Sevoflurane

2.4

2.4

1.75

1505 at 25 °C/D

Relative density of the vapour/air-mixture at 20 °C (air = 1): 1.1

Very slightly soluble

1.48e+00 g/L

58.5

58.1-58.2 °C at 751 mm Hg; 585.5 °C at 760 mm Hg

58.5 °C

< 25 °C

< 25 °C

157.0 [mmHg]

VP: 200 torr at 25 °C; 160 torr

193 mm Hg at 25 °C

Vapor pressure, kPa at 20 °C: 21

A clear, nonflammable colorless liquid with a non-irritating odor; [ACGIH TLVs and BEIs]

Solid

COLOURLESS LIQUID.

409

498.1

Partition coefficient at 37 °C: (blood/gas): 0.60; (water/gas): 0.36; (corn oil/gas): 41.6

Hydroxyl radical reaction rate constant = 7.30X10-14 cu cm/molec-sec at 25 °C

Warning

H315 (44.7%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (45.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H336 (56.4%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]；H361 (53.2%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 94 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

TLV Basis = CNS impairment; Human data demonstrates sedation starting at 2,000 ppm. Epidemiologic studies provide inconsistent evidence regarding the role of sevoflurane in adverse health effects, including spontaneous abortion, congenital abnormalities, kidney and liver damage, genotoxicity, and developmental neurotoxicity. [ACGIH TLVs and BEIs]

Sevoflurane: ... For induction and maintenance of general anesthesia in dogs.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sevoflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Sevoflurane is included on this list.

Sevoflurane reacts through direct contact with CO2 absorbents (soda lime and barium hydroxide lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C5H6F6O), also known as Compound B.

As with other inhalational anesthetics, degradation and production of degradation products can occur when sevoflurane is exposed to desiccated absorbents.

An exothermic reaction occurs when sevoflurane is exposed to CO2 absorbents. This reaction is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Rare cases of extreme heat, smoke, and/or spontaneous fire in the anesthesia breathing circuit have been reported during sevoflurane use in conjunction with the use of desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g. Baralyme). KOH containing CO2 absorbents are not recommended for use with sevoflurane. An unusually delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporizer setting may be associated with excessive heating of the CO2 absorbent and chemical breakdown of sevoflurane.

Halogenated volatile anesthetics can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide (CO) that may result in elevated carboxyhemoglobin levels in some patients. To prevent this reaction, sevoflurane should not be passed through desiccated soda lime or barium hydroxide lime.

Fresh air, rest. Artificial respiration may be needed. Refer for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Refer for medical attention .

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Water fog, dry chemical, or carbon dioxide as appropriate for surrounding fire and materials. Do not use water jet as an extinguisher, as this will spread the fire.

Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible.Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing vapor. Place spillage in appropriately labeled container for disposal. Wash spill site. Small quantities of liquid anesthetic agents may evaporate readily at room temperature. Large Spills: Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible. Cover with plastic sheet to prevent spreading. Absorb in vermiculite, dry sand or earth and place into containers. Following product recovery, flush area with water.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Personal protection: self-contained breathing apparatus. Collect leaking and spilled liquid in sealable containers as far as possible. Ventilation. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Clean equipment and work surfaces with suitable detergent or solvent after use. After removing gloves, wash hands and other exposed skin thoroughly. Handle and open container with care.

In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of sevoflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. (L1712)

As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N2O anesthesia, sevoflurane and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium. Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane. Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation.

