Sevorane

Sevoflurane is a nonflammable liquid anaesthetic agent administered by vaporization. It is a fluorinated derivative of methyl isopropyl ether. Sevoflurane is fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether and has a molecular weight of 200.05.
Sevoflurane has the following physical and chemical properties: Boiling point at 760 mmHg: 58.6°C; specific gravity at 20°C: 1.520-1.525; vapor pressure (calculated) in mmHg^**: 157 mmHg at 20°C, 197 mmHg at 25°C and 317 mmHg at 36°C.
^**Equation for vapor pressure (calculated), mmHg: Log₁₀P_vap=A+B/T, where: A=8.086, B=-1726.68 and T=°C+273.16°K.
Distribution Partition Coefficients at 37°C: Blood/gas: 0.63-0.69; water/gas: 0.36; olive oil/gas: 47.2-53.9; brain/gas: 1.15.
Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications: Conductive rubber: 14; butyl rubber: 7.7; polyvinyl chloride: 17.4; polyethylene: 1.3.
Sevoflurane is nonflammable and non-explosive as defined by the requirements of International Electrotechnical Commission 601-2-13. It is a clear, colorless liquid containing no additives or chemical stabilizers. It is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene and is slightly soluble in water.
Sevoflurane is stable when stored under normal room lighting conditions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. The only known degradation reaction is through direct contact with CO₂ absorbents (soda lime and Baralyme), producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C₄H₂F₆O), a haloalkene derivative, also known as compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C₅H₆F₆O), also known as Compound B, in the clinical setting. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium alloy.

Pharmacology: In a variety of animal species, including man, sevoflurane has been demonstrated to be a fast-acting, non-irritating agent. Administration has been associated with a smooth, rapid loss of consciousness during inhalational induction and a rapid recovery following discontinuation of anaesthesia.
Induction is accomplished with a minimum of excitement or signs of upper respiratory irritation, no evidence of excessive secretions within the tracheobronchial tree and no central nervous system stimulation. In pediatric studies in which mask induction was performed, the incidence of coughing was statistically significantly lower with sevoflurane than with halothane. Like other potent inhalational anesthetics, sevoflurane depresses respiratory function and blood pressure in a dose-related manner.
In both dogs and humans, the epinephrine-induced arrhythmogenic threshold for sevoflurane was comparable to that of isoflurane and higher than that of halothane. Studies in dogs have demonstrated that sevoflurane does not reduce collateral myocardial infarction perfusion. In clinical studies, the incidence of myocardial ischaemia and myocardial infarction in patients at risk for myocardial ischemia was comparable between sevoflurane and isoflurane.
Animal studies have shown that regional blood flow (eg, hepatic, renal, cerebral circulations) is well maintained with sevoflurane. In both animal studies (dogs, rabbits) and clinical studies, changes in neurohemodynamics (intracranial pressure, cerebral blood flow/blood flow velocity, cerebral metabolic rate for oxygen and cerebral perfusion pressure) were comparable between sevoflurane and isoflurane. Sevoflurane has minimal effect on ICP (intracranial pressure) and preserves CO₂ responsiveness.
Sevoflurane does not affect renal concentrating ability, even after prolonged anesthetic exposure, up to approximately 9 hrs.
Minimum Alveolar Concentration: The minimum alveolar concentration (MAC) is the concentration at which 50% of the population tested does not move in response to a single stimulus of skin incision. MAC equivalents for sevoflurane for various age groups are summarized in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

