Sevoflurane (DB01236): A Comprehensive Pharmacological Review

1. Introduction

1.1. Overview of Sevoflurane as an Inhalational Anesthetic Agent

Sevoflurane is a highly fluorinated methyl isopropyl ether, widely utilized as a volatile inhalational anesthetic for the induction and maintenance of general anesthesia across diverse patient populations, including adults and pediatrics, for both inpatient and outpatient surgical interventions.[1] Its clinical utility is largely attributed to a favorable combination of properties: a rapid, smooth onset of action and quick emergence from anesthesia, a non-pungent, pleasant odor which facilitates mask induction (particularly advantageous in pediatric patients), and a general lack of irritation to the respiratory tract.[1] These characteristics, alongside a generally well-tolerated safety profile and predictable pharmacokinetics, have positioned sevoflurane as a cornerstone agent in contemporary anesthetic practice.[1]

The landscape of inhalational anesthesia has seen a progressive shift, with agents like sevoflurane, often alongside desflurane, increasingly supplanting older volatile anesthetics such as isoflurane and halothane in modern clinical settings.[11] Sevoflurane's global adoption since its introduction reflects its perceived advantages in clinical practice.[1] This evolution is driven by a pursuit of anesthetic agents that offer enhanced control, improved patient experience, and more favorable recovery profiles. Older agents, while effective, presented certain limitations; for instance, isoflurane has a slower onset and offset, and halothane carried concerns regarding arrhythmogenicity and hepatotoxicity. Sevoflurane's low blood:gas solubility coefficient is a primary determinant of its rapid induction and emergence characteristics, a significant improvement for both procedural efficiency and patient recovery post-anesthesia.[1] Furthermore, its non-pungent, sweet odor makes it particularly well-suited for mask induction, especially in pediatric patients or adults who may be averse to more pungent agents, thereby enhancing patient comfort and cooperation during the critical induction phase.[1] Compared to some older agents, sevoflurane generally exhibits a favorable cardiovascular and respiratory profile.[1] These combined benefits, particularly in the context of outpatient surgery where rapid turnover is essential, and in pediatric anesthesia where patient comfort and smooth induction are paramount, underpin its preference. This increasing preference for sevoflurane signifies a broader trend in anesthesia towards agents that provide enhanced control over anesthetic depth, faster recovery times, and improved patient comfort. This shift occurs even as newer agents bring their own specific considerations, such as the potential for Compound A formation with sevoflurane under certain conditions [9] or differing cost structures [6], indicating a continuous and dynamic re-evaluation of the risk-benefit and cost-effectiveness profiles in clinical practice.

1.2. DrugBank ID: DB01236, CAS Number: 28523-86-6

Sevoflurane is uniquely identified in pharmacological and chemical databases by DrugBank ID DB01236 and CAS (Chemical Abstracts Service) Number 28523-86-6.[1] These identifiers are crucial for accurate referencing in scientific literature, regulatory documentation, and clinical practice, ensuring unambiguous communication regarding the specific chemical entity.

1.3. Historical Context and Development

Sevoflurane was first synthesized in the early 1960s. Ross Terrell and Louise Speers, working at Airco Industrial Gases, are credited with its discovery, while Richard Wallen is noted for its concurrent synthesis.11 The compound was subsequently patented in 1972.1

The initial development and patent rights for sevoflurane were associated with Baxter Travenol Laboratories. Baxter later licensed development and marketing rights, with Maruishi Pharmaceutical Co., Ltd. playing a pivotal role in its commercial development, particularly in Japan, where it was first approved for clinical use in 1990.1 Following its success in Japan, Abbott Laboratories became involved in the global marketing of sevoflurane, often under the brand name Ultane, through agreements with Maruishi and Baxter.17 Currently, AbbVie (a spin-off from Abbott Laboratories) holds worldwide rights for some branded versions, such as Sevorane.11

Regulatory approvals in major markets followed its Japanese introduction. The United States Food and Drug Administration (FDA) approved sevoflurane for clinical use in 1995/1996.[1] Records for NDA 020478 (Ultane, Abbott) indicate supplemental approval activity as of December 11, 2002, confirming earlier primary approval.[18] In Europe, the European Medicines Agency (EMA) has granted marketing authorizations for several sevoflurane products for human use. For instance, "Sevoflurane Baxter" received its initial marketing authorisation on September 1, 1995.[19] Other sevoflurane products, including those from Piramal, also hold EMA authorizations.[19] Additionally, sevoflurane is approved for veterinary use in Europe under brand names like Sevohale and SevoFlo.[4]

The journey of sevoflurane from its discovery in the 1960s to its widespread clinical adoption in the 1990s was not immediate. Its development was somewhat protracted, partly due to the high initial cost of synthesis and early concerns regarding potential toxicity, which were later attributed to flawed experimental designs.[8] A specific manufacturing challenge arose when an uncharacteristically pungent odor was detected in one lot of sevoflurane, caused by the formation of hydrogen fluoride. This was traced to a Lewis acid-fluorocarbon reaction involving ferric oxide contaminants in the handling equipment. Abbott Laboratories resolved this issue by modifying the production process to include water as a Lewis acid inhibitor, resulting in a "high water" formulation of sevoflurane.[8] This historical context underscores that the path of a drug from laboratory discovery to routine clinical use often involves overcoming significant scientific, manufacturing, economic, and commercial hurdles. The resolution of these early challenges was crucial for sevoflurane to achieve its current status as a widely used and valued anesthetic agent.

2. Chemical and Physical Properties

2.1. Chemical Structure and Class

Sevoflurane is chemically designated as 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane.[1] Its molecular formula is C4​H3​F7​O [1], and it has a molecular weight of approximately 200.05 g/mol.[1] Structurally, sevoflurane is a halogenated ether, more specifically, a highly fluorinated methyl isopropyl ether.[1] The finished medicinal product typically consists solely of the active ingredient, sevoflurane, without any additives.[9]

2.2. Physical Characteristics

Sevoflurane presents as a clear, colorless, volatile liquid at standard room temperature and pressure.[8] A defining characteristic is its pleasant, sweet, and non-pungent odor, which significantly contributes to its ease of use, particularly for inhalational induction via mask, especially in pediatric populations where airway irritability can be a concern.[1]

The solubility profile of sevoflurane is critical to its pharmacokinetic behavior. It exhibits low solubility in blood, quantified by a blood:gas partition coefficient typically ranging from 0.63 to 0.69 at 37°C.[1] This low blood solubility is a primary factor enabling its rapid onset of anesthetic action and swift emergence upon discontinuation. Its water:gas partition coefficient is 0.36, and its oil:gas partition coefficient is 47.2, indicating moderate lipid solubility.[4] Sevoflurane is miscible with common organic solvents such as ethanol, ether, chloroform, and benzene, and it is only slightly soluble in water.[4]

Regarding stability, sevoflurane is stable under normal room lighting conditions and when stored as recommended.[9] It does not undergo discernible degradation in the presence of strong acids or heat.[9] However, a significant chemical property is its potential for degradation when in contact with alkaline carbon dioxide (CO₂) absorbents used in anesthesia circuits. This interaction, particularly with desiccated absorbents or those containing strong bases like potassium hydroxide (e.g., Baralyme), can lead to the formation of degradation products, most notably Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFE), and other minor degradants.[8] This reactivity necessitates specific precautions in its clinical administration, as discussed in later sections. Sevoflurane is not corrosive to materials commonly used in anesthesia delivery systems, such as stainless steel, brass, and aluminum.[9]

From a safety perspective, sevoflurane is non-flammable and non-explosive under standard operating room conditions.[1] Its vapor pressure is 157 mmHg at 20°C [4] and approximately 200 Torr (200 mmHg) at 25°C.[4] The boiling point of sevoflurane is 58.5 - 58.6°C at atmospheric pressure.[4]

The unique combination of these physicochemical properties dictates sevoflurane's clinical performance and its specific safety considerations. The low blood:gas partition coefficient is fundamental to its rapid pharmacokinetic profile, allowing for swift induction of anesthesia and quick emergence when administration is ceased.[1] This rapid control is highly advantageous in managing the depth of anesthesia and facilitating efficient patient turnover. The non-pungent, sweet odor is a significant factor in its preference for mask induction, particularly in pediatric patients and individuals averse to more pungent anesthetic agents, thereby enhancing patient comfort and cooperation during the induction phase.[2] Its non-flammability is a critical safety attribute within the operating room environment, where potential ignition sources may be present.[1] Conversely, the chemical reactivity of sevoflurane with CO₂ absorbents, leading to the formation of Compound A, is a distinct aspect of its chemistry that mandates careful attention to administrative practices, such as ensuring the freshness and proper hydration of absorbents and maintaining adequate fresh gas flow rates, to mitigate potential risks associated with degradant exposure.[8] Thus, sevoflurane's physicochemical profile is directly responsible for both its clinical advantages and the specific precautions required for its safe use.