To determine the effect of intravenous ketamine on the minimum alveolar concentration of sevoflurane needed to block autonomic response (MAC(BAR)) to a noxious stimulus in dogs, a randomized, crossover, prospective study /was conducted/ in eight, healthy, adult male, mixed-breed dogs, weighing 11.2-16.1 kg. Dogs were anesthetized with sevoflurane on two occasions, 1 week apart, and baseline MAC(BAR) (B-MAC(BAR)) was determined on each occasion. MAC(BAR) was defined as the mean of the end-tidal sevoflurane concentrations that prevented and allowed an increase (>/=15%) in heart rate or invasive mean arterial pressure in response to a noxious electrical stimulus (50 V, 50 Hz, 10 ms). Dogs then randomly received either a low-dose (LDS) or high-dose series (HDS) of ketamine, and treatment MAC(BAR) (T-MAC(BAR)) was determined. The LDS had an initial loading dose (LD) of 0.5 mg kg(-1) and constant rate infusion (CRI) at 6.25 ug kg(-1) minute(-1), followed, after T-MAC(BAR) determination, by a second LD (1 mg kg(-1)) and CRI (12.5 ug kg(-1) minute(-1)). The HDS had an initial LD (2 mg kg(-1)) and CRI (25 ug kg(-1) minute(-1)) followed by a second LD (3 mg kg(-1)) and CRI (50 ug kg(-1) minute(-1)). Data were analyzed with a mixed-model anova and are presented as Least squares mean (LSM) +/- standard error of the mean (SEM). The B-MAC(BAR) was not significantly different between treatments. Ketamine at 12.5, 25, and 50 ug kg(-1) minute(-1) decreased sevoflurane MAC(BAR), and the maximal decrease (22%) occurred at 12.5 ug kg(-1) minute(-1). The percentage change in MAC(BAR) was not correlated with either the log plasma ketamine or norketamine concentration. Ketamine at clinically relevant doses of 12.5, 25, and 50 ug kg(-1) minute(-1) decreased sevoflurane MAC(BAR), although the reduction was neither dose-dependent nor linear.

... In order to test whether a combination of cholinergic antagonists with general anesthetics improves their potency, ...the effects of clinically relevant concentrations of atropine on sevoflurane potency in cortical and spinal slice cultures during cholinergic overstimulation /were investigated/. As the spinal cord and neocortex are important substrates for general anesthetics cultured spinal and cortical tissue slices were obtained from embryonic and newborn mice, respectively. Drug effects were assessed by extracellular voltage recordings of spontaneous action potential activity. Application of acetylcholine elevated spontaneous activity in neocortical and spinal slices. Atropine (10 nM) reduced discharge rates and reversed the increase of spontaneous activity induced by acetylcholine. In the presence of acetylcholine and atropine sevoflurane caused a concentration-dependent decrease of neuronal activity in neocortical (EC(50)=0.35+/-0.33 MAC) and spinal slices (EC(50)=0.43+/-0.03 MAC). .../It was/ concluded that small concentrations of atropine increase sevoflurane potency in cortical networks during cholinergic overstimulation. ...

In anesthetized patients, electro-acupuncture (EA) has been found to reduce sevoflurane-induced suppression of cranial and spinal motor responses to surgery without influencing the level of anesthesia. ... In the present study, blood samples were analyzed to evaluate if the increased clinical motor responses to surgery in patients subjected to EA under sevoflurane anesthesia are also reflected in higher plasma levels of catecholamines, adrenocorticotrophic hormone (ACTH), or cortisol. Blood samples were obtained before anesthetic induction, soon after the study or control procedures had been completed under general anesthesia, and after 30 minutes of surgery under steady-state anesthesia with 1.8% of sevoflurane, in 45 healthy female patients, scheduled for sterilization by laparoscopy, randomized for bilateral 2 Hz-burst EA (study group; n = 22) or control (control group; n = 23) procedures. Plasma levels of adrenaline were found to approach the higher preanesthetic level after 30 minutes of surgery in patients given EA stimulation but to remain low in control patients (P < 0.05)-in agreement with the stronger clinical motor responses to skin incision in the EA group. Plasma levels of noradrenaline, ACTH, and cortisol did not change in or differ between the two groups. The clinical facilitation of both cranial and spinal motor responses to surgery in patients given acupuncture under sevoflurane anesthesia is associated with increased plasma levels of adrenaline, possibly reflecting sympathetic activation.

For more Interactions (Complete) data for Sevoflurane (14 total), please visit the HSDB record page.

