism and signaling.[6]
• Unitary/Lipid Bilayer Theory: An older, less specific theory, known as the Meyer-Overton or lipid bilayer theory, proposed that anesthetics function by dissolving in the lipid membrane of neurons. This was thought to cause membrane expansion and disorder, thereby disrupting the function of embedded ion channels.[2] While some membrane effects do occur, the modern view favors the more specific protein-binding model at ion channels as the primary mechanism of action.

Pharmacodynamics (Systemic Effects)

Desflurane produces dose-dependent physiological changes across multiple organ systems, generally resembling those of isoflurane but with some important distinctions.[7]

• Central Nervous System (CNS):
• It induces a dose-dependent depression of the CNS, resulting in hypnosis, amnesia, and unconsciousness.[7]
• It decreases the cerebral metabolic rate of oxygen consumption (CMRO2​), which can be neuroprotective during periods of ischemia.[1]
• Simultaneously, it is a potent cerebral vasodilator, which increases cerebral blood flow (CBF). The combination of decreased CMRO2​ and increased CBF (a phenomenon known as uncoupling) leads to a dose-dependent increase in intracranial pressure (ICP).[1] This effect requires careful management, often with hyperventilation to induce hypocapnia and cerebral vasoconstriction, in patients with intracranial space-occupying lesions, head trauma, or other risks for elevated ICP.[3]
• Desflurane does not appear to be epileptogenic; on the contrary, it produces dose-dependent suppression of the electroencephalogram (EEG), and at concentrations greater than 1.24 MAC, it can induce burst suppression.[7]
• Cardiovascular System:
• Desflurane causes a dose-dependent decrease in systemic vascular resistance (SVR), which leads to a reduction in mean arterial pressure (MAP).[1]
• Unlike some older anesthetics, cardiac output is generally well-maintained or preserved, as the drop in blood pressure is primarily due to vasodilation rather than direct myocardial depression.[2]
• A unique and clinically significant pharmacodynamic property of Desflurane is its capacity to induce a transient sympathetic surge. Rapid increases in the inspired concentration, particularly above 1 MAC, can trigger a robust sympathetic nervous system response. This is not merely a baroreceptor reflex to hypotension but a direct sympathomimetic effect, characterized by marked, transient increases in heart rate and blood pressure, driven by the release of catecholamines like epinephrine and norepinephrine.[1] This property makes Desflurane a potentially poor choice for anesthetic induction in patients with coronary artery disease or other conditions where tachycardia and hypertension are highly undesirable.[21] To avoid this response, clinicians must increase the delivered concentration slowly and gradually. The effect can also be blunted by the co-administration of opioids, alpha-2 agonists, or beta-blockers.[2]
• Cases of QTc interval prolongation have been reported, warranting caution and ECG monitoring when used in patients with a predisposition to arrhythmias.[2]
• Respiratory System:
• Like all volatile anesthetics, Desflurane is a dose-dependent respiratory depressant. This manifests as a decrease in tidal volume and an increase in respiratory rate, with a net effect of decreasing minute ventilation and increasing arterial carbon dioxide levels (PaCO2​) in spontaneously breathing patients.[4]
• It significantly blunts the normal ventilatory responses to both hypercapnia (high CO2​) and hypoxia (low O2​).[1]
• Despite being a notable airway irritant due to its pungency, it is also a bronchodilator, which can be beneficial in patients with reactive airway disease once the airway is secured.[1]
• Neuromuscular System:
• Desflurane provides dose-dependent skeletal muscle relaxation. It also significantly potentiates the effects of both depolarizing (e.g., succinylcholine) and non-depolarizing (e.g., rocuronium, vecuronium) neuromuscular blocking agents (NMBAs).[1] This potentiation is greater than that seen with sevoflurane and requires a reduction in the dosage of the NMBA to avoid prolonged paralysis.[1]
• Other Systems:
• It produces a dose-dependent relaxation of uterine smooth muscle, which can increase uterine bleeding during obstetric procedures.[10]
• It can cause a transient decrease in hepatic and renal blood flow, related to the overall decrease in systemic blood pressure.[22]

Pharmacokinetics (ADME)

The pharmacokinetic profile of Desflurane is defined by its rapid movement into and out of the body, a direct result of its low solubility and resistance to metabolism.