The MAC of sevoflurane in oxygen was determined to be 2.05% for a 40-year old adult. As with other halogenated agents, MAC decreases with age and with the addition of nitrous oxide.
Pharmacokinetics: Solubility: The low solubility of sevoflurane in blood would suggest that alveolar concentrations should rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent. This was confirmed in a clinical study where inspired and end-tidal concentrations (F₁ and F_A) were measured. The F_A/F₁ (wash-in) value at 30 min for sevoflurane was 0.85. The F_A/F_AO (wash-out) value at 5 min was 0.15.
Distribution: The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated. Other fluorinated volatile anaesthetics have been shown to displace drugs from serum and tissue proteins in vitro. The clinical significance of this is unknown.
Clinical studies have shown no untoward effects when sevoflurane is administered to patients taking drugs that are highly bound and have a small volume of distribution (eg, phenytoin).
Metabolism: The rapid pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism. In humans, <5% sevoflurane absorbed is metabolized via cytochrome P-450 2E1 isoform to hexafluorisopropanol (HFIP), with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. It is the only fluorinated volatile anesthetic which is not metabolized to trifluoroacetic acid.
Fluoride Ion: Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of sevoflurane administered and the composition of the anesthetic gas mixture.
The defluorination of sevoflurane is not inducible by barbiturates.
Approximately 7% of adults evaluated for inorganic fluoride concentrations in the Abbott Clinical Program experienced concentrations >50 mcM; no clinically significant effect on renal function was observed in any of these individuals.
Toxicology: Sevoflurane has a low order of acute toxicity in rats, mice, rabbits, dogs and monkeys.
Anesthesia induction was smooth and rapid, with no struggling, signs of gasping or other undesirable reactions. Deaths from exposure to lethal concentrations were due to respiratory arrest. Exposure was not associated with any specific organ toxicity or developmental toxicity in laboratory animals.
Fischer 344 rats were anesthetized within 2-3 min after start of exposure to sevoflurane (1.4%) for up to 10 hrs. There were no functional or morphologic defects following administration of sevoflurane.
In a Segment I reproduction study, sevoflurane had no significant effects on male or female reproductive capabilities at exposure concentrations of up to 1 MAC (2.2%). Segment II and III studies in rats indicate that sevoflurane is not a selective developmental toxicant.
Compound A: In Wistar rats, the LC₅₀ of Compound A was 1050-1090 ppm in animals exposed for 1 hr and 400-420 ppm in animals exposed for 3 hrs (median lethal concentrations were approximately 1070 and 330-490 ppm, respectively). In rats exposed to 30, 60 or 120 ppm of Compound A in an 8-week chronic toxicity study (24 exposures, 3 hrs/exposure), no apparent evidence of toxicity was observed other than loss of body weight in females on the last study day.
Sprague-Dawley rats were administered with Compound A via nose-only inhalation exposure in an open system [25, 50, 100 or 200 ppm (0.0025-0.02%) of Compound A]. Control groups were exposed to air. The threshold, at which reversible alterations in urinary and clinical parameters indicative of renal changes (concentration-dependent increases in BUN, creatinine, glucose, protein/creatinine ratios and N-acetyl glucosamidase/creatinine ratios) were observed, was 114 ppm of Compound A. Histological lesions were also reversible.
Since the uptake of inhalational agents in small rodents is substantially higher than in humans, higher levels of drug, Compound A (degradant of sevoflurane) or 2-bromo-2-chloro-1, 1-difluoro ethylene (BCDFE) (degradant/metabolite of halothane) would be expected in rodents. Also, the activity of the key enzyme (β-lyase) involved in haloalkene nephrotoxicity is 10-fold greater in the rat than it is in humans.