3. Pharmacology

3.1. Mechanism of Action

Sevoflurane, consistent with other halogenated inhalational anesthetics, exerts its primary effects by modulating the function of various ligand-gated ion channels within the central nervous system (CNS). This modulation leads to a global depression of neuronal excitability, resulting in the characteristic components of general anesthesia: reversible loss of consciousness, amnesia, analgesia, akinesia (immobility in response to noxious stimuli), and blockade of autonomic reflexes.[1] While the precise and complete molecular mechanisms underlying general anesthesia remain an area of active research, significant evidence points to specific interactions of sevoflurane with key ion channel targets.[1] Additionally, sevoflurane is known to alter tissue excitability by diminishing the extent of gap junction-mediated cell-cell coupling and by modifying the activity of various ion channels that are fundamental to the generation and propagation of action potentials.[1]

3.1.1. Interaction with GABA-A Receptors

A primary mechanism through which sevoflurane exerts its anesthetic effects is the potentiation of γ-aminobutyric acid type A (GABA-A) receptors.[1] These receptors are ligand-gated chloride channels that mediate the majority of fast inhibitory neurotransmission in the mammalian brain. Sevoflurane acts as a positive allosteric modulator of GABA-A receptors, meaning it enhances the effect of the endogenous neurotransmitter GABA.[1] This potentiation leads to an increased influx of chloride ions (Cl−) into the neuron when GABA binds, resulting in hyperpolarization of the neuronal membrane and a subsequent decrease in neuronal excitability. This widespread reduction in CNS activity contributes significantly to the sedative, hypnotic, and amnesic properties of sevoflurane.

Studies have indicated that sevoflurane interacts with various GABA-A receptor subunit compositions. It has been shown to enhance the responses of GABA-A receptors containing α2β1 subunits, with a reported EC50​ (half-maximal effective concentration) of 0.45 mM.[16] Furthermore, sevoflurane at a concentration of 360 µM increases the amplitude of GABA-A receptor responses to GABA stimulation for receptors composed of α1β2γ2 subunits.[16] The γ2 subunit, which is critical for the action of benzodiazepines, is also implicated in the effects of sevoflurane, although the direct anesthetic action of sevoflurane on the GABA-A receptor appears to be largely independent of the specific γ2L or γ2S splice variants.[30] The robust and multifaceted interaction of sevoflurane with GABA-A receptors is considered a cornerstone of its anesthetic efficacy, explaining a substantial part of its capacity to induce and maintain the anesthetic state by globally depressing neuronal activity. The diversity of GABA-A receptor subtypes throughout the CNS may also contribute to the spectrum of effects observed with sevoflurane administration.

3.1.2. Modulation of Glycine Receptors

Sevoflurane also significantly potentiates glycine receptors, which, like GABA-A receptors, are inhibitory ligand-gated chloride channels.[1] These receptors are densely expressed in the spinal cord and brainstem, where they play a crucial role in mediating inhibitory neurotransmission. Sevoflurane acts as an agonist at the glycine receptor subunit alpha-1 [1] and enhances the responses of α1 subunit-containing glycine receptors with an EC50​ of 0.36 mM.[16] By increasing chloride conductance through glycine receptors, sevoflurane contributes to further neuronal hyperpolarization and inhibition, particularly at the spinal level. This action is believed to be important for the muscle relaxant properties of sevoflurane and its ability to produce immobility in response to surgical stimulation.[33] The combined potentiation of both GABA-A and glycine receptors by sevoflurane results in a more profound and widespread depression of the CNS, contributing to the multifaceted nature of general anesthesia, encompassing sedation, amnesia, and immobility.

3.1.3. Effects on NMDA Receptors

In addition to enhancing inhibitory neurotransmission, sevoflurane also modulates excitatory pathways by inhibiting N-methyl-D-aspartate (NMDA) receptors.[1] NMDA receptors are ionotropic glutamate receptors critical for excitatory synaptic transmission, synaptic plasticity, learning, and memory. Sevoflurane acts as an antagonist at NMDA receptors, thereby reducing excitatory signaling.[1]

The degree of NMDA receptor antagonism by sevoflurane at clinically relevant concentrations (Minimum Alveolar Concentration, MAC) is generally considered more modest compared to its potentiation of GABA-A and glycine receptors.[33] However, this interaction likely contributes to the amnesic and some analgesic effects of sevoflurane. An interesting interplay has been suggested by research indicating that if glycine receptor-mediated inhibition is compromised (e.g., by strychnine antagonism), the anesthetic reliance on NMDA receptor inhibition by sevoflurane may increase at MAC.[33] This suggests a degree of functional redundancy or a compensatory shift in molecular targets depending on the overall state of neuronal excitability. Furthermore, under specific experimental conditions, such as sevoflurane preconditioning, NMDA receptor modulation has been implicated in neuroprotective effects against ischemic injury.[34] While not its primary mode of anesthetic action, NMDA receptor inhibition by sevoflurane contributes to the overall depression of CNS activity and the anesthetic state.

3.1.4. Interaction with Nicotinic Acetylcholine (nACh) Receptors

Sevoflurane also inhibits the activity of excitatory nicotinic acetylcholine receptors (nAChRs).[1] These ligand-gated ion channels are involved in various CNS functions, including arousal, cognition, and modulation of neurotransmitter release. Sevoflurane has been shown to inhibit the binding of the high-affinity nicotinic agonist epibatidine to nAChRs in mouse brain membranes with an IC50​ (half-maximal inhibitory concentration) of 0.77 mM.[16] This inhibition of nAChR function would contribute to the overall reduction in neuronal excitation and the anesthetic state.

3.1.5. Modulation of Potassium Channels

Sevoflurane exerts significant effects on various types of potassium channels, which play a crucial role in setting resting membrane potential and regulating neuronal excitability. It is known to affect the slowly activating delayed rectifier K+ currents (IKs​).[1]

A notable action of sevoflurane is its role as an activator or opener of several potassium channel families. This includes mitochondrial ATP-sensitive potassium channels [1] and, importantly, members of the two-pore domain potassium (K2P) channel family, such as TASK-1 (KCNK3), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), and TALK-1 (KCNK16).[26] Activation of these K2P channels, often referred to as "leak" channels, leads to an increased efflux of potassium ions (K+) from neurons. This K+ efflux hyperpolarizes the cell membrane, making neurons less excitable and contributing significantly to the generalized neuronal inhibition characteristic of anesthesia.[29]

Furthermore, sevoflurane has a distinct modulatory effect on voltage-gated Shaker-related potassium channels (Kv1.x), particularly the Kv1.2 subunit, which is ubiquitously expressed in the brain.[36] Unlike some other anesthetics that may weakly inhibit these channels, sevoflurane acts as a positive modulator of Kv1.x channels.[37] Studies using photoaffinity labeling with azisevoflurane (a sevoflurane analog) have identified specific binding sites on the Kv1.2 channel. These include Leu317, located within the internal S4-S5 linker (a critical helix connecting the voltage sensor to the pore region), and Thr384, near the external selectivity filter (in a G329T mutant Kv1.2 channel).[37] Mutagenesis of the Leu317 residue has been shown to abolish the voltage-dependent positive modulation of Kv1.2 by sevoflurane.[37] Mechanistic studies suggest that sevoflurane preferentially binds to the open-conductive state of the Kv1.2 channel, thereby shifting its open probability leftward, which means the channel is more likely to be open at a given membrane potential.[36] This positive modulation of Kv1.x channels is thought to be relevant to sevoflurane's pharmacology, as inhibition of these channels during sevoflurane anesthesia has been linked to regaining consciousness in animal models.[37] The effects of sevoflurane on these various potassium channels, leading to neuronal hyperpolarization, are a significant component of its overall anesthetic mechanism, working synergistically with its actions on inhibitory neurotransmitter receptors.

3.1.6. Effects on Calcium Channels and Other Targets

Sevoflurane's molecular interactions extend to calcium channels and other cellular components. It is known to affect T-type and L-type calcium currents (ICa,T​ and ICa,L​) [1], which are involved in neuronal excitability and neurotransmitter release. Additionally, sevoflurane inhibits calcium-transporting ATPases [1], potentially altering intracellular calcium homeostasis.

Sevoflurane has also been shown to bind to calmodulin (CaM) in a calcium-dependent manner. CaM is a crucial intracellular calcium sensor that regulates a vast array of cellular processes, including the function of many ion channels and signaling proteins. Interaction with CaM could therefore represent an indirect pathway through which sevoflurane modulates neuronal function.[35]

Other reported molecular targets include the inhibition of NADH-ubiquinone oxidoreductase chain 1 (Complex I of the mitochondrial respiratory chain) [1], which could have implications for cellular energy metabolism. Sevoflurane also decreases the extent of gap junction-mediated cell-cell coupling [1], potentially disrupting coordinated neuronal activity. Finally, it inhibits serotonin (5-HT3) receptors, another class of excitatory ligand-gated ion channels.[1] The collective impact of these diverse molecular interactions contributes to the profound and reversible depression of CNS function that characterizes general anesthesia induced by sevoflurane.