• Absorption (Wash-in): Absorption occurs via inhalation into the alveoli. Due to its very low blood:gas partition coefficient, the partial pressure of Desflurane in the arterial blood and brain rapidly equilibrates with the concentration being delivered to the alveoli. The ratio of alveolar concentration (FA​) to inspired concentration (FI​) reaches approximately 0.91 within 30 minutes, a rate significantly faster than that of isoflurane (~0.74).[7] This translates to a very rapid onset of anesthesia.
• Distribution: Once in the bloodstream, Desflurane is distributed to the body's tissues. It first rapidly saturates the vessel-rich group of organs (brain, heart, kidneys, liver) before more slowly distributing to muscle and fat. Its median volume of distribution has been reported as 612 mL/kg.[6]
• Metabolism: A key safety feature of Desflurane is its profound resistance to biotransformation.
• It undergoes negligible hepatic metabolism, with less than 0.02% of an absorbed dose being recovered as urinary metabolites.[1] This is approximately one-tenth the metabolism of isoflurane (~0.2%).[13]
• The minimal metabolism that does occur is mediated by the cytochrome P450 enzyme CYP2E1, which can defluorinate the molecule to produce trifluoroacetic acid (TFA).[6]
• This minimal metabolism is directly linked to its excellent organ safety profile. The development of modern anesthetics focused on increasing fluorination to enhance stability and reduce the production of reactive metabolites that caused the hepatotoxicity seen with older agents like halothane.[4] Desflurane represents the pinnacle of this design strategy. Its resistance to metabolism means it does not produce clinically significant levels of inorganic fluoride ions (associated with nephrotoxicity) and the incidence of immune-mediated hepatitis from TFA-protein adducts is considered extremely rare.[10] This makes it a theoretically advantageous agent for patients with pre-existing renal or hepatic dysfunction.[2]
• Elimination (Washout):
• Elimination is almost entirely via exhalation from the lungs.[6]
• The low blood solubility that facilitates rapid wash-in also drives a very rapid washout. The concentration in the blood and brain falls quickly once administration is stopped. The washout rate is about 2 to 2.5 times faster than that of isoflurane during the initial recovery period.[7]
• The terminal elimination half-life is very short, reported as 8.16 ± 3.15 minutes.[6] This results in a rapid, predictable, and consistent emergence from anesthesia, typically with patients opening their eyes within 5 to 6 minutes of discontinuation.[9]

Clinical Applications, Dosage, and Administration

The clinical use of Desflurane is defined by its specific FDA-approved indications, which differ between adult and pediatric populations, and its strict requirements for administration and dosing based on the principle of Minimum Alveolar Concentration (MAC).

Approved Indications

• Adults: Desflurane is indicated for both the induction and maintenance of general anesthesia for inpatient and outpatient surgical procedures.[2] While approved for induction, its pungency and airway irritant properties often lead clinicians to prefer an intravenous induction agent like propofol.[15]
• Pediatric Patients: The indications in children are much more restricted. Desflurane is indicated only for the maintenance of anesthesia in infants and children. This use is further limited to patients who have already been induced with a different agent and have had their airway secured with an endotracheal tube.[2]
• Specific Contraindication for Pediatric Induction: Desflurane is explicitly contraindicated for mask induction of anesthesia in pediatric patients. This is due to a very high incidence of moderate-to-severe upper airway adverse events, including frequent coughing, breath-holding, laryngospasm, and increased secretions.[1] For the same reasons, it is not approved for the maintenance of anesthesia in non-intubated children.[21]

Dosage and Administration

The administration of Desflurane must be individualized, with the delivered concentration titrated to the patient's physiological response. The depth of anesthesia, as well as the degree of hypotension and respiratory depression, increases with the concentration of the agent.[3]

