Piramal
Sevoflurane
Sevoflurane

 

 

Clinical Pharmacology

Sevoflurane is an inhalational Anaesthetic agent for induction and maintenance of general anesthesia. The Minimum Alveolar Concentration (MAC) of sevoflurane as determined in 18 dogs is 2.36%.2 MAC is defined as that alveolar concentration at which 50% of healthy patients fail to respond to noxious stimuli. Multiples of MAC are used as a guide for surgical levels of anesthesia,which are typically 1.3 to 1.5 times the MAC value.

Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient at 37°C = 0.63-0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. During sevoflurane induction, there is a rapid increase in alveolar concentration toward the inspired concentration.

Sevoflurane produces only modest increases in cerebral blood flow and metabolic rate, and has little or no ability to potentiate seizures.3 Sevoflurane has a variable effect on heart rate, producing increases or decreases depending on experimental conditions.4,5 Sevoflurane produces dose-dependent decreases in mean arterial pressure, cardiac output and myocardial contraction.6 Among inhalation anesthetics, sevoflurane has low arrhythmogenic potential.

Sevoflurane is chemically stable. No discernible degradation occurs in the presence of strong acids or heat. Sevoflurane reacts through direct contact with CO2 absorbents (soda lime and barium hydroxide lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F60), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C5H6F60), also known as Compound B.

Compound A
The production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (potassium hydroxide and/or NaOH) forming an alkene (Compound A) from sevoflurane.

Compound A is produced when sevoflurane interacts with soda lime or barium hydroxide lime. Reaction with barium hydroxide lime results in a greater production of Compound A than does reaction with soda lime. Its concentration in a circle absorber system increases with increasing sevoflurane concentrations and with decreasing fresh gas flow rates. Sevoflurane degradation in soda lime has been shown to increase with temperature. Since the reaction of carbon dioxide with absorbents is exothermic, this temperature increase will be determined by the quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the Anaesthetic circle system, metabolic status of the patient and ventilation. Although Compound A is a dose-dependent nephrotoxin in rats, the mechanism of this renal toxicity is unknown. Two spontaneously breathing dogs under sevoflurane anesthesia showed increases in concentrations of Compound A as the oxygen flow rate was decreased at hourly intervals, from 500 mL/min (36 and 18 ppm Compound A) to 250 mL/min (43 and 31 ppm) to 50 mL/min (61 and 48 ppm).

Fluoride ion metabolite
Sevoflurane 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. 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 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. In a study in which 4 dogs were exposed to 4% sevoflurane for 3 hours, maximum serum fluoride concentrations of 17.0-27.0 mcmole/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.

In a safety study, eight healthy dogs were exposed to sevoflurane for 3 hours/day, 5 days/week for 2 weeks (total 30 hours exposure) at a flow rate of 500 mL/min in a semi-closed, rebreathing system with soda lime. Renal toxicity was not observed in the study evaluation of clinical signs, hematology, serum chemistry, urinalysis, or gross or microscopic pathology.

 

Top

Drug Interactions

In the clinical trial, sevoflurane was used safely in dogs that received frequently used veterinary products including steroids and heartworm and flea preventative products.

Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, propofol and other commonly used intravenous anesthetics.

Benzodiazepines and Opioids: Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as other inhalational anesthetics. Sevoflurane is compatible with benzodiazepines and opioids as commonly used in surgical practice.

Phenothiazines and Alpha2-Agonists: Sevoflurane is compatible with phenothiazines and alpha2-agonists as commonly used in surgical practice.

In a laboratory study, the use of the acepromazine/oxymorphone/thiopental/sevoflurane Anaesthetic regimen resulted in prolonged recoveries in eight (of 8) dogs compared to recoveries from sevoflurane
alone.

 

Top

Clinical Effectiveness

The effectiveness of sevoflurane was investigated in a clinical study involving 196 dogs. Thirty dogs were mask-induced with sevoflurane using Anaesthetic regimens that included various premedicants. During the clinical study, one hundred sixty-six dogs received sevoflurane maintenance anesthesia as part of several Anaesthetic regimens that used injectable induction agents and various premedicants.

The duration of anesthesia and the choice of Anaesthetic regimens were dependent upon the procedures that were performed. Duration of anesthesia ranged from 16 to 424 minutes among the individual dogs. Sevoflurane vaporizer concentrations during the first 30 minutes of maintenance anesthesia were similar among the various Anaesthetic regimens. The quality of maintenance anesthesia was considered good or excellent in 169 out of 196 dogs.

The table shows the average vaporizer concentrations and oxygen flow rates during the first 30 minutes for all sevoflurane maintenance anesthesia regimens:

Average Vaporizer Concentrations among Anaesthetic Regimens Average Vaporizer Concentrations among Individual Dogs Average Oxygen Flow Rates among Anaesthetic Regimens Average Oxygen Flow Rates among Individual Dogs
3.31 -3.63% 1.6-5.1% 0.97-1.31 L/minute 0.5-3.0 L/minute

 

During the clinical trial, when a barbiturate was used for induction, the times to extubation, sternal recumbency and standing recovery were longer for dogs that received Anaesthetic regimens containing two preanesthetics compared to regimens containing one preAnaesthetic. Recovery times were shorter when Anaesthetic regimens used sevoflurane or propofol for induction. The quality of recovery was considered good or excellent in 184 out of 196 dogs.

Anaesthetic regimen drug dosages, physiological responses, and the quality of induction, maintenance and recovery were comparable between 10 sighthounds and other breeds evaluated in the study. During the clinical study there was no indication of prolonged recovery times in the sighthounds.

 

 

Top

How Supplied

PetremTM (sevoflurane) is packaged in amber colored bottles containing 250 mL sevoflurane,
NDC 60307-320-25.

 

Top

Storage Conditions

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

 

Top

References

  1. Plumb, D.C. ed., Veterinary Drug Handbook, Second Edition, University of Iowa Press, Ames,
    IA: p. 424 (1995).
  2. Kazama, T. and Ikeda, K., Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology. 68: 435-437 (1988).
  3. Scheller, M.S., Nakakimura, K., Fleischer, J.E. and Zornow, M.H., Cerebral effects of sevoflurane in the dog: Comparison with isoflurane and enflurane. Brit. J. Anesthesia 65:388-392 (1990).
  4. Frink, E.J., Morgan, S.E., Coetzee, A., Conzen, P.F. and Brown, B.R., Effects of sevoflurane, halothane, enflurane and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76: 85-90 (1992).
  5. Kazama, T. and Ikeda, K., The comparative cardiovascular effects of sevoflurane with halothane and isoflurane. J. Anesthesiology 2: 63-8 (1988).
  6. Bernard, J. M., Wouters, P.F., Doursout, M.F., Florence, B., Chelly, J.E. and Merin, R.G., Effects of sevoflurane on cardiac and coronary dynamics in chronically instrumented dogs. Anesthesiology 72: 659-662 (1990).
  7. Hayaski, Y., Sumikawa, K., Tashiro, C., Yamatodani, A. and Yoshiya, I., Arrhythmogenic threshold of epinephrine during sevoflurane, enflurane and isoflurane anesthesia in dogs. Anesthesiology 69: 145-147 (1988).
  8. Muir, W.W. and Gadawski, J., Cardiorespiratory effects of low-flow and closed circuit inhalation anesthesia, using sevoflurane delivered with an in-circuit vaporizer and concentrations of compound A. Amer. J. Vet. Res. 59 (5): 603-608 (1998).

 

Top