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from sevoflurane is very rare, only isolated case reports having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to sevoflurane induced hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.；Likelihood score: B (highly likely cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 270(SRC), determined from a structure estimation method(2), indicates that sevoflurane is expected to have moderate mobility in soil(SRC). Volatilization of sevoflurane from moist soil surfaces is to be an important fate process(SRC) given an estimated Henry's Law constant of 1.9X10-1 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Sevoflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 193 mm Hg at 25 °C(4). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 270(SRC), determined from a structure estimation method(2), indicates that sevoflurane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.9X10-1 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 4 hours and 6 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 7(SRC), from an estimated log Kow of 1.75(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sevoflurane, which has a vapor pressure of 193 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase sevoflurane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 220 days(SRC), calculated from its rate constant of 7.3X10-14 cu cm/molecule-sec at 25 °C(3). Sevoflurane absorbs light at wavelengths <200 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Neurotoxin - Acute solvent syndrome

Cardiovascular；Sevoflurane induces a dose-dependent reduction in blood pressure and cardiac output primarily by reducing systemic vascular resistance.；Respiratory；Like all volatile anesthetic agents, sevoflurane is an airway irritant and may precipitate coughing, apnea, and laryngospasm. These reactions are less likely to be seen with sevoflurane than desflurane and isoflurane due to the sweet smell and low pungency of sevoflurane. Respiratory side effects are more common in patients with pre-existing lung pathology such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Sevoflurane and other inhaled anesthetics also result in bronchodilation, blunting of the hypoxia/hypercapnia ventilatory response, and reverse hypoxic pulmonary vasoconstriction.；Central Nervous System；Sevoflurane causes dose-dependent vasodilation of cerebral vasculature, thereby increasing cerebral blood flow and intracranial pressure. Sevoflurane reduces the cerebral metabolic rate.；Pregnancy and Neurodevelopmental deficits: While several observational studies have found an increased risk of neurodevelopmental deficits in children exposed to anesthesia, at this time, there is no compelling evidence to attribute this effect to the anesthesia directly. At this time, no specific anesthetic agent should be avoided during pregnancy, nor should any necessary surgery be delayed due to concerns regarding neurotoxicity. A very small study covering sevoflurane during caesarian sections did not show any adverse effects on the mother or fetus. At present, there are no controlled data regarding its use in pregnancy in human subjects, and until there is more definitive data, the use of this drug during pregnancy should be limited to when it is absolutely necessary.；Adverse Reactions；Less than 10%；* Dose-dependent cardiovascular collapse: Hypotension (4% to 11%)；* Central nervous system: Emergence delirium and agitation (7% to 15%)；* Gastrointestinal: Nausea (25%); vomiting (18%)；One to 10%；* Cardiovascular: Tachycardia, bradycardia, hypertension；* Respiratory: Laryngospasm (2 to 8%), breath-holding, apnea；Less than 1%；Anaphylaxis, anaphylactoid reaction, cardiac arrhythmias, QT prolongation, increased intracranial pressure, hepatotoxicity, electrolyte disturbances, malignant hyperthermia；Drug Interactions；Sevoflurane undergoes minimal hepatic metabolism. The small percentage, that is, acts as a substrate for multiple CYP enzymes (CYP2A6, CYP2B6, CYP3A4, CYP2E1). This metabolism creates the potential for many clinically relevant drug interactions secondary to the large percentage of drugs metabolized by these hepatic enzymes.

The substance can be absorbed into the body by inhalation of its vapour and by ingestion.

Rapidly absorbed into circulation via the lungs, however solubility in the blood is low.

The concentrations of sevoflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, sevoflurane concentrations in milk are predicted to be below those found with many other volatile anesthetics.

Sevoflurane poses a potential risk of hepatotoxicity, nephrotoxicity, and neurotoxicity.；Hepatotoxicity；Several proposed mechanisms for post-operative hepatic dysfunction have been proposed, including viral hepatitis, impaired hepatic perfusion, and intrahepatic cholestasis. However, newer evidence suggests an immune-mediated mechanism. Like other volatile anesthetics, sevoflurane is partially oxidized in the liver by a specific CYP enzyme (2E1) to a metabolite, fluoro acetic acid. This specific metabolite has been found to modify liver microsomal proteins that subsequently act as triggering antigens for an immune-mediated antibody response. Although this response is rare due to the low percentage of sevoflurane metabolized in this fashion, the theoretical risk exists.；Nephrotoxicity；The potential nephrotoxic effect of sevoflurane is attributable to two factors. The first factor is the metabolite discussed above, fluoro acetic acid, which has demonstrated nephrotoxicity, as well as hepatotoxicity. The second is the creation of Compound A. Compound A is another fluorinated byproduct created from an exothermic reaction between sevoflurane and the carbon dioxide absorbents utilized in anesthetic delivery systems, which can reportedly cause mild and reversible renal injury in animal studies. The theoretical risk of Compound A-induced nephrotoxicity in humans may be dose and exposure time-dependent.；Neurotoxicity；Currently, there are no anesthetic agents, including sevoflurane, that must be avoided during pregnancy, in neonates, or the pediatric population due to concerns regarding neurotoxicity. At this time, there are several animal studies suggesting sevoflurane to induce neurotoxicity via microRNA manipulation. However, there is not yet any compelling evidence to attribute neurotoxicity development in humans secondary to sevoflurane use directly. Animal studies have thus far not revealed any evidence of fetal harm or impaired fertility.

Sevoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Sevoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase and also binds to the GABA receptor, the large conductance Ca²⁺ activated potassium channel, the glutamate receptor, and the glycine receptor.

/BIRDS and MAMMALS/ To evaluate the cardiorespiratory changes induced by sevoflurane (SEV) anesthesia in the crested caracara (Caracara plancus), eight crested caracaras (Caracara plancus) weighing 1.0 (0.9-1.1) kg were used /in a/ prospective experimental trial. The birds were anesthetized by face mask with isoflurane for brachial artery catheterization. After recovery, anesthesia was re-induced with 6% SEV via face mask. After induction, a noncuffed endotracheal tube was placed and anesthesia was maintained with SEV (3.5% end-tidal) in oxygen (1 L/min) using an Ayre's T-piece nonrebreathing circuit, with spontaneous ventilation. Electrocardiography (ECG), direct systolic, diastolic and mean arterial blood pressure (SAP, DAP, and MAP), respiratory rate (f(R)), end-tidal carbon dioxide (Pe'CO(2)), and cloacal temperature (T °C) were measured before induction (baseline - under physical restraint) and after 5, 10, 15, 20, 25, 30, 35 and 40 minutes of SEV anesthesia. Arterial blood samples were collected for gas analysis at baseline and then at 10, 25 and 40 minutes. No ventricular arrhythmias were observed in the present study. Respiratory rate, SAP, DAP, MAP, T °C and pH decreased from pre-induction values, while arterial partial pressures of oxygen and carbon dioxide, bicarbonate concentration, and Pe'CO(2) were significantly higher than baseline. None of the birds were apneic.

Dizziness. Drowsiness. Headache. Unconsciousness.

Dry skin. Redness.

Redness. Pain.

See Inhalation.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of sevoflurane can be estimated to be 270(SRC). According to a classification scheme(2), this estimated Koc value suggests that sevoflurane is expected to have moderate mobility in soil.

/HUMAN EXPOSURE STUDIES/ Potentiation of inhibitory transmissions in the spinal cord is considered to be an important mechanism for the mediation of the immobilizing effects of anesthetics. However, the depressant effects on motoneurons could be counterbalanced by presynaptic effects that inhibit the depressant pathways. /In this study, the authors/ investigated the effect of sevoflurane on a disynaptic inhibitory pathway onto motoneurons in a human reflex model. The study was performed with 9 volunteers receiving sevoflurane anesthesia (end tidal: 0.8% sevoflurane). Reciprocal inhibition was estimated from the depression of the H-reflex following a conditioning stimulation of the muscle spindle afferents from the tibialis anterior muscle. Measurements were performed before, during and after drug administration. The inhibition (mean +/- SE) amounted to 15.4% +/- 6.8%, 1.9% +/- 4.2% and 15.7% +/- 8.8% for measurements before, during and after sevoflurane administration, respectively. Differences between the anesthetic state and the two controls were statistically significant (mixed-effect ANOVA, p<0.01). Sevoflurane reduces reciprocal Ia-inhibition on motoneurons in humans. These findings seem to contradict the accepted view that sevoflurane enhances inhibitory synaptic transmission. This contradiction might be explained by the inhibitory actions of sevoflurane within the disynaptic pathway prior to the final glycinergic transmission onto the motoneuron. ...Results suggest that even in presumably simple pathways, postsynaptic effects of anesthetics could be superimposed by their presynaptic effects.