Compound A concentrations are reported to increase with increasing absorber temperature, increasing sevoflurane concentrations and with decreasing fresh gas flow rates. In clinical situation, the highest concentration of Compound A in the anesthesia circuit with soda lime as the CO₂ absorbent was 15 ppm in pediatrics and 32 ppm in adults. However, concentrations up to 61 ppm have been observed in patients attached to systems with baralyme as the CO₂ absorbent. Although exposure to sevoflurane in low flow systems is limited, there has been no evidence of renal dysfunction attributable to Compound A.
Compound B: In clinical situation, the concentration of Compound B detected in the anesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for 3 hrs resulted in no adverse effects on renal parameters or tissue histology in Wistar rats.
Clinical Safety and Efficacy Studies: Efficacy: Numerous clinical studies have been conducted with sevoflurane as the anesthetic agent for pediatric and adult patients. The results have shown that sevoflurane provides smooth, rapid induction of, as well as rapid emergence from anesthesia.
Sevoflurane was associated with faster times to induction and to such recovery events as emergence, response to command and orientation compared to reference drugs.
Adult Anesthesia: Mask Induction: In adult studies in which mask induction was performed, sevoflurane was demonstrated to provide smooth and rapid induction of anesthesia.
Maintenance: In 3 outpatient and 25 inpatient studies involving 3591 adult patients (2022 sevoflurane, 1196 isoflurane, 111 enflurane, 262 propofol) sevoflurane was demonstrated to be an effective agent for the maintenance of anesthesia.
Sevoflurane was demonstrated to be an appropriate agent for use in neurosurgery, cesarian section, patients undergoing coronary artery bypass surgery (CABG), and noncardiac patients at risk for myocardial ischemia.
Pediatric Anesthesia: In 2 outpatient and 3 inpatient studies involving 1498 pediatric patients (837 sevoflurane, 661 halothane), sevoflurane was demonstrated to be an effective agent for the induction and maintenance of anesthesia.
Mask Induction: In pediatric studies in which mask induction was performed, the induction time was statistically significantly shorter and the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.
Safety: Clinical studies in a wide variety of patient populations (children, adults, elderly, renally impaired, hepatically impaired, obese, patients undergoing cardiac bypass surgery, patients treated with aminoglycosides or metabolic inducers, patients exposed to repeat surgeries, patients undergoing surgeries ≥6 hrs in duration), the results of evaluations of laboratory parameters (eg, SGPT, SGOT, alkaline phosphatase, total bilirubin, serum creatinine, BUN) as well as investigator-reported incidence of adverse events relating to hepatic and renal function, demonstrated that sevoflurane does not have a clinically significant effect on liver or kidney function, nor does it exacerbate preexisting renal or hepatic impairment. These studies also demonstrated that there were no statistically significant differences between sevoflurane and reference agents in the proportions of patients showing changes in any clinical chemistry parameter.
The impact on renal function was comparable among sevoflurane and the reference drugs, between types of anesthesia circuits, among flow rates and between patients with or without inorganic fluoride concentrations ≥50 mcm.
The incidence of renal dysfunction was <1% for both sevoflurane (0.17%) and reference drugs (0.22%; isoflurane, halothane, enflurane, propofol) in comparative studies. This overall incidence is consistent with that of a general surgical population. In all cases, an alternate cause or reasonable explanation existed for the renal dysfunction.
Hepatically Impaired: Sevoflurane is effective and well tolerated when used as the primary agent for the maintenance of anesthesia in patients with impaired hepatic function, Child-Pugh Class A and B. Sevoflurane did not exacerbate preexisting hepatic impairment.
Renally Impaired: Sevoflurane was evaluated in renally impaired patients with baseline serum creatinine ≥1.5 mg/dL (130 micromole/L). Based on the incidence and magnitude of changes in serum creatinine concentrations, sevoflurane did not further deteriorate renal function.