3.2. Pharmacodynamics

3.2.1. Anesthetic Effects: Onset and Recovery Characteristics

The pharmacodynamic profile of sevoflurane is largely defined by its rapid onset of action and swift recovery upon discontinuation, characteristics highly valued in clinical anesthesia.[1] These favorable kinetics are primarily attributed to its low blood:gas partition coefficient (typically 0.63-0.69), which signifies that only a minimal amount of the anesthetic needs to dissolve in the blood to achieve equilibrium between the alveolar and arterial partial pressures.[1] This rapid equilibration facilitates a quick build-up of anesthetic concentration in the brain, leading to a fast induction of anesthesia.

Similarly, upon cessation of administration, the low blood solubility allows for rapid elimination of sevoflurane from the body, primarily via the lungs, resulting in a correspondingly quick emergence from anesthesia.[1] Patients often emerge more alert in the early recovery period when compared to those anesthetized with older agents like halothane or isoflurane.[6]

A significant advantage of sevoflurane, contributing to its smooth induction characteristics, is its non-pungent, pleasant odor and lack of significant airway irritation.[1] This makes it particularly well-suited for inhalational induction via mask, a common technique in pediatric anesthesia and for adult patients who may be anxious about intravenous cannulation.

3.2.2. Minimum Alveolar Concentration (MAC)

The Minimum Alveolar Concentration (MAC) is a standard measure of inhalational anesthetic potency. It is defined as the alveolar concentration of an anesthetic at 1 atmosphere that prevents movement in 50% of subjects in response to a standardized supramaximal noxious stimulus, typically a surgical skin incision.[8] MAC values are crucial for guiding the clinical administration of volatile anesthetics, allowing for dose titration to achieve the desired depth of anesthesia.

MAC values for sevoflurane are influenced by several factors, most notably patient age and the concomitant administration of other anesthetic agents like nitrous oxide (N2​O).[2] MAC is highest in infants around 6 months of age and progressively decreases with advancing age.[2] The co-administration of N2​O significantly reduces the MAC of sevoflurane, allowing for lower inspired concentrations of the volatile agent.[8] Some evidence also suggests that ethnic factors might influence MAC values, with studies in Japanese adults reporting slightly lower MAC values compared to those reported in US studies.[8] Gender, however, does not appear to significantly affect sevoflurane MAC.[8]

The following table summarizes commonly cited MAC values for sevoflurane:

Table 3.2.2.1: MAC Values of Sevoflurane

Age of Patient (years)	Sevoflurane in Oxygen	Sevoflurane in ~60-65% N2​O / ~35-40% O2​	References
0 – 1 month<sup>a</sup>	3.3%	2.0%<sup>c</sup>	5
1 – < 6 months	3.0%		9
6 months – < 3 years	2.8%	2.0%<sup>b</sup>	5
3 – 12	2.5%		5
25	2.6%	1.4%	9
40	2.1%	1.1%	8
60	1.7%	0.9%	9
80	1.4%	0.7%	9

^a Neonates are full-term gestational age. MAC in premature infants has not been determined.

^b In 1 – < 3 year old pediatric patients, 60% N2​O/40% O2​ was used.

^c Value for 0-1 month with N2​O from.19

Understanding these MAC values and the factors that modify them is essential for the safe and effective administration of sevoflurane, allowing clinicians to tailor anesthetic depth to individual patient needs and surgical requirements.

3.2.3. Comparison with Other Inhalational Anesthetics

Sevoflurane's pharmacodynamic profile positions it uniquely among commonly used inhalational anesthetics. In terms of potency, sevoflurane is approximately three times more potent than desflurane but is less potent than older agents like halothane and isoflurane.[1]

Its onset and recovery characteristics are generally faster than those of isoflurane and halothane, a direct consequence of its lower blood:gas solubility.[1] When compared to desflurane, which has an even lower blood:gas partition coefficient, sevoflurane's onset may be comparable, while its recovery might be similar or slightly slower in some circumstances, though desflurane's pungency limits its utility for mask induction.[7]

A key distinguishing feature is sevoflurane's lack of airway irritation and its pleasant odor, making it significantly better tolerated for mask induction than more pungent agents like desflurane and isoflurane.[1]

Regarding cardiovascular effects, sevoflurane tends to provide a more stable heart rate profile compared to isoflurane or desflurane, which can cause tachycardia, particularly with rapid increases in inspired concentration.[2] The decrease in blood pressure observed with sevoflurane is generally similar to that seen with other modern volatile anesthetics.[2]

This balance of properties—rapid kinetics, low pungency facilitating smooth inductions, and generally good cardiovascular stability—underpins sevoflurane's established role. While desflurane may offer marginally faster overall kinetics, its airway irritancy is a notable disadvantage for induction. Older agents like isoflurane have slower kinetics, and halothane carries more significant concerns regarding hepatotoxicity and arrhythmogenicity. Consequently, sevoflurane often occupies a favorable position for a wide range of clinical scenarios, particularly in pediatric anesthesia and outpatient procedures where smooth induction and rapid, predictable recovery are highly valued. Its characteristics represent a significant refinement over many older volatile anesthetic agents.

3.3. Pharmacokinetics

3.3.1. Absorption: Pulmonary Uptake, Influence of Blood:Gas Solubility

Sevoflurane is administered by inhalation and is rapidly absorbed into the systemic circulation through the lungs.[1] The rate and extent of uptake are primarily governed by its low blood:gas partition coefficient, which is approximately 0.63-0.69 at 37°C.[1] This low solubility in blood means that only a minimal amount of sevoflurane needs to dissolve in the blood before the partial pressure of the anesthetic in the arterial blood equilibrates with the alveolar partial pressure. This characteristic is fundamental to its rapid onset of action, as the brain (a vessel-rich organ) quickly reaches anesthetic concentrations. Other factors influencing uptake include the inspired concentration of sevoflurane, alveolar ventilation, and pulmonary blood flow (cardiac output).

3.3.2. Distribution: Tissue Perfusion and Solubility

Once absorbed into the bloodstream, sevoflurane is distributed to various body tissues. The distribution pattern follows a multi-compartment model, which includes the lungs, the vessel-rich group of organs (e.g., brain, heart, kidneys, liver), muscle, and fat.[8] The rate at which sevoflurane equilibrates with these tissues depends on their perfusion (blood flow) and the tissue:blood partition coefficients of the anesthetic.

The vessel-rich organs, due to their high blood flow, rapidly equilibrate with the arterial concentration of sevoflurane. Muscle and fat compartments, being less perfused, take longer to equilibrate. Sevoflurane has moderate lipid solubility, as indicated by its oil:gas partition coefficient of 47.2.[8] While this allows for some accumulation in fatty tissues during prolonged anesthesia, its lipid solubility is generally lower than that of some older, more soluble agents. This contributes to a relatively faster wash-out from these tissues upon discontinuation of administration, aiding in quicker recovery.

Specific pharmacokinetic parameters reported include a peripheral volume of distribution of 1634 mLvapour​/kgbw​ and a total volume of distribution of 1748 mLvapour​/kgbw​ in a study involving patients undergoing maxillofacial surgery with low-flow sevoflurane anesthesia.[1]

Information on plasma protein binding of sevoflurane itself is not extensively detailed. However, it is generally understood that other fluorinated volatile anesthetics can displace drugs from serum and tissue proteins in vitro, though the clinical significance of such interactions for sevoflurane is considered unclear.[1] Clinical studies have suggested that sevoflurane administration does not have a significant effect in patients concurrently taking drugs that are highly protein-bound and have a small volume of distribution.[1] The pharmacokinetic profile, characterized by rapid uptake and distribution primarily dictated by its low blood solubility, allows for precise control over the depth of anesthesia and contributes to its predictable recovery characteristics.

3.3.3. Metabolism: Role of CYP2E1, Formation of Hexafluoroisopropanol (HFIP) and Inorganic Fluoride, Generation and Implications of Compound A

Sevoflurane undergoes a limited degree of biotransformation in the body, with approximately 2-5% of the absorbed dose being metabolized, primarily in the liver.[1] The principal enzyme responsible for this metabolism is Cytochrome P450 2E1 (CYP2E1).[1]

The metabolic process involves defluorination of sevoflurane, yielding two main products: hexafluoroisopropanol (HFIP) and inorganic fluoride ions (F−), along with carbon dioxide.[1] HFIP is subsequently rapidly conjugated with glucuronic acid, and this conjugate is then eliminated via the urine.[1] Serum concentrations of inorganic fluoride typically peak within two hours after the cessation of sevoflurane anesthesia and return to preoperative baseline levels within 48 hours.[1] Certain substances, such as chronic ethanol exposure and the drug isoniazid, are known inducers of CYP2E1 activity and can therefore increase the metabolism of sevoflurane.[1] Conversely, barbiturates do not appear to affect its metabolism.[1]

A significant aspect of sevoflurane's chemistry related to its use in anesthesia circuits is the formation of Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFE). Compound A is not a direct metabolite of sevoflurane biotransformation within the body but rather a degradation product formed ex vivo when sevoflurane vapor comes into contact with carbon dioxide absorbents used in anesthesia breathing systems.[2] The formation of Compound A is enhanced by several factors, including increased temperature of the CO₂ absorbent (an exothermic reaction occurs when CO₂ reacts with the absorbent), the use of desiccated (dry) absorbents, low fresh gas flow rates, higher sevoflurane concentrations, and the type of absorbent used (absorbents containing strong bases, particularly potassium hydroxide, such as Baralyme, produce higher levels of Compound A than soda lime).[8] Compound A has demonstrated nephrotoxicity in animal studies (rats) [2], raising concerns about potential renal effects in humans, which has led to specific recommendations for sevoflurane administration, particularly regarding fresh gas flow rates and absorbent management (see Section 6.3.1).