/CASE REPORTS/...A 66-year-old woman with breast carcinoma, ... underwent sevoflurane general anesthesia twice in 25 days. Soon after the second elective surgical procedure, jaundice and marked elevations in serum transaminases developed. The patient died 66 days thereafter. Autopsy results denied evidence of major cardiovascular abnormality, and histological examination confirmed massive liver cell necrosis with no feature of chronic liver injury. Sevoflurane anesthesia was imputed as the cause after exclusion of other possible etiological agents. Besides, coexistent malignant tumors found in the patient could have modulated the immunological response to the applied anesthetic followed by fatal consequences.

/CASE REPORTS/ Polyuria has been reported as a side effect of sevoflurane administration, but because of its relative rarity, many practitioners are not aware of this potential phenomenon. Polyuria in its extreme form can cause undesirable hemodynamic changes. A case study, in an 18-year-old man, is presented highlighting polyuria as a probable side effect of sevoflurane administration.

/CASE REPORTS/ When inhalational induction is indicated, sevoflurane is the most popular choice in both children and adults. Higher inspired concentrations of sevoflurane can cause adverse cardiac arrhythmias that are seen to disappear once the agent is discontinued. /The authors/ report the occurrence of isorhythmic atrioventricular dissociation and junctional rhythm with absent P waves during sevoflurane anesthesia in an adult and a child, respectively.

For more Human Toxicity Excerpts (Complete) data for Sevoflurane (12 total), please visit the HSDB record page.

Sevoflurane: ... For induction and maintenance of general anesthesia in dogs.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sevoflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Sevoflurane is included on this list.

N01AB08

N - Nervous system；N01 - Anesthetics；N01A - Anesthetics, general；N01AB - Halogenated hydrocarbons；N01AB08 - Sevoflurane

QN - Nervous system；QN01 - Anesthetics；QN01A - Anesthetics, general；QN01AB - Halogenated hydrocarbons；QN01AB08 - Sevoflurane

N01AB08

Sevoflurane protein binding has not been evaluated. _In vitro_ analyses have shown that other fluorinated volatile anesthetics can displace drugs from serum and tissue proteins; however, it is unclear if this is clinically significant. Clinical studies have shown that the administration of sevoflurane does not have a significant effect in patients taking drugs that are highly bound and have a small volume of distribution.

Sevoflurane induces muscle relaxation and reduces sensitivity by altering tissue excitability with a fast onset of action. It does so by decreasing the extent of gap junction-mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. Compared to [halothane] and [isoflurane], sevoflurane has a shorter emergence time, as well as a shorter time to first analgesia. To reach an equilibrium between alveolar and arterial partial pressure, only a minimal amount of sevoflurane needs to be dissolved in blood. The use of sevoflurane can increase the risk of renal injury, respiratory depression, and QT prolongation. Also, it can lead to malignant hyperthermia, perioperative hyperkalemia, and pediatric neurotoxicity. Episodes of severe bradycardia and cardiac arrest have been reported in pediatric patients with Down Syndrome given sevoflurane. Sevoflurane anesthesia may impair the performance of activities requiring mental alertness, such as driving or operating machinery.

The precise mechanism of action of sevoflurane has not been fully elucidated. Like other halogenated inhalational anesthetics, sevoflurane induces anesthesia by binding to ligand-gated ion channels and blocking CNS neurotransmission. It has been suggested that inhaled anesthetics enhance inhibitory postsynaptic channel activity by binding GABA_A and glycine receptors, and inhibit excitatory synaptic channel activity by binding nicotinic acetylcholine, serotonin, and glutamate receptors. Sevoflurane has an effect on several ionic currents, including the hyperpolarisation-activated cation current (I_f), the T-type and L-type Ca²⁺ currents (I_{Ca, T} and I_{Ca, L}), the slowly activating delayed rectifier K⁺ currents (I_Ks), and the Na⁺/Ca²⁺ exchange current (I_NCX). This ability to modulate ion channel activity can also regulate cardiac excitability and contractility.

Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. ...It has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, /investigators/ examined the effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na(v)1.8, Na(v)1.4, and Na(v)1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na(v)1.8, Na(v)1.4, and Na(v) 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane.