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

Premedication: Premedication should be selected according to the need of the individual patient and at the discretion of the anesthesiologist.
Surgical Anesthesia: The concentration of sevoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane.
Induction: Dosage should be individualized and titrated to the desired effect according to the patient's age and clinical status. A short-acting barbiturate or other IV induction agent may be administered, followed by inhalation of sevoflurane. Induction with sevoflurane may be achieved in oxygen or in combination with oxygen-nitrous oxide mixtures. In adults, inspired concentrations of up to 5% sevoflurane usually produce surgical anesthesia in <2 min. In children, inspired concentrations of up to 7% sevoflurane usually produce surgical anesthesia in <2 min.
Maintenance: Surgical levels of anesthesia may be sustained with concentrations of 0.5-3% sevoflurane with or without the concomitant use of nitrous oxide. (See Table 2.)

Click on icon to see table/diagram/image

Emergence: Emergence times are generally short following sevoflurane anesthesia. Therefore, patients may require postoperative pain relief earlier.

In the event of apparent 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.

Patients with known sensitivity to sevoflurane or to other halogenated agents or with known or suspected genetic susceptibility to malignant hyperthermia.

Sevoflurane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation and oxygen enrichment, and circulatory resuscitation must be immediately available.
Since levels of anesthesia may be altered easily and rapidly, only vaporizers specifically calibrated for sevoflurane should be used. Hypotension and respiratory depression increase as anesthesia is deepened.
Malignant Hyperthermia: In susceptible individuals, potent inhalation anesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In clinical trials, 1 case of malignant hyperthermia was reported. In genetically susceptible pigs, sevoflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia, acute hypoxia, hypercapnia and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of dantrolene sodium IV and application of supportive therapy. (Consult prescribing information for dantrolene sodium IV for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.

General: During maintenance of anesthesia, increasing the concentration of sevoflurane produces dose-dependent decreases in blood pressure. Excessive decrease in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of sevoflurane.
As with all anesthetics, maintenance of hemodynamic stability is important to the avoidance of myocardial ischemia in patients with coronary artery disease.
The recovery from general anesthesia should be assessed carefully before patients are discharged from the post-anesthesia care unit.
Renal Impairment: Because of the small number of patients with renal insufficiency (baseline serum creatinine >1.5 mg/dL) studies, the safety of sevoflurane administration in this group has not yet been fully established. Therefore, sevoflurane should be used with caution in patients with renal insufficiency.
Neurosurgery: In patients at risk for elevations of ICP, sevoflurane should be administered cautiously in conjunction with ICP-reducing maneuvers eg, hyperventilation.
Information to Patients: Although recovery of consciousness following sevoflurane administration generally occurs within minutes, the impact on intellectual function for 2 or 3 days following anesthesia has not been studied. As with other anesthetics, small changes in moods may persist for several days following administration.
Effects on the Ability to Drive or Operate Machinery: Patients should be advised that performance of activities requiring mental alertness eg, operating a motor vehicle or hazardous machinery, may be impaired for some time after general anesthesia.
Carcinogenicity: Studies on carcinogenesis have not been performed. No mutagenic effect was noted in the Ames test and no chromosomal aberrations were induced in cultured mammalian cells.
Use in pregnancy: Pregnancy Category B: Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of impaired fertility or harm to the fetus due to sevoflurane. There are no adequate and well-controlled studies in pregnant women, therefore, sevoflurane should be used during pregnancy only if clearly needed.
Labor and Delivery: In a clinical trial, the safety of sevoflurane was demonstrated for mothers and infants when used for anesthesia during cesarian section. The safety of sevoflurane in labor and vaginal delivery has not been demonstrated.
Use in lactation: It is not known whether sevoflurane is excreted in human milk. Caution should be exercised when sevoflurane is administered to nursing women.
Use in the elderly: MAC decreases with increasing age. The average concentration of sevoflurane to achieve MAC in an 80-year old is approximately 50% of that required in a 20-year old.

Use in pregnancy: Pregnancy Category B: Reproduction studies in rats and rabbits at doses up to 1 MAC have revealed no evidence of impaired fertility or harm to the fetus due to sevoflurane. There are no adequate and well-controlled studies in pregnant women, therefore, sevoflurane should be used during pregnancy only if clearly needed.
Labor and Delivery: In a clinical trial, the safety of sevoflurane was demonstrated for mothers and infants when used for anesthesia during cesarian section. The safety of sevoflurane in labor and vaginal delivery has not been demonstrated.
Use in lactation: It is not known whether sevoflurane is excreted in human milk. Caution should be exercised when sevoflurane is administered to nursing women.