The limited extent of sevoflurane metabolism is generally considered a favorable characteristic, as it minimizes the potential for systemic toxicity from metabolites and contributes to the rapid elimination of the parent drug. However, the nature of its byproducts—inorganic fluoride from biotransformation and Compound A from ex vivo degradation—necessitates careful clinical management. The inducibility of CYP2E1 by common substances like ethanol implies that patient-specific factors can influence the extent of sevoflurane metabolism and, theoretically, the exposure to fluoride ions. While fluoride itself can be nephrotoxic at high concentrations, the transient elevations seen with sevoflurane are generally not associated with clinical renal dysfunction in patients with normal preoperative renal function when used as directed. The primary concern regarding renal effects stems from Compound A. This underscores that even minor metabolic pathways or chemical degradation pathways can have significant clinical relevance if they produce potentially active or toxic compounds, highlighting the importance of understanding the complete disposition of an anesthetic agent.

3.3.4. Excretion: Primary Route (Exhalation of Unchanged Drug), Urinary Metabolites

The primary route of elimination for sevoflurane is exhalation of the unchanged drug via the lungs. Due to its low blood solubility, sevoflurane is rapidly cleared from the blood and eliminated in expired air, with approximately 95-98% of the administered dose being excreted unchanged through this pathway.[1]

The small fraction of sevoflurane that undergoes metabolism (2-5%) results in metabolites that are excreted renally. As mentioned, HFIP is conjugated with glucuronic acid and eliminated in the urine.[1] Up to 3.5-5% of the total sevoflurane dose can appear in the urine as inorganic fluoride.[1] It is also noted that as much as 50% of fluoride clearance may be nonrenal, with uptake into bone being a possibility.[1]

The terminal elimination half-life of sevoflurane, reflecting its clearance from the peripheral fat compartment, is reported to be approximately 20 hours.[1] The transport clearance from the central to the peripheral compartment was measured at 13.0 mLvapour​/kgbw​⋅min in one study.[1]

4. Clinical Use and Administration

4.1. Approved Indications (FDA, EMA)

Sevoflurane is approved by major regulatory agencies worldwide for the induction and maintenance of general anesthesia in both adult and pediatric patients undergoing inpatient and outpatient surgical procedures.[2]

• United States (FDA): Sevoflurane is FDA-approved for these indications.[2] It is available under brand names such as Ultane (originally Abbott, now AbbVie) and also as a generic drug.[11]
• Europe (EMA): Sevoflurane has marketing authorisation in the European Union for similar indications in human medicine. Examples include "Sevoflurane Baxter" (authorised since September 1, 1995) and products from Piramal and Chanelle Medical.[4] It is also authorised for veterinary use in dogs and cats (e.g., Sevohale, SevoFlo).[4]
• Japan (PMDA): Sevoflurane was first approved for clinical use in Japan in 1990.[1]

The administration of sevoflurane should be performed only by personnel trained in the administration of general anesthesia, with facilities for airway maintenance, artificial ventilation, oxygen enrichment, and circulatory resuscitation readily available.[5]

4.2. Dosage Guidelines for Induction and Maintenance of Anesthesia (Adult and Pediatric)

The dosage of sevoflurane must be individualized and carefully titrated to achieve the desired clinical effect, taking into account the patient's age, clinical status, and the type of surgical procedure.[9] Premedication is not specifically indicated or contraindicated and is determined by the anesthesiologist based on individual patient needs.[5]

• Induction of Anesthesia:
• Sevoflurane's non-pungent odor and lack of airway irritation make it well-suited for mask induction in both adults and children.[2]
• In adults, inspired concentrations of up to 5% sevoflurane (or up to 8% in unpremedicated patients) typically produce surgical anesthesia in less than 2 minutes.[5]
• In children, inspired concentrations of up to 7% sevoflurane usually achieve surgical anesthesia within 2 minutes.[5]
• Alternatively, induction can be initiated with an intravenous agent (e.g., propofol, a short-acting barbiturate), followed by inhaled sevoflurane for maintenance.[19]
• Maintenance of Anesthesia:
• Surgical levels of anesthesia are generally maintained with inspired sevoflurane concentrations of 0.5% to 3%.[9]
• The concentration required is age-dependent, with MAC values decreasing with increasing age (see Table 3.2.2.1).[5]
• Concomitant use of nitrous oxide (N2​O) reduces the sevoflurane requirement (MAC reduction of approximately 50% in adults and 25% in pediatric patients with ~60-65% N2​O).[8]
• Emergence: Emergence from sevoflurane anesthesia is generally rapid.[9] Clinicians should anticipate the need for early postoperative pain relief due to this rapid recovery.[19]

4.3. Administration Techniques and Vaporizer Settings

Sevoflurane is administered by inhalation of its vapor.[19] It is crucial that the concentration of sevoflurane being delivered from the vaporizer is precisely known and controlled. This is achieved by using vaporizers specifically designed and calibrated for sevoflurane.[9] Standard vaporizer technology is suitable for sevoflurane administration.[6] Monitoring of end-tidal sevoflurane concentration is a valuable tool to guide administration and assess anesthetic depth.[27]

Special considerations apply to low-flow anesthesia techniques to minimize patient exposure to Compound A (see Section 6.3.1). Current recommendations advise that sevoflurane exposure should not exceed 2 MAC-hours when fresh gas flow rates are between 1 and <2 L/min. Fresh gas flow rates below 1 L/min are generally not recommended.[9] Sevoflurane can be used with any type of anesthesia circuit.[9]

4.4. Advantages in Clinical Practice

Sevoflurane offers several distinct advantages that have contributed to its widespread adoption in clinical anesthesia:

• Rapid and Smooth Induction: Its low blood:gas solubility and non-pungent, pleasant odor make it an excellent agent for rapid and smooth inhalational induction, particularly via mask. This is especially beneficial in pediatric anesthesia, where patient cooperation can be challenging, and for adults who prefer to avoid intravenous induction.[1]
• Rapid Emergence and Recovery: The same low solubility that facilitates rapid induction also allows for quick elimination and emergence from anesthesia once administration is discontinued. This leads to patients being more alert in the early postoperative period compared to older, more soluble agents.[1] This characteristic is advantageous for outpatient surgery, allowing for faster discharge.
• Cardiovascular Stability: Sevoflurane generally provides good cardiovascular stability, with preserved cardiac output and a more stable heart rate profile compared to some other volatile anesthetics.[2]
• Bronchodilating Properties: Sevoflurane possesses bronchodilating effects and is less irritating to the airways than many other volatile agents, making it a suitable choice for patients with reactive airway disease, such as asthma.[2]
• Control and Titratability: The rapid changes in alveolar concentration with adjustments in inspired concentration allow for precise control over the depth of anesthesia.[6]

The combination of these clinical advantages makes sevoflurane a versatile anesthetic agent. Its suitability for diverse patient populations, from neonates to the elderly, and for various types of surgical procedures, underscores its importance in modern anesthesiology. The ability to use standard vaporizer technology further enhances its practicality.[6] While specific precautions are necessary (e.g., regarding Compound A formation), its overall profile often represents a favorable balance of efficacy, safety, and patient comfort, solidifying its role as a frequently chosen inhalational anesthetic.