• Minimum Alveolar Concentration (MAC): The potency of all volatile anesthetics is measured in terms of MAC. One MAC is defined as the end-tidal concentration of the anesthetic, at one atmosphere, that prevents movement in 50% of patients in response to a standard surgical skin incision.[2]
• The MAC value is not fixed; it is influenced by several factors. It decreases significantly with increasing patient age.[21]
• MAC is also reduced by the concomitant administration of other CNS depressants, most notably nitrous oxide (N2​O), opioids, and benzodiazepines. The dose of Desflurane must be adjusted downward when these agents are used concurrently.[13]
• Adult Dosing Guidelines:
• Induction: When used for inhalational induction, a common starting concentration is 3%, which is then increased in increments of 0.5-1.0% every 2 to 3 breaths. End-tidal concentrations in the range of 4-11%, with or without N2​O, are typically required to achieve surgical anesthesia within 2 to 4 minutes.[15] More commonly, after induction with an intravenous agent (e.g., propofol, thiopental), Desflurane can be initiated at a maintenance concentration of approximately 0.5-1 MAC.[15]
• Maintenance: Surgical levels of anesthesia are generally maintained with inspired concentrations of 2.5-8.5% Desflurane, with or without the concomitant use of N2​O.[15]
• Pediatric Dosing Guidelines (Maintenance Only):
• Maintenance: In intubated infants and children, surgical levels of anesthesia are maintained with concentrations ranging from 5.2-10%, with or without N2​O.[15] The required concentration is highly dependent on the child's age, with infants requiring the highest concentrations.[31]

Table 2: Minimum Alveolar Concentration (MAC) of Desflurane

Age	Carrier Gas	MAC (vol %)	Source(s)
9 months	100% O2​	10.0%	31
9 months	60% N2​O	7.5%	31
3 years	60% N2​O	6.4%	31
7 years	100% O2​	8.1%	31
25 years	100% O2​	7.3%	13
25 years	60% N2​O	4.0%	31
45 years	100% O2​	6.0%	21
45 years	60% N2​O	2.8%	31
70 years	100% O2​	5.2%	21
70 years	60% N2​O	1.7%	31

Anesthetic Delivery and Handling

Safe and effective administration of Desflurane requires specific equipment and adherence to strict protocols.

• It must only be administered by personnel trained and credentialed in the administration of general anesthesia, with full facilities for airway management, artificial ventilation, oxygen enrichment, and circulatory resuscitation immediately available.[3]
• It must be delivered using a vaporizer specifically designed, tested, and designated for use with Desflurane (e.g., the Tec 6 or subsequent models). This vaporizer is electrically heated and pressurized to ensure accurate and stable delivery of the anesthetic vapor.[1]
• The vaporizer is equipped with a unique filling system that is compatible only with the corresponding valve on the Desflurane bottle to prevent accidental filling with the wrong agent.[23]
• The liquid should be stored at controlled room temperature (15-30°C or 59-86°F), and the bottle cap must be replaced securely after each use to prevent evaporation.[21]

Safety Profile, Contraindications, and Adverse Events

The safety profile of Desflurane is characterized by a high incidence of airway-related adverse events, particularly during induction, and several serious, albeit rare, systemic risks that are common to the class of volatile anesthetics. A thorough understanding of its adverse effects, warnings, and contraindications is essential for its safe clinical use.

Adverse Reactions

• Common Adverse Events: The most frequently encountered adverse effects are related to its pungency and airway irritability, especially when used for inhalational induction. These include:
• Coughing: Reported in up to 34% of adults and 72% of pediatric patients during induction.[16]
• Breath-holding: Occurs in up to 27% of adults and 63% of pediatric patients.[16]
• Laryngospasm: A serious reflex closure of the vocal cords, reported in up to 8% of adults and 50% of pediatric patients during induction.[16]
• Increased Salivation/Secretions: A common response to airway irritation.[16]
• Apnea: A transient cessation of breathing.[15]
• Other common systemic effects include postoperative nausea and vomiting (PONV), with nausea reported in up to 27% and vomiting in 16% of patients.[16] Transient hypertension and tachycardia, particularly with rapid increases in concentration, are also common.[1]
• Serious Adverse Events: While less common, Desflurane is associated with several potentially life-threatening adverse events, including: malignant hyperthermia, cardiac arrest, severe perioperative hyperkalemia, QTc prolongation leading to Torsades de Pointes, convulsions, severe hypotension, respiratory arrest, and rare cases of severe hepatotoxicity or jaundice.[2]

Warnings and Precautions

While the FDA-approved labeling for Desflurane does not contain a formal, delineated "Black Box Warning," the "Warnings and Precautions" section of its prescribing information details a number of severe, life-threatening risks.[32] The absence of a black box should not be misconstrued as an indication of superior safety concerning these specific risks. These warnings are largely considered class effects for all potent volatile anesthetics and are well-known within the specialty of anesthesiology. The risks are of a severity often associated with black box warnings for other medications, and they demand the highest level of vigilance from clinicians.

