title: The Effectiveness and Stability of a 20% Emulsified Sevoflurane Formulation for Intravenous Use in Rats.
abstract: BACKGROUND
  Halogenated volatile anesthetics can be safely and rapidly administered to animals and humans using emulsion formulations. However, they must be administered simultaneously with a high dose of lipids. Increasing the concentration of volatile anesthetics may solve this clinical issue. Moreover, careful observation is needed when the emulsion is injected because anaphylactic reactions have been reported.
  
  
  METHODS
  We prepared a 20% sevoflurane lipid emulsion and administered it to 69 male Sprague-Dawley rats via the tail vein. The median