5. Systemic Effects and Organ-Specific Considerations

5.1. Cardiovascular System Effects

Sevoflurane exerts dose-dependent effects on the cardiovascular system. The most prominent effect is a decrease in arterial blood pressure, which is primarily attributed to a reduction in systemic vascular resistance.[2] This vasodilatory effect may be slightly less pronounced than that observed with isoflurane at higher MAC values.[12]

Despite the reduction in blood pressure, cardiac output is generally well preserved at clinically relevant concentrations of sevoflurane.[2] Heart rate typically remains stable or may even decrease slightly; unlike desflurane or higher concentrations of isoflurane, sevoflurane is not usually associated with significant tachycardia.[2] However, some studies in specific animal models (dogs) and in non-premedicated children have reported small increases in heart rate.[12]

Myocardial contractility is mildly depressed by sevoflurane, an effect comparable in magnitude to that seen with equianesthetic concentrations of isoflurane and desflurane.[2] Sevoflurane maintains coronary blood flow and does not appear to induce coronary steal phenomenon, a concern with some older vasodilating anesthetics.[2] It also does not significantly potentiate epinephrine-induced cardiac arrhythmias, which is a safety advantage over agents like halothane.[2]

There are reports that sevoflurane may prolong the QT interval on the electrocardiogram [1], which warrants caution in susceptible individuals. Like other volatile anesthetics, sevoflurane reduces baroreflex function in a dose-dependent manner.[12]

The overall cardiovascular profile of sevoflurane, characterized by vasodilation with generally preserved cardiac output and heart rate stability, is considered favorable for many patients. The lack of significant sympathetic activation contributes to its hemodynamic stability. However, the potential for hypotension necessitates careful patient monitoring and dose titration, especially in individuals who are hypovolemic or have pre-existing cardiovascular compromise.[19] The risk of QT prolongation, although rare, should be considered in patients with relevant predispositions or those receiving other QT-prolonging medications.

5.2. Respiratory System Effects

Sevoflurane produces a dose-dependent depression of respiration, which can manifest as a decrease in tidal volume and respiratory rate, potentially leading to apnea at concentrations around 1.5 to 2.0 MAC.[1] This respiratory depression results from a combination of central effects on medullary respiratory neurons and peripheral effects on diaphragmatic function and contractility.[8]

A significant advantage of sevoflurane is its relative lack of airway irritation. Its non-pungent, sweet odor allows for smooth mask induction with a lower incidence of coughing, breath-holding, laryngospasm, and bronchospasm compared to more pungent agents like desflurane or isoflurane.[1] Sevoflurane also possesses bronchodilating properties and can attenuate bronchial smooth muscle constriction induced by agents like histamine or acetylcholine, making it a suitable choice for patients with asthma or other reactive airway diseases.[2]

Like other volatile anesthetics, sevoflurane blunts the ventilatory responses to both hypoxia and hypercapnia.[2] It also inhibits hypoxic pulmonary vasoconstriction (HPV) in a dose-dependent manner [2], which can potentially increase intrapulmonary shunting if not managed appropriately, particularly in patients with significant pre-existing lung disease or one-lung ventilation scenarios.

5.3. Central Nervous System Effects

Sevoflurane exerts profound effects on the central nervous system to produce anesthesia. It causes dose-dependent vasodilation of the cerebral vasculature, which can lead to an increase in cerebral blood flow (CBF) and, potentially, intracranial pressure (ICP).[2] In patients with normal baseline ICP, the effect on ICP is generally minimal and can be mitigated by techniques such as controlled hyperventilation.[19]

Concurrently, sevoflurane reduces the cerebral metabolic rate of oxygen (CMRO₂), a desirable effect during anesthesia.[2] This uncoupling of CBF (increased or maintained) and CMRO₂ (decreased) can be neuroprotective by ensuring adequate oxygen and substrate delivery to the brain while reducing its metabolic demands, particularly during periods of potential stress or ischemia.[29] Cerebral autoregulation, the brain's ability to maintain constant CBF despite changes in systemic blood pressure, is generally maintained at lower concentrations of sevoflurane but may become impaired at higher doses.[8]

During its clinical development program, sevoflurane was not associated with evidence of seizure activity on the electroencephalogram (EEG).[19] However, rare post-marketing reports have described seizures occurring in association with sevoflurane administration, predominantly in children and young adults, some of whom had no predisposing risk factors. These events have been reported during induction, emergence, and in the early postoperative period.[9] Clinical judgment is therefore advised when using sevoflurane in patients with a history of seizures or other risk factors.

A significant area of ongoing research and discussion is the potential for pediatric neurotoxicity associated with general anesthetics, including sevoflurane. Animal studies, particularly in young animals during periods of rapid brain growth and synaptogenesis, have suggested that prolonged or repeated exposure to anesthetic agents can lead to alterations in synaptic morphology, neurogenesis, and long-term neurobehavioral abnormalities.[1] While the direct translation of these findings to human pediatric patients is complex and human evidence remains less clear and often confounded by surgical and underlying illness factors, these concerns have led to cautious use and further investigation.[2] Current clinical guidelines generally do not preclude the use of sevoflurane or other anesthetics when clinically indicated in children but emphasize the importance of careful risk-benefit assessment, particularly for lengthy or multiple procedures in very young patients.

The balance of sevoflurane's CNS effects involves providing profound anesthesia while managing potential changes in cerebral hemodynamics. The reduction in CMRO₂ is a beneficial neuroprotective aspect. However, the potential for increased CBF and ICP requires careful management, especially in neurosurgical patients or those with pre-existing intracranial hypertension. The issue of pediatric neurotoxicity remains a critical area of research, prompting ongoing efforts to understand long-term outcomes and refine anesthetic practices for the youngest patients.

5.4. Hepatic System Effects

Sevoflurane undergoes minimal metabolism in the liver, with only about 2-5% of the absorbed dose being biotransformed, primarily by the cytochrome P450 enzyme CYP2E1.[1] This limited metabolism is generally considered an advantage, reducing the potential for dose-dependent hepatotoxicity.

However, rare cases of postoperative hepatic dysfunction or hepatitis, ranging from mild, transient elevations in liver enzymes to severe hepatic necrosis, have been reported following sevoflurane anesthesia.[2] The mechanism for severe sevoflurane-associated hepatotoxicity, when it occurs, is thought to be immune-mediated, similar to halothane hepatitis. This involves the formation of trifluoroacetylated (TFA) protein adducts as a result of metabolism, which can act as neoantigens and elicit an immune response in susceptible individuals.[2] The risk of such immune-mediated hepatic injury may be increased with repeated exposures to halogenated hydrocarbon anesthetics within short intervals.[9]

Regarding hepatic blood flow, sevoflurane generally preserves hepatic arterial blood flow, and total hepatic blood flow and oxygen supply are typically well-maintained, especially at clinically relevant anesthetic concentrations.[2] Some studies suggest sevoflurane may reduce portal venous blood flow but can increase hepatic arterial flow, thereby maintaining overall hepatic oxygenation comparably to isoflurane.[10]

Clinical judgment is advised when administering sevoflurane to patients with pre-existing hepatic conditions or those receiving other potentially hepatotoxic drugs.[9]

5.5. Renal System Effects

The effects of sevoflurane on the renal system have been a subject of considerable investigation, primarily due to two factors: the release of inorganic fluoride ions (F−) during its metabolism, and the formation of Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFE) from its degradation by CO₂ absorbents in the anesthesia circuit.[1]

Inorganic fluoride is a known nephrotoxin at high concentrations. During sevoflurane metabolism, F− ions are released. Serum fluoride levels peak within about two hours after anesthesia and return to baseline within 48 hours.[1] While transient increases occur, numerous clinical studies have generally failed to demonstrate clinically significant renal injury attributable to fluoride release from sevoflurane when used as recommended in patients with normal renal function.[6]

Compound A has demonstrated dose- and duration-dependent nephrotoxicity in animal studies (rats).[2] Its formation is favored by low fresh gas flow rates, desiccated CO₂ absorbents (especially those containing potassium hydroxide), higher sevoflurane concentrations, and increased absorbent temperature.[2] This has led to specific recommendations to minimize Compound A exposure, such as maintaining minimum fresh gas flow rates (e.g., >1 L/min, and >2 L/min for exposures longer than 2 MAC-hours) and avoiding the use of desiccated or KOH-containing absorbents.[9] Some studies have reported transient proteinuria and glycosuria in patients undergoing prolonged sevoflurane anesthesia at low flow rates (>2 MAC-hours at <2 L/min).[9]

Due to limited clinical data and theoretical concerns, caution is advised when administering sevoflurane to patients with pre-existing significant renal insufficiency (e.g., serum creatinine >1.5 mg/dL or 133 µmol/L).[8] However, for patients with normal or mildly impaired renal function, sevoflurane is generally considered safe from a renal perspective when administered according to current guidelines. Sevoflurane typically causes a mild reduction in renal blood flow.[10]

6. Safety Profile

6.1. Adverse Reactions

Sevoflurane is generally well-tolerated, and most adverse events reported are mild to moderate in severity and transient in nature. Many of these events are common to general anesthesia and the surgical setting itself.[9]

Common Adverse Events

The most frequently reported adverse events vary slightly between adult and pediatric populations and the phase of anesthesia (induction, maintenance, emergence).