• Malignant Hyperthermia (MH): Desflurane, like all volatile anesthetics, can trigger MH, a rare but potentially fatal hypermetabolic crisis of skeletal muscle. It occurs in genetically susceptible individuals, often those with inherited variants in the ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) genes. The risk is increased with concomitant use of succinylcholine. Early signs include muscle rigidity, unexplained tachycardia, and hypercapnia. Immediate discontinuation of all triggering agents and administration of intravenous dantrolene are critical.[1]
• Perioperative Hyperkalemia: Rare cases of sudden, severe, and sometimes fatal hyperkalemia have been reported following administration of volatile anesthetics. Pediatric patients with underlying, and often undiagnosed, neuromuscular diseases (e.g., Duchenne muscular dystrophy) appear to be the most vulnerable population. Early and aggressive treatment of the hyperkalemia and associated arrhythmias is essential.[6]
• QTc Prolongation: Desflurane has been reported to prolong the QTc interval on the electrocardiogram. This effect can increase the risk of serious ventricular arrhythmias, including Torsades de Pointes. Caution and cardiac rhythm monitoring are advised when administering Desflurane to susceptible patients, such as those with congenital long QT syndrome or those taking other QTc-prolonging medications.[2]
• Hepatobiliary Disorders: Although Desflurane undergoes minimal metabolism, rare cases of postoperative hepatic dysfunction, ranging from mild, transient elevations in liver enzymes to severe or fatal fulminant hepatic necrosis, have been reported. This is believed to be an immunoallergic reaction ("sensitivity hepatitis") in patients who have been sensitized by a previous exposure to a halogenated anesthetic. Repeated anesthesia with any halogenated agent should be approached with caution in patients who have experienced unexplained liver dysfunction following a prior exposure.[6]
• Interaction with Desiccated CO₂ Absorbents: Desflurane can react with dry carbon dioxide absorbents to produce clinically significant amounts of carbon monoxide (CO), which can lead to elevated carboxyhemoglobin levels in the patient. Anesthesiologists must ensure CO₂ absorbent is fresh and not desiccated.[1]
• Pediatric Neurotoxicity: A warning common to all general anesthetic and sedation drugs addresses the potential for adverse effects on brain development. Published animal studies have shown that prolonged or repeated exposure (greater than 3 hours) during the period of peak brain development can cause widespread neuronal apoptosis and long-term neurocognitive deficits. The relevance of these findings to humans is still being investigated, but caution is advised for elective procedures in children under 3 years of age and in pregnant women during their third trimester.[6]

Contraindications

The use of Desflurane is absolutely contraindicated in the following situations [1]:

• In patients with a known or suspected genetic susceptibility to Malignant Hyperthermia.
• For the induction of anesthesia in pediatric patients via mask inhalation.
• In patients with a known sensitivity or allergy to Desflurane or any other halogenated anesthetic agent.
• In patients with a history of moderate to severe hepatic dysfunction (e.g., jaundice, unexplained fever) that occurred after a previous administration of a halogenated anesthetic.
• In any patient for whom general anesthesia itself is contraindicated.

Drug Interactions

Desflurane participates in several clinically significant drug interactions, primarily pharmacodynamic in nature.

• CNS Depressants: Desflurane has synergistic effects with other CNS depressants, including opioids, benzodiazepines, barbiturates, and propofol. Concomitant use increases the risk of hypotension, respiratory depression, and profound sedation. The MAC of Desflurane is significantly reduced by these agents, and their doses must be adjusted accordingly.[3]
• Neuromuscular Blocking Agents (NMBAs): Desflurane potentiates the effects of both depolarizing (succinylcholine) and non-depolarizing (e.g., rocuronium, atracurium, vecuronium) muscle relaxants. The dose of the NMBA must be reduced to avoid excessive and prolonged neuromuscular blockade.[1]
• QTc-Prolonging Agents: The risk of cardiac arrhythmia is increased when Desflurane is co-administered with other drugs known to prolong the QTc interval. Examples include many antiarrhythmics (e.g., amiodarone, sotalol), certain antibiotics (e.g., azithromycin), antipsychotics (e.g., amisulpride), and others. Such combinations should generally be avoided or used with extreme caution and continuous ECG monitoring.[6]
• Sympathomimetics: The co-administration of sympathomimetic drugs such as epinephrine or dopamine may increase the risk of arrhythmias and hypertension, especially in the context of Desflurane's intrinsic ability to stimulate the sympathetic nervous system.[25]
• Antihypertensives: Desflurane's vasodilatory effects can potentiate the action of antihypertensive medications, including beta-blockers and ACE inhibitors, increasing the risk of hypotension.[6]

Use in Special Patient Populations

The administration of Desflurane requires careful consideration and specific adjustments in various patient populations due to differences in physiology, drug handling, and risk profiles.