Sevoflurane has been demonstrated to vasodilate the feto-placental vasculature. /Investigators/ aimed to determine the contribution of modulation of potassium and calcium channel function to the vasodilatory effect of sevoflurane in isolated human chorionic plate arterial rings. Quadruplicate ex vivo human chorionic plate arterial rings were used in all studies. Series 1 and 2 examined the role of the K+ channel in sevoflurane-mediated vasodilation. Separate experiments examined whether tetraethylammonium, which blocks large conductance calcium activated K+ (KCa++) channels (Series 1A+B) or glibenclamide, which blocks the ATP sensitive K+ (KATP) channel (Series 2), modulated sevoflurane-mediated vasodilation. Series 3 - 5 examined the role of the Ca++ channel in sevoflurane induced vasodilation. Separate experiments examined whether verapamil, which blocks the sarcolemmal voltage-operated Ca++ channel (Series 3), SK&F 96365 an inhibitor of sarcolemmal voltage-independent Ca++ channels (Series 4A+B), or ryanodine an inhibitor of the sarcoplasmic reticulum Ca++ channel (Series 5A+B), modulated sevoflurane-mediated vasodilation. Sevoflurane produced dose dependent vasodilatation of chorionic plate arterial rings in all studies. Prior blockade of the KCa++ and KATP channels augmented the vasodilator effects of sevoflurane. Furthermore, exposure of rings to sevoflurane in advance of TEA occluded the effects of TEA. Taken together, these findings suggest that sevoflurane blocks K+ channels. Blockade of the voltage-operated Ca++channels inhibited the vasodilator effects of sevoflurane. In contrast, blockade of the voltage-independent and sarcoplasmic reticulum Ca++channels did not alter sevoflurane vasodilation. Sevoflurane appears to block chorionic arterial KCa++ and KATP channels. Sevoflurane also blocks voltage-operated calcium channels, and exerts a net vasodilatory effect in the in vitro feto-placental circulation.

Administration of sevoflurane at the onset of reperfusion has been confirmed to provide a cerebral protection. However, little is known about the mechanism. In this study, /investigators/ tested the hypothesis that sevoflurane postconditioning induces neuroprotection through the up-regulation hypoxia inducible factor-1 alpha (HIF-1 alpha) and heme oxygenase-1 (HO-1) involving phosphatidylinositol-3-kinase (PI3K)/Akt pathway. In the first experiment, male Sprague-Dawley rats were subjected to focal cerebral ischemia. Postconditioning was performed by exposure to 2.5% sevoflurane immediately at the onset of reperfusion. The mRNA and protein expression of HIF-1 alpha and its target gene, HO-1, intact neurons and the activity of caspase-3 was evaluated at 6, 24 and 72 hr after reperfusion. In the second experiment, ... the relationship between PI3K/Akt pathway and the expression of HIF-1alpha and HO-1 in the neuroprotection induced by sevoflurane /was investigated/. Cerebral infarct volume, apoptotic neuron and the expression of HIF-1alpha, HO-1 and p-Akt were evaluated at 24hr after reperfusion. Compared with the control group, sevoflurane postconditiong significantly ameliorated neuronal injury, up-regulated mRNA and protein levels of HIF-1 alpha and HO-1, inhibited the activity of caspase-3, and decreased the number of TUNEL-positive cells and infarct sizes. However, the selective PI3K inhibitor, wortmannin not only partly eliminated the neuroprotection of sevoflurane as shown by reducing infarct size and apoptotic neuronal cells, but also reversed the elevation of HIF-1 alpha, HO-1 and p-Akt expression in the ischemic penumbra induced by sevoflurane. Therefore, /the/ data demonstrates that the cerebral protection from sevoflurane postconditioning is partly mediated by PI3K/Akt pathway via the up-regulation of HIF-1 alpha and HO-1.

Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on mu-opioid receptor (uOR) functions is still unclear. In this study, the effects of sevoflurane on uOR functions were analyzed by using Xenopus oocytes expressing a uOR fused to chimeric G alpha protein G(qi5) (uOR-G(qi5)). Sevoflurane by itself did not elicit any currents in oocytes expressing uOR-G(qi5), whereas sevoflurane inhibited the [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO)-induced Cl(-) currents at clinically used concentrations. Sevoflurane did not affect the Cl(-) currents induced by AlF(4)(-), which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit uOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.

For more Mechanism of Action (Complete) data for Sevoflurane (9 total), please visit the HSDB record page.