• During Induction (Adults, N=118) [9]:
• Cardiovascular: Bradycardia (5%), Hypotension (4%), Tachycardia (2%)
• Nervous System: Agitation (7%)
• Respiratory System: Laryngospasm (8%), Airway obstruction (8%), Breathholding (5%), Increased Cough (5%)
• During Induction (Pediatrics, N=507) [9]:
• Cardiovascular: Tachycardia (6%), Hypotension (4%)
• Nervous System: Agitation (15%)
• Respiratory System: Breathholding (5%), Increased Cough (5%), Laryngospasm (3%), Apnea (2%)
• Digestive System: Increased salivation (2%)
• During Maintenance and Emergence (All Patients, N=2906) [9]:
• Digestive System: Nausea (25%), Vomiting (18%)
• Cardiovascular: Hypotension (11%)
• Respiratory System: Increased Cough (11%)
• Nervous System: Somnolence (9%), Agitation (9%)
• Body as a Whole: Shivering (6%)
• Cardiovascular: Bradycardia (5%)

A FAERS database analysis focused on pediatric patients (0-18 years) identified significant adverse event signals associated with sevoflurane primarily within the System Organ Classes (SOCs) of "Cardiac disorders," "Respiratory, thoracic, and mediastinal disorders," and "Vascular disorders".[20]

The following table summarizes common adverse reactions based on data from clinical trials as reported in product monographs [9]:

Table 6.1.1: Summary of Common Adverse Reactions to Sevoflurane (Incidence >1%)

Adverse Reaction	Adult (Induction) (%)	Pediatric (Induction) (%)	All Patients (Maintenance/Emergence) (%)	Frequency Category (SmPC)
Nervous System
Agitation	7	15	9	Very Common
Somnolence			9	Common
Dizziness			4	Common
Headache			1	Common
Cardiovascular
Hypotension	4	4	11	Very Common
Bradycardia	5		5	Very Common
Tachycardia	2	6	2	Common
Hypertension			2	Common
Respiratory System
Laryngospasm	8	3	2	Common
Airway Obstruction	8			Common (Induction)
Cough Increased	5	5	11	Very Common
Breathholding	5	5	2	Common
Apnea		2		Common
Digestive System
Nausea			25	Very Common
Vomiting			18	Very Common
Salivary Hypersecretion		2	4	Common
General Disorders
Shivering			6	Common
Pyrexia (Fever)			1	Common
Hypothermia			1	Common

Frequencies from SmPC [19]: Very Common (≥1/10); Common (≥1/100 to <1/10). Note that specific percentages from [9] may not directly align with SmPC frequency categories due to different study populations or reporting thresholds.

Serious Adverse Events

• Malignant Hyperthermia (MH): Sevoflurane is a known potent trigger of MH in susceptible individuals. This is a rare, life-threatening hypermetabolic state of skeletal muscle requiring immediate discontinuation of the triggering agent and specific treatment with dantrolene sodium.[1]
• Perioperative Hyperkalemia: Rare instances of significant increases in serum potassium levels, leading to cardiac arrhythmias and, in some pediatric cases, death, have been reported postoperatively. This appears to be more prevalent in pediatric patients with latent or overt neuromuscular diseases, particularly Duchenne muscular dystrophy. Concomitant use of succinylcholine has been implicated in many of these cases.[1]
• QT Prolongation: There have been reports of QT interval prolongation associated with sevoflurane administration, and in exceptional cases, this has been linked to Torsade de Pointes, which can be fatal.[1]
• Emergence Delirium/Agitation: This is a common occurrence, particularly in children, during recovery from sevoflurane anesthesia. It is usually transient but can be distressing.[2]
• Seizures: Although not observed during the initial clinical development program [19], rare post-marketing cases of seizures have been reported, predominantly in children and young adults. Some of these patients had no predisposing risk factors. Seizures have occurred during various phases of anesthesia, including induction, emergence, and up to a day postoperatively.[9]
• Hepatotoxicity: Very rare cases of mild, moderate, or severe postoperative hepatic dysfunction or hepatitis, with or without jaundice, have been reported. Isolated cases of hepatic necrosis and hepatic failure have also been documented. The mechanism is suspected to be immune-mediated in some cases.[2]
• Cardiac Arrest: Episodes of severe bradycardia and cardiac arrest have been reported in pediatric patients with Down Syndrome receiving sevoflurane.[1]
• Renal Injury: While direct nephrotoxicity from sevoflurane itself is not clearly established in humans with normal renal function when used as directed, concerns exist regarding Compound A (see Section 6.3.1) and inorganic fluoride, particularly in patients with pre-existing renal impairment or during prolonged low-flow anesthesia.[1]

6.2. Contraindications

Sevoflurane is contraindicated in the following situations:

• Patients with known sensitivity or hypersensitivity to sevoflurane or other halogenated inhalation anesthetics.[9]
• Patients with a history of unexplained liver dysfunction (e.g., jaundice), fever, or leukocytosis of unknown cause occurring after a previous administration of a halogenated anesthetic.[19] This suggests a potential predisposition to immune-mediated hepatic reactions.
• Patients with known or suspected genetic susceptibility to malignant hyperthermia, or a personal or family history of malignant hyperthermia.[9]
• Situations where general anesthesia itself is contraindicated.[19]

6.3. Warnings and Precautions

6.3.1. Compound A Toxicity and Mitigation Strategies

Compound A (pentafluoroisopropenyl fluoromethyl ether, PIFE) is a degradation product of sevoflurane formed by its interaction with CO₂ absorbents in the anesthesia circuit.[2] In vitro and animal (rat) studies have demonstrated that Compound A is nephrotoxic in a dose- and duration-dependent manner.[2] Factors that enhance its formation include the use of desiccated CO₂ absorbents (especially those containing potassium hydroxide, like Baralyme, which are not recommended [9]), low fresh gas flow rates, increased absorbent temperature, and higher sevoflurane concentrations.[8]

The clinical significance of Compound A exposure in humans has been a subject of extensive discussion. While definitive evidence of Compound A-induced clinical nephrotoxicity in humans at typical exposure levels is limited, the potential risk has led to specific precautions. To minimize exposure, it is recommended that sevoflurane administration should not exceed 2 MAC-hours at fresh gas flow rates of 1 to <2 L/min. Fresh gas flow rates below 1 L/min are generally not recommended.[9] Clinicians should consider all factors contributing to Compound A exposure, including the duration of anesthesia, fresh gas flow rate, sevoflurane concentration, and the condition and type of CO₂ absorbent used.[9] Regular replacement of CO₂ absorbents, irrespective of color indicator changes (as desiccation may not always cause a color change), is also advised.[9] This careful management of the anesthesia circuit and technique is crucial for mitigating the risk associated with Compound A.

6.3.2. Risk of QT Prolongation

There have been post-marketing reports of QT interval prolongation, which in rare and exceptional cases has been associated with Torsade de Pointes and fatalities.[1] Therefore, caution should be exercised when administering sevoflurane to susceptible patients. This includes individuals with congenital Long QT Syndrome, those with a history of Torsade de Pointes, or patients concurrently receiving other medications known to prolong the QT interval.[9]

6.3.3. Pediatric Neurotoxicity Concerns

The potential for adverse effects of general anesthetics on the developing brain is an area of ongoing research and concern. Animal studies, particularly in young animals exposed during critical periods of brain growth and synaptogenesis, have suggested that prolonged or repeated exposure to agents like sevoflurane may lead to neuronal apoptosis, alterations in synaptic morphology, and long-term neurodevelopmental or behavioral abnormalities.[1]

Translating these findings to human pediatric patients is complex, as human studies are often observational and confounded by factors such as the underlying illness requiring surgery and the surgical procedure itself. While some human studies have suggested associations between early anesthetic exposure and later neurodevelopmental issues, others have not confirmed these findings.[2] Currently, regulatory agencies and professional bodies generally advise that necessary surgical procedures in young children should not be delayed or avoided due to these concerns. However, a careful risk-benefit assessment is recommended, especially for prolonged or multiple anesthetic exposures in children younger than 3 years or in pregnant women during their third trimester.[9]

6.3.4. Malignant Hyperthermia

Sevoflurane is a potent triggering agent for malignant hyperthermia (MH) in genetically susceptible individuals.[1] MH is a rare but life-threatening pharmacogenetic disorder characterized by a hypermetabolic state of skeletal muscle. Clinical signs include unexplained hypercapnia, muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. A late sign is hyperthermia. If MH is suspected, sevoflurane and other triggering agents must be discontinued immediately, and specific treatment, primarily with intravenous dantrolene sodium, along with intensive supportive therapy, must be initiated.[9]

6.3.5. Perioperative Hyperkalemia

Rare instances of significant increases in serum potassium levels have been reported in the perioperative period in pediatric patients receiving inhaled anesthetic agents, including sevoflurane. These episodes have, in some cases, resulted in cardiac arrhythmias and death.[1] Patients with latent or overt neuromuscular diseases, particularly Duchenne muscular dystrophy, appear to be most vulnerable. The concomitant use of succinylcholine has been associated with most, but not all, of these cases. Early and aggressive intervention to treat hyperkalemia and any resistant arrhythmias is crucial, followed by an evaluation for underlying latent neuromuscular disease.[9]