Table 4: Summary of Clinical Considerations for Desflurane Use in Special Populations

Population	Key Considerations & Risks	Dosing Adjustments
Pediatric	Contraindicated for mask induction due to high risk of severe airway irritation (coughing, laryngospasm). Risk of postoperative agitation. Risk of perioperative hyperkalemia (esp. with neuromuscular disease). Concerns about neurotoxicity with prolonged exposure.	Maintenance only. Higher MAC requirements than adults, dose is age-dependent (5.2-10%).
Geriatric	Increased likelihood of adverse effects. Conflicting evidence on Postoperative Cognitive Dysfunction (POCD)/delirium; rapid recovery may be beneficial, but some data suggests it may be a risk factor for delirium.	MAC is significantly reduced. Dose must be decreased accordingly (e.g., 5.2% at 70 years).
Pregnancy	No adequate human studies. Animal data show embryofetal toxicity and potential for neurodevelopmental effects with prolonged exposure. Use only if benefit clearly outweighs risk.	Not assigned a pregnancy category by FDA. Use with caution.
Lactation	Unknown if excreted in milk. Due to very short maternal half-life, significant infant exposure is unlikely. Breastfeeding can resume once mother is recovered from anesthesia.	No specific adjustments needed. No waiting period required.
Hepatic Impairment	Contraindicated if history of halogenated anesthetic-induced hepatitis. Use with caution in other liver disease. Minimal metabolism makes it a theoretically safe choice.	No dosage adjustment is generally required.
Renal Impairment	Considered safe due to negligible metabolism and lack of production of nephrotoxic fluoride ions.	No dosage adjustment is required.
Coronary Artery Disease	Sympathetic surge with rapid concentration increase can cause dangerous tachycardia and hypertension. Should not be used for induction in these patients.	Use with other agents (e.g., opioids) to blunt hemodynamic response. Increase concentration slowly and gradually.
Neurosurgical	Causes cerebral vasodilation and can increase intracranial pressure (ICP). Rapid recovery allows for prompt neurological assessment post-op.	Administer at ≤0.8 MAC with hyperventilation to manage ICP. Considered a niche indication where rapid wake-up is critical.

Pediatric Patients

The use of Desflurane in the pediatric population is highly restricted. It is strictly contraindicated for inhalational induction due to an unacceptably high rate of severe respiratory adverse events, including laryngospasm, coughing, and breath-holding.[16] Its use is limited to the maintenance of anesthesia in children whose airways have already been secured via endotracheal intubation.[2] Even during maintenance, children with asthma or a recent upper airway infection are at an increased risk for airway narrowing and resistance.[24] Furthermore, children may experience a brief state of agitation or emergence delirium upon recovery.[6] The risk of perioperative hyperkalemia is also a significant concern, particularly in boys with undiagnosed Duchenne muscular dystrophy.[6] Dosing in children requires higher concentrations than in adults to achieve the same anesthetic depth, with MAC values being highly age-dependent.[25]

Geriatric Patients

Desflurane can be used in elderly patients, but with significant caution and dose adjustments.[29] The primary physiological consideration is that anesthetic requirement (MAC) decreases progressively and significantly with age; for example, the MAC at age 70 is about 30% lower than at age 25.[21] The role of Desflurane in postoperative cognitive dysfunction (POCD) and delirium in the elderly is a subject of ongoing debate and presents a complex picture. The initial hypothesis was that Desflurane's very rapid elimination would lead to less residual anesthetic effect and therefore a faster recovery of cognitive function, reducing the incidence of POCD.[34] Some early studies supported this, showing faster emergence compared to isoflurane.[7] However, this theoretical benefit has not been consistently demonstrated in clinical practice. More recent and direct comparisons have found no significant difference in cognitive outcomes between Desflurane and sevoflurane.[35] Most strikingly, a large secondary analysis of a clinical trial identified Desflurane use as an independent risk factor for a

higher incidence of postoperative delirium when compared to both sevoflurane and propofol-based anesthesia.[37] This counterintuitive finding suggests that the relationship between anesthetic choice and postoperative cognition is far more complex than drug clearance alone and may involve other pharmacodynamic effects on the aging brain's inflammatory or neurotransmitter systems. Therefore, while Desflurane's rapid recovery may be perceived as an advantage, it cannot be assumed to confer a benefit regarding POCD, and the choice of anesthetic may be less important than meticulous overall perioperative care in this vulnerable population.