As with all potent inhaled anesthetics, sevoflurane may cause dose-dependent cardiorespiratory depression. Most adverse events are mild or moderate in severity and transient in duration. Nausea and vomiting have been observed in the postoperative period, common sequelae of surgery and general anesthesia, which may be due to inhalational anesthetic, other agents administered intraoperatively or postoperatively, and to the patient's response to the surgical procedure.
Adverse Event Data Derived from Controlled Clinical Trials: The most frequent adverse events (≥10%) considered to be probably related to sevoflurane administration overall were: Nausea, vomiting, increased cough and hypotension.
Adults: Most Frequent Adverse Events (≥10%): Nausea, vomiting and hypotension.
Elderly (≥10%): Hypotension, nausea and bradycardia.
Children (>10%): Vomiting, agitation, increased cough and nausea.
The type, severity, and frequency of adverse events in sevoflurane patients were comparable to adverse events in reference-drug patients.
The most frequent adverse events (>10%) considered to be probably related to sevoflurane administration overall were: Nausea, vomiting, increased cough, hypotension, agitation, somnolence, chills, bradycardia, dizziness, increased salivation, respiratory disorder, hypertension, tachycardia, laryngismus and fever.
Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents.
Transient increases in serum inorganic fluoride levels may occur during and after sevoflurane anesthesia. Concentrations of inorganic fluoride generally peak within 2 hrs of the end of sevoflurane anesthesia and return within 48 hrs to preoperative levels. In clinical trials, elevated fluoride concentrations were not associated with impairment of renal functions.
Occasional cases of transient changes in hepatic function tests were reported with sevoflurane and reference agents.
In the Abbott Clinical Program, which included 5560 patients/volunteers, 17 deaths (9 sevoflurane, 8 isoflurane) were reported. All deaths were considered to be of unknown origin or to have no relationship to study drug.
Post-Marketing Experience: Rare reports of postoperative hepatitis exist, but with an uncertain relationship to sevoflurane.
As with other anesthetic agents, cases of dystonic movement with spontaneous resolution have been reported in children receiving sevoflurane for induction of anesthesia, with an uncertain relationship to sevoflurane.
As with other halogenated agents, rare events of malignant hyperthermia have been reported (see Warnings).
Drug Abuse and Dependence: None known.

Sevoflurane has been shown to be safe and effective when administered concurrently with a wide variety of agents commonly encountered in surgical situations eg, central nervous system agents, autonomic drugs, smooth muscle relaxants, anti-infective agents including aminoglycosides, hormones and synthetic substitutes, blood derivatives and cardiovascular drugs.
Barbiturates: Sevoflurane administration is compatible with barbiturates as commonly used in surgical practice.
Benzodiazepine and Opioids: Benzodiazepines and opioids are expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice.
Nitrous Oxide: As with other halogenated volatile anesthetics, the MAC of sevoflurane is decreased when administered in combination with nitrous oxide. The MAC equivalent is reduced approximately 50% in adults and approximately 25% in pediatric patients.
Neuromuscular-Blocking Agents: As with other inhalational anesthetic agents, sevoflurane affects both the intensity and duration of neuromuscular blockade by nondepolarizing muscle relaxants. When used to supplement alfentanil-N₂O anesthesia, sevoflurane potentiates neuromuscular block induced with pancuronium, vecuronium or atracurium. The dosage adjustments for these muscle relaxants when administered with sevoflurane are similar to those required with isoflurane. The effect of sevoflurane on succinylcholine and the duration of depolarizing neuromuscular blockade has not been studied.
Dosage reduction of neuromuscular-blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation because potentiation of neuromuscular-blocking agents is observed a few minutes after the beginning of sevoflurane administration.
Among nondepolarizing agents, vecuronium, pancuronium and atracurium interactions have been studied. In the absence of specific guidelines: For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants; and during maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N₂O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.

Store at room temperature 15-30°C (59-86°F).

Anaesthetics - Local & General

N01AB08 - sevoflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.

S