6.3.6. Hepatic Dysfunction

While sevoflurane undergoes minimal hepatic metabolism, very rare post-marketing reports of mild, moderate, and severe postoperative hepatic dysfunction or hepatitis, with or without jaundice, have been documented.[2] Isolated cases of hepatic necrosis and hepatic failure have also occurred. The etiology is often multifactorial, but an immune-mediated reaction (similar to halothane hepatitis) is suspected in some instances, particularly with repeated exposures to halogenated anesthetics within a short timeframe.[9] Clinical judgment should be exercised when administering sevoflurane to patients with underlying hepatic conditions or those receiving other medications known to be hepatotoxic.[9]

6.3.7. Desiccated CO₂ Absorbents

As previously mentioned in the context of Compound A, desiccated CO₂ absorbents pose a significant risk when used with sevoflurane. The exothermic reaction between sevoflurane and dried-out absorbents (especially those containing potassium hydroxide) can lead to extreme heat generation, smoke, and, in rare cases, spontaneous fire within the anesthesia breathing circuit.[9] An unusually delayed rise or an unexpected decline in the inspired sevoflurane concentration compared to the vaporizer setting may be an indicator of excessive heating and chemical breakdown of the absorbent. Therefore, CO₂ absorbents should be replaced routinely, and desiccated absorbents must be avoided. KOH-containing absorbents are not recommended for use with sevoflurane.[9]

6.4. Drug Interactions

Sevoflurane can interact with several other medications commonly used in the perioperative setting. These interactions can affect its MAC requirements, hemodynamic effects, neuromuscular blockade, and metabolism.

6.4.1. Neuromuscular Blocking Agents (NMBAs)

Sevoflurane potentiates the effects of non-depolarizing neuromuscular blocking agents (NMBAs) such as pancuronium, vecuronium, and atracurium, increasing both the intensity and duration of neuromuscular blockade.6 Dosage adjustments for these NMBAs are generally required when used concomitantly with sevoflurane, similar to adjustments needed with isoflurane. Reduced doses of NMBAs during induction might lead to a delay in achieving adequate intubating conditions or insufficient muscle relaxation. During maintenance of anesthesia, the dose of NMBAs is likely to be less than that required with N2​O/opioid anesthesia. The use of a peripheral nerve stimulator to monitor neuromuscular blockade and guide supplemental NMBA dosing is recommended.9

The concomitant use of succinylcholine, a depolarizing NMBA, with inhaled anesthetics like sevoflurane has been associated with rare cases of perioperative hyperkalemia in pediatric patients, particularly those with underlying neuromuscular disorders.9

6.4.2. Opioids and Benzodiazepines

Opioids (e.g., fentanyl, alfentanil, sufentanil) and benzodiazepines (e.g., midazolam, diazepam) are commonly used for premedication or as adjuncts to general anesthesia. These CNS depressant drugs are expected to decrease the MAC of sevoflurane, similar to their effect on other volatile anesthetics.[6] This MAC-sparing effect allows for lower inspired concentrations of sevoflurane to achieve the desired anesthetic depth. However, this combination may also lead to an augmentation of respiratory depression and hemodynamic effects, such as a synergistic fall in heart rate, blood pressure, and respiratory rate when opioids like alfentanil or sufentanil are combined with sevoflurane.[19] Careful titration and monitoring are essential when these agents are used together.

6.4.3. CYP2E1 Inducers

Sevoflurane is metabolized to a small extent by the hepatic enzyme CYP2E1. Drugs that induce CYP2E1 activity, such as isoniazid (an antitubercular agent) and chronic alcohol consumption, can potentially increase the metabolism of sevoflurane.[1] This increased metabolism may lead to higher plasma concentrations of inorganic fluoride. Furthermore, concomitant use of isoniazid with sevoflurane may potentiate the hepatotoxic effects of isoniazid.[19]

6.4.4. Other Interactions

• Nitrous Oxide (N2​O): Co-administration of N2​O significantly reduces the MAC of sevoflurane. In adults, 60-65% N2​O can reduce sevoflurane MAC by approximately 50%, while in pediatric patients, the reduction is around 25%.[8]
• Beta-Blockers: These agents may enhance the negative inotropic (myocardial contractility), chronotropic (heart rate), and dromotropic (atrioventricular conduction) effects of sevoflurane by blocking cardiovascular compensatory mechanisms.[19]
• Calcium Channel Blockers: Concomitant use, particularly with dihydropyridine derivatives like verapamil, may lead to marked hypotension and potentially impair atrioventricular conduction due to additive negative inotropic effects.[19]
• Indirect-Acting Sympathomimetics: Drugs like amphetamines and ephedrine, which cause release of endogenous catecholamines, may pose a risk of acute hypertensive episodes if used with sevoflurane.[19]
• Non-Selective Monoamine Oxidase Inhibitors (MAOIs): There is a risk of an intraoperative crisis (e.g., hypertensive crisis). It is generally recommended that non-selective MAOIs be discontinued at least two weeks prior to elective surgery.[19]
• St. John's Wort (Hypericum perforatum): Long-term use of this herbal supplement has been anecdotally associated with severe hypotension and delayed emergence from anesthesia with halogenated agents, including sevoflurane.[19]
• Intravenous Anesthetics: Sevoflurane is compatible with commonly used intravenous anesthetics like barbiturates and propofol. The use of these agents for induction may reduce the subsequent inspired concentration of sevoflurane needed for maintenance.[19]
• Epinephrine/Adrenaline: Sevoflurane, similar to isoflurane, sensitizes the myocardium to the arrhythmogenic effects of exogenously administered epinephrine to a lesser extent than halothane. Careful dosing and monitoring are advised if epinephrine is used for local hemostasis.[19]

The following table summarizes key drug interactions with sevoflurane:

Table 6.4.1: Clinically Significant Drug Interactions with Sevoflurane

Interacting Drug/Class	Effect of Interaction	Clinical Recommendation/Management	References
Non-depolarizing NMBAs	Potentiation of neuromuscular blockade (intensity and duration)	Reduce NMBA dose; monitor with nerve stimulator.	6
Succinylcholine	Increased risk of perioperative hyperkalemia (especially in pediatrics with neuromuscular disease)	Use with caution; monitor potassium levels; be prepared for hyperkalemia management.	9
Opioids	Decreased MAC of sevoflurane; augmented respiratory depression and hemodynamic depression (bradycardia, hypotension)	Titrate doses carefully; monitor respiratory and cardiovascular parameters closely.	6
Benzodiazepines	Decreased MAC of sevoflurane; potential for augmented sedation and respiratory depression	Titrate doses carefully; monitor level of consciousness and respiratory status.	6
Nitrous Oxide (N2​O)	Decreased MAC of sevoflurane	Adjust sevoflurane concentration accordingly (approx. 50% reduction in adults, 25% in pediatrics with 60-65% N2​O).	8
CYP2E1 Inducers (e.g., isoniazid, chronic alcohol)	Increased metabolism of sevoflurane; potentially higher plasma fluoride. Isoniazid may potentiate hepatotoxicity.	Monitor for altered anesthetic requirements or signs of toxicity, particularly hepatic with isoniazid.	1
Beta-Blockers	Enhanced negative inotropic, chronotropic, and dromotropic effects	Monitor cardiovascular parameters closely; anticipate potential for exaggerated bradycardia or hypotension.	19
Calcium Channel Blockers	Potential for marked hypotension; impaired AV conduction (with verapamil)	Monitor blood pressure closely; use with caution, especially verapamil.	19
Indirect-Acting Sympathomimetics	Risk of acute hypertensive episode	Avoid concomitant use if possible, or use with extreme caution and readiness to manage hypertension.	19
Non-Selective MAOIs	Risk of intraoperative crisis (e.g., hypertensive crisis)	Discontinue MAOIs at least 2 weeks before elective surgery.	19
St. John's Wort	Reports of severe hypotension and delayed emergence	Inquire about herbal supplement use; be aware of potential for exaggerated hemodynamic effects and prolonged recovery.	19
Epinephrine (exogenous)	Myocardial sensitization to arrhythmogenic effects (less than halothane)	Limit dose and concentration of epinephrine used for local infiltration; monitor ECG for arrhythmias.	19

7. Regulatory Status and Market Overview

7.1. Global Regulatory Approvals

Sevoflurane has received regulatory approval for clinical use in numerous countries worldwide, establishing it as a standard inhalational anesthetic.

• United States (FDA): Sevoflurane was approved by the FDA in 1995/1996 for the induction and maintenance of general anesthesia.[1] It is marketed under brand names such as Ultane (originally by Abbott Laboratories, now AbbVie) and is also available as a generic formulation.[11] The New Drug Application (NDA) number for Ultane is 020478.[18]
• Europe (EMA): Sevoflurane is authorized for human use across the European Union. Marketing authorisations have been granted for various products, including "Sevoflurane Baxter," which received its initial authorisation on September 1, 1995.[19] Other companies, such as Piramal and Chanelle Medical, also hold authorisations for sevoflurane products for human use.[19] Additionally, sevoflurane is approved for veterinary use in the EU (e.g., for dogs and cats under brand names like Sevohale and SevoFlo).[4]
• Japan (PMDA): Japan was the first country to approve sevoflurane for clinical use, with approval granted in 1990.[1] This early adoption in Japan played a significant role in its subsequent global development.