Pregnancy and Lactation

• Pregnancy: There are no adequate and well-controlled studies on the use of Desflurane in pregnant women.[2] The US FDA has not assigned it a pregnancy category, while the Australian TGA classifies it as B3, indicating limited human data but evidence of fetal damage in animal studies.[33] Animal reproduction studies have shown embryofetal toxicity, including increased post-implantation loss.[33] Furthermore, a general warning applies to all anesthetics regarding potential neurodevelopmental effects on the fetus with prolonged or repeated exposure, based on animal data showing increased neuronal apoptosis.[33] Therefore, Desflurane should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[33]
• Lactation: It is not known whether Desflurane is excreted in human milk.[2] However, given its extremely short maternal serum half-life (less than 3 minutes) and rapid pulmonary elimination, significant transfer into breast milk and subsequent absorption by the infant is considered highly unlikely. Expert opinion and clinical guidelines suggest that breastfeeding can be safely resumed as soon as the mother has recovered sufficiently from anesthesia to nurse, with no mandatory waiting period or need to discard milk.[2]

Patients with Hepatic or Renal Impairment

• Hepatic Impairment: The minimal metabolism of Desflurane (<0.02%) makes it a theoretically safe agent in patients with pre-existing liver disease, and no dosage adjustments are typically required.[22] Clinical studies in patients with hepatic impairment, including those with cirrhosis undergoing liver resection, have found Desflurane to be safe and well-tolerated.[27] Some evidence even suggests it may be associated with a more rapid decline in postoperative liver enzymes compared to sevoflurane.[41] The critical exception is the contraindication in patients with a history of halogenated anesthetic-induced hepatitis, as this is an immunoallergic phenomenon, not a direct toxic effect, and re-exposure can trigger a severe reaction regardless of the agent's metabolic profile.[16]
• Renal Impairment: Desflurane is considered an excellent choice for patients with renal impairment. Its negligible metabolism means it does not produce nephrotoxic inorganic fluoride ions, a concern with older, more heavily metabolized agents. Clinical studies have shown no adverse effects on renal function, and no dosage adjustment is necessary for patients with renal insufficiency.[2]

Comparative Analysis with Alternative Anesthetic Agents

The clinical utility of Desflurane is best understood through direct comparison with the other commonly used volatile anesthetics, sevoflurane and isoflurane, as well as with total intravenous anesthesia (TIVA) using agents like propofol. The choice among these agents involves a trade-off between speed, side effects, cost, and environmental impact.

Table 3: Comparative Profile: Desflurane vs. Sevoflurane and Isoflurane

Feature	Desflurane	Sevoflurane	Isoflurane
Potency (MAC, ~40 y/o)	~6.6% (Least Potent)	~2.0%	~1.2% (Most Potent)
Blood:Gas Coefficient	0.42 (Lowest)	0.65	1.4 (Highest)
Onset/Offset Speed	Fastest	Fast	Slower
Airway Irritation (Pungency)	High	Low (Sweet)	Moderate
Suitability for Mask Induction	Poor (Adults only)	Excellent	Poor
Cardiovascular Effects	Tachycardia on rapid increase	More stable heart rate	More stable heart rate
Metabolism	<0.02% (Negligible)	~5%	~0.2%
Vaporizer Requirement	Specialized (Heated/Pressurized)	Standard (Variable Bypass)	Standard (Variable Bypass)
Acquisition Cost	Highest	High	Lowest
Environmental Impact (GWP-20)	~3714 (Very High)	~440 (Moderate)	~1401 (High)

Potency and Cost

Desflurane is the least potent of the three major volatile agents, as indicated by its high MAC value of approximately 6-7% in a middle-aged adult.[7] This means that a higher concentration must be delivered to achieve and maintain a surgical plane of anesthesia compared to sevoflurane (MAC ~2%) and isoflurane (MAC ~1.2%).[11] Compounding this low potency is its high acquisition cost per milliliter of liquid; it is the most expensive of the volatile agents.[1] The combination of requiring a higher concentration and having a higher unit cost makes Desflurane the most expensive anesthetic to use on a per-hour basis, particularly at high fresh gas flows.[1] While using low-flow anesthesia techniques can mitigate this cost difference, it generally remains the most expensive option.[10]