The terminal elimination half-life of sevoflurane from the peripheral fat compartment is approximately 20 hours.

Compared with healthy individuals, the fluoride ion half-life was prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impairment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 hours (range 21-61 hours) as compared to a mean of approximately 21 hours (range 10-48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18-72 hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16-47 hours).

The half-life is in the range of 15-23 hours.

Sevoflurane is metabolized to hexafluoroisopropanol by cytochrome P450 2E1 in a reaction that promotes the release of inorganic fluoride and carbon dioxide. Hexafluoroisopropanol is rapidly conjugated with glucuronic acid and eliminated in urine. _In vivo_ metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized. In most cases, inorganic fluoride reaches its highest concentration within 2 hours of the end of sevoflurane anesthesia, and returns to baseline levels within 48 hours. Sevoflurane metabolism may be induced by chronic exposure to isoniazid and ethanol, and it has been shown that barbiturates do not affect it.

Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevofluran

Sevoflurane, USP is metabolized to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Fluoride ion concentrations are influenced by the duration of anesthesia and the concentration of sevoflurane, USP. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane, USP have been identified. In humans, the fluoride ion half-life was prolonged in patients with renal impairment, but human clinical trials contained no reports of toxicity associated with elevated fluoride ion levels.

Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane which is metabolized via a variety of cytochrome P450 isoforms. The metabolism of sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism.

Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized.

In a study in which 4 dogs were exposed to 4% sevoflurane, USP for 3 hours, maximum serum fluoride concentrations of 17.0-27.0 umole/L were observed after 3 hours of anesthesia. Serum fluoride fell quickly after anesthesia ended, and had returned to baseline by 24 hours post-anesthesia.

38LVP0K73A

SEVOFLURANE

Physiologic Effects [PE] - General Anesthesia

Established Pharmacologic Class [EPC] - General Anesthetic

Sevoflurane is a General Anesthetic. The physiologic effect of sevoflurane is by means of General Anesthesia.

SEVOFLURANE

Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system.

Gases or volatile liquids that vary in the rate at which they induce anesthesia; potency; the degree of circulation, respiratory, or neuromuscular depression they produce; and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration. Because of their rapid elimination, any postoperative respiratory depression is of relatively short duration. (From AMA Drug Evaluations Annual, 1994, p173)

Sevoflurane is rapidly absorbed into circulation through the lungs; however, solubility in the blood is low (blood/gas partition coefficient at 37°C ranges from 0.63 to 0.69). Therefore, a minimal amount of sevoflurane needs to be dissolved in blood in order to induce anesthesia.

The low solubility of sevoflurane facilitates its rapid elimination through the lungs, where 95% to 98% of this anesthetic is eliminated. Up to 3.5% of the sevoflurane dose appears in urine as inorganic fluoride, and as much as 50% of fluoride clearance is nonrenal (fluoride taken up into bone).

Patients given low-flow sevoflurane anesthesia during maxillofacial surgery (n=16) had a peripheral volume of distribution of 1634 ml_vapour/kg_bw and a total volume of distribution of 1748 ml_vapour/kg_bw.

In patients given low-flow sevoflurane anaesthesia during maxillofacial surgery (n=16), the transport clearance from the central to the peripheral compartment was 13.0 ml_vapour/kg_bw⋅min.

Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into bone).

The low solubility of sevoflurane facilitates rapid elimination via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration following termination of anesthesia (FA), relative to the last alveolar concentration (FaO) measured immediately before discontinuance of the anesthetic.

Used as an inhalation anesthetic; [ACGIH TLVs and BEIs]

MEDICATION

Use (kg) in Switzerland (2009): >2500；Use (kg; approx.) in Germany (2009): >50000；Use (kg) in USA (2002): 160000；Consumption (g per capita) in Switzerland (2009): 0.32；Consumption (g per capita; approx.) in Germany (2009): 0.61；Consumption (g per capita) in the USA (2002): 0.57；Calculated removal (%): 98.6

Used for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.

SOJOURN

SEVOFLO

Petrem (sevoflurane, USP) is packaged in amber colored bottles containing 250 mL sevoflurane, USP.

ULTANE (sevoflurane), Volatile Liquid for Inhalation, is packaged in amber colored bottles containing 250 mL sevoflurane.