7.2. Key Manufacturers and Patent Holders

The original discovery of sevoflurane is credited to Ross Terrell and Louise Speers at Airco Industrial Gases in the early 1960s.[11] Early patents related to sevoflurane were held by Baxter Travenol Laboratories.[17] The commercialization and global distribution involved a complex history of licensing and partnerships. Maruishi Pharmaceutical Co., Ltd. was instrumental in the development and initial marketing in Japan.[17] Abbott Laboratories (now AbbVie) later acquired rights and marketed sevoflurane globally under the brand name Ultane/Sevorane.[11]

Currently, several pharmaceutical companies manufacture and/or market sevoflurane. Key players include:

• AbbVie (inheriting from Abbott Laboratories) [11]
• Baxter International Inc. [8]
• Piramal Pharma Solutions (Piramal Critical Care) [23]
• Maruishi Pharmaceutical Co., Ltd. [17]
• Shandong N.T. Pharma [43]
• Central Glass (a supplier mentioned in early agreements) [17]
• Jiangsu Hengrui Pharmaceuticals [55]
• Lunan Pharmaceutical Group [55]
• Wellona Pharma [47]
• Rewine Pharmaceutical [47]
• Rochem International, Inc. [50]

The availability of generic sevoflurane has also impacted the market landscape.[11]

7.3. Current Market Status and Trends

The global market for sevoflurane is substantial and continues to show steady growth. Market valuations vary slightly between different market research reports due to methodologies and base years, but the overall trend is positive. For instance, one report valued the global sevoflurane market at USD 370.2 million in 2022, projecting a compound annual growth rate (CAGR) of 4.4% between 2022 and 2030.[47] Another report estimated the market size at USD 145.76 million in 2024, expecting it to reach USD 190.22 million by 2033, with a CAGR of 3.0% from 2025 to 2033.[55] A third report indicated a value of USD 1.54 billion in 2024, projected to reach USD 2.76 billion by 2033, growing at a CAGR of 6.69%.[56] Despite the numerical discrepancies (with one source, Spherical Insights [58], reporting figures in billions which is likely a typographical error for millions), the consistent theme is market expansion.

Several factors drive this growth:

• Increasing Volume of Surgical Procedures: A global rise in the number of surgeries, including aesthetic procedures and those necessitated by chronic diseases, is a primary driver. With millions of surgeries performed annually, the demand for effective and safe anesthetic agents like sevoflurane remains high.[43]
• Rising Prevalence of Chronic Disorders: Conditions such as cancer and cardiovascular diseases often require surgical intervention, contributing to the demand for anesthesia.[43]
• Advancements in Healthcare Technologies and Infrastructure: Improvements in surgical techniques, anesthesia delivery systems, and overall healthcare accessibility, particularly in developing regions, support the increased use of general anesthesia.[43]
• Favorable Clinical Profile: Sevoflurane's rapid onset and offset, cardiovascular stability, and suitability for diverse patient populations, including the elderly and pediatric patients, make it a preferred choice for many clinicians.[55]
• Growth in Outpatient and Veterinary Sectors: The trend towards outpatient surgeries, where rapid recovery is crucial, favors sevoflurane. Additionally, its safety profile has led to its increasing adoption in veterinary medicine.[55]

In terms of market segmentation, sevoflurane often dominates the inhalation anesthesia market by drug type.[56] The maintenance phase of anesthesia typically accounts for a larger market share than induction.[58] Hospital pharmacies remain a major distribution channel, though online pharmacies are also gaining traction.[43]

Regionally, North America has historically held the largest market share, attributed to high-quality surgical care and medical innovation.[47] The Asia Pacific region is projected to experience the fastest growth, driven by increasing populations, rising demand for surgical procedures, and improving healthcare infrastructure in countries like China and India.[47]

The sustained growth of the sevoflurane market is indicative of its established clinical advantages. Its versatility and safety profile, when used appropriately, continue to make it a valuable tool in anesthesia. While cost can be a consideration, particularly in resource-limited settings [6], the benefits offered by sevoflurane often outweigh this, especially with the availability of generic versions. The ongoing need for safe and effective general anesthesia globally ensures a continued demand for sevoflurane.

8. Conclusion and Implications

8.1. Summary of Sevoflurane's Profile as an Anesthetic Agent

Sevoflurane has established itself as a cornerstone of modern inhalational anesthesia due to a compelling combination of favorable pharmacokinetic and pharmacodynamic properties. Its rapid and smooth induction and emergence characteristics, largely attributable to its low blood:gas solubility, make it highly desirable for a wide range of surgical procedures in both adult and pediatric populations.[1] The non-irritating nature and pleasant odor of sevoflurane further enhance its utility, particularly for mask induction, minimizing patient discomfort.[1]

Mechanistically, sevoflurane exerts its anesthetic effects through complex interactions with multiple molecular targets in the CNS. Key actions include the positive allosteric modulation of inhibitory GABA-A and glycine receptors, leading to neuronal hyperpolarization.[1] It also inhibits excitatory neurotransmission by antagonizing NMDA and nicotinic acetylcholine receptors and modulates various potassium channels, further contributing to the depression of neuronal excitability.[1]

While generally well-tolerated, the safety profile of sevoflurane necessitates awareness of specific considerations. These include the potential for malignant hyperthermia in susceptible individuals, the formation of Compound A with certain CO₂ absorbents (requiring specific administrative precautions), rare instances of hepatic or renal effects (particularly in predisposed patients or with improper use), and ongoing discussions regarding potential pediatric neurotoxicity with prolonged or repeated exposures.[1]

8.2. Implications for Clinical Practice

The clinical use of sevoflurane demands adherence to best practices to maximize its benefits while minimizing potential risks. Individualized dosing based on patient age, clinical status, and concomitant medications is paramount, facilitated by the use of specifically calibrated vaporizers.[9] To mitigate the risk of Compound A exposure, particularly during low-flow anesthesia, clinicians must ensure CO₂ absorbents are fresh, not desiccated, and preferably do not contain potassium hydroxide. Adherence to recommended fresh gas flow rates (e.g., not exceeding 2 MAC-hours at 1 to <2 L/min, and avoiding flows <1 L/min) is crucial.[9]

Vigilance for patient-specific risk factors is essential. This includes careful assessment for a history or predisposition to malignant hyperthermia, pre-existing renal or hepatic impairment, and conditions that might increase susceptibility to QT prolongation.[8] The rapid emergence from sevoflurane anesthesia often necessitates proactive planning for postoperative analgesia.[19] Its favorable profile for smooth induction makes it a valuable agent in pediatric anesthesia and for patients with difficult airways or needle phobia, where inhalational induction is preferred.

8.3. Potential Areas for Future Research

Despite its extensive clinical use, several aspects of sevoflurane's pharmacology and long-term effects warrant further investigation. The precise molecular binding sites and the full cascade of downstream signaling events resulting from its interaction with various ion channels and neuronal pathways are not yet completely understood.[1] Continued research in this area could lead to a more refined understanding of anesthetic mechanisms in general and potentially to the development of agents with even more specific target interactions.

The issue of potential pediatric neurotoxicity remains a significant concern and a priority for research.[1] Well-designed, long-term prospective cohort studies in humans are needed to definitively assess the neurodevelopmental outcomes in children exposed to sevoflurane and other anesthetics early in life, and to differentiate anesthetic effects from confounding factors related to surgery and illness.

Further research into strategies to eliminate or further mitigate Compound A formation, or to fully understand its clinical relevance at low exposure levels in humans, would be beneficial. This could involve the development of novel CO₂ absorbent technologies or more definitive studies on the threshold for Compound A-induced nephrotoxicity in diverse patient populations.

Comparative effectiveness research continues to be valuable, comparing sevoflurane with newer anesthetic agents or alternative anesthetic techniques (e.g., total intravenous anesthesia) in specific patient populations or for particular types of surgical procedures to optimize outcomes and resource utilization.

Finally, exploring the non-anesthetic properties of sevoflurane, such as its potential organ-protective effects (e.g., ischemic preconditioning) observed in some experimental models [10], could unveil new therapeutic applications or a deeper understanding of its cellular actions beyond the CNS. The journey of sevoflurane from its discovery to its current prominent role in anesthesia highlights the continuous interplay between chemical properties, pharmacological understanding, clinical utility, and safety considerations that drive the evolution of medical practice.

References

(Note: Due to the extensive number of snippets, a full bibliography is not generated here but would be included in a formal publication. Citations in the text refer to the provided snippet IDs.)

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