Speed of Recovery

The single greatest clinical advantage of Desflurane is its unparalleled speed of recovery. This is a direct result of its extremely low blood:gas partition coefficient (0.42).[1] Clinical studies and meta-analyses consistently show that emergence from Desflurane anesthesia—measured by time to eye-opening, following commands, or extubation—is significantly faster than from isoflurane (by a mean of 4-5 minutes) and is also demonstrably faster than from sevoflurane and propofol in many clinical settings.[1] This rapid recovery is most advantageous in ambulatory (day-case) surgery, in very long procedures where tissue accumulation of other agents can delay waking, and in neuroanesthesia, where a swift return to consciousness is critical for immediate neurological assessment.[4]

Side Effect Profiles

• Airway Reactivity: This is a key differentiating factor. Desflurane is a potent airway irritant, making it a poor choice for smooth inhalational induction of anesthesia. In contrast, sevoflurane is non-pungent and has a pleasant, sweet smell, making it the agent of choice for mask induction, especially in children.[1] Isoflurane is also pungent, though generally considered less irritating than Desflurane.[43]
• Hemodynamic Stability: While all volatile agents cause vasodilation and can decrease blood pressure, Desflurane's unique tendency to cause a sympathetically-mediated tachycardia and hypertension upon rapid increases in concentration sets it apart. Sevoflurane and isoflurane tend to provide more stable hemodynamics without this pronounced sympathetic response, although they can cause a more dose-dependent decrease in cardiac contractility.[7]
• Postoperative Nausea and Vomiting (PONV): The incidence of PONV is a concern with all volatile anesthetics, and clinical trials have generally shown no significant difference in the rates of nausea and vomiting between patients receiving Desflurane, sevoflurane, or isoflurane.[15]

The choice of Desflurane often hinges on a complex "cost-benefit-time" equation. The drug's direct acquisition cost is unequivocally the highest.[11] The primary benefit offered in return for this cost is a saving of time during the immediate recovery phase.[7] The critical question for healthcare systems is whether this time saving translates into a net economic advantage. In a high-throughput surgical center, shaving several minutes off the wake-up time for each case could theoretically allow for an additional surgical procedure to be performed each day, generating revenue that far outweighs the increased drug cost. However, in an environment where operating rooms have scheduled downtime, the time saved may have no economic value, rendering Desflurane simply a more expensive alternative. Furthermore, while immediate recovery is faster, studies looking at later recovery milestones, such as time to be "fit for discharge" from the post-anesthesia care unit (PACU) or time to home readiness, often find no significant difference between Desflurane and other agents.[7] This suggests that the very rapid initial awakening may not always translate into a shorter overall hospital stay. Therefore, the cost-effectiveness of Desflurane is not an intrinsic property but is highly contingent on the specific operational and economic context of the institution in which it is used.

Regulatory Status, Environmental Impact, and Future Perspective

The contemporary role of Desflurane is being profoundly shaped by factors beyond its clinical pharmacology, most notably its regulatory standing and its significant environmental footprint. These external pressures are forcing a global re-evaluation of its place in the anesthetic armamentarium.

Regulatory History and Global Standing

Desflurane was approved for use by the US FDA in 1992.[3] Its labeling includes numerous serious warnings and precautions but does not carry a formal Black Box Warning, likely because its most severe risks are considered class effects for volatile anesthetics and are managed by specialists.[32]

More recently, a significant global trend has emerged to restrict or decommission Desflurane, driven almost entirely by environmental concerns. National health systems and professional societies in many parts of the world have taken decisive action. Desflurane has been eliminated or is being actively phased out in Scotland (eliminated 2023), England (phasing out 2024), the entire European Union (by 2026), Australia, and New Zealand.[5] While its use continues in the United States and parts of Asia, its status as a routine anesthetic agent is under intense scrutiny worldwide.[5]

Environmental Impact

Desflurane is an exceptionally potent greenhouse gas (GHG), a fact that has become the single most significant threat to its continued use.[1]

• Global Warming Potential (GWP): The GWP is a measure of how much heat a greenhouse gas traps in the atmosphere over a specific time horizon, relative to carbon dioxide (CO2​). The 20-year GWP for Desflurane is 3714, meaning that the emission of one kilogram of Desflurane has the same atmospheric warming effect as emitting 3,714 kilograms of CO2​ over a 20-year period.[1] This is substantially higher than the GWP of sevoflurane (~440) and isoflurane (~1401).[1]
• Contributing Factors: Its high GWP is a result of several factors: its molecular structure (highly fluorinated molecules are efficient at absorbing infrared radiation), its long atmospheric lifetime, and the relatively high concentrations required for clinical effect due to its low potency.[5]
• Clinical Practice Recommendations: In response to this environmental data, leading professional bodies, such as the American Society of Anesthesiologists (ASA), have issued guidelines recommending that providers avoid inhaled anesthetics with disproportionately high climate impacts, like Desflurane. They advocate for prioritizing agents with lower GWP, using the lowest possible fresh gas flows to minimize waste, and considering regional anesthesia or TIVA as environmentally preferable alternatives when clinically appropriate.[5]

The Future of Desflurane: Niche Agent or Obsolescence?

The future of Desflurane is at the center of a clash between clinical idealism and environmental pragmatism. From a purely pharmacokinetic standpoint, its rapid kinetics make it an ideal agent for achieving precise control and swift recovery. This provides tangible clinical benefits in a select group of high-risk patients. For example, the ability to rapidly awaken a patient after a long neurosurgical procedure for immediate neurological assessment can be critically important for detecting and managing postoperative complications like a hematoma.[5] Similarly, its low solubility in fat makes it advantageous for morbidly obese patients, in whom other, more soluble agents can accumulate in adipose tissue and significantly prolong recovery. Recognizing these specific benefits, some health systems, like the British NHS, have created explicit exceptions for its continued use in neurosurgery and for bariatric patients, despite a general policy of decommissioning.[5]

However, from an environmental and cost perspective, Desflurane is arguably the worst of the available options.[1] This creates a profound ethical and clinical dilemma for practitioners and healthcare systems: is the marginal clinical benefit of a few minutes' faster recovery in a specific patient worth the substantial and cumulative environmental cost?

The emerging global consensus suggests that for routine surgical cases, the answer is increasingly "no." The burden of proof has shifted, and clinicians must now actively justify the use of Desflurane on a case-by-case basis against effective, less costly, and far less environmentally harmful alternatives. Its future does not appear to be as a mainstream anesthetic. Instead, it is being relegated to the status of a highly specialized, niche drug, reserved for specific, well-defined clinical scenarios where its unique properties offer a clear and defensible advantage that outweighs its significant drawbacks. Future technological developments, such as effective systems for capturing and recycling waste anesthetic gases, could potentially alter this calculus, but such technologies are not yet widely implemented and face their own economic and logistical challenges.[5]

Conclusion

Desflurane (Suprane) is a potent, volatile general anesthetic that embodies a fundamental trade-off in modern pharmacology. Its development was a triumph of chemical engineering, producing an agent with the lowest blood solubility of its class, which translates into an unmatched speed of recovery and precise control over anesthetic depth. Its minimal metabolism confers an excellent organ safety profile, making it a safe choice for patients with renal or hepatic disease. These pharmacokinetic advantages have secured it a valuable, albeit narrow, niche in complex clinical scenarios such as prolonged neurosurgery and anesthesia for morbidly obese patients, where rapid emergence is of paramount importance.

However, these benefits come at a steep price. The same physicochemical properties that enable its rapid kinetics also necessitate expensive, specialized delivery systems, limiting its use. Its pronounced airway irritability makes it unsuitable for inhalational induction, and its high acquisition cost further restricts its routine application. Most critically, Desflurane's significant environmental impact as a potent greenhouse gas has become an overriding concern for the global medical community. This has led to a paradigm shift, where the drug's clinical benefits are being weighed against its ecological and economic costs, resulting in its widespread decommissioning across many developed nations.

Ultimately, Desflurane serves as a powerful case study in the evolving definition of an "ideal" drug. While it approaches the ideal from a purely pharmacokinetic perspective, its future is being dictated by the broader principles of sustainability and stewardship. Its trajectory is one of transition—from a mainstream agent to a highly specialized tool, reserved for select cases where its unique clinical advantages are deemed indispensable and can be justified against its considerable liabilities. The story of Desflurane underscores that the evaluation of a medication in the 21st century extends far beyond the patient, encompassing its impact on the healthcare system and the global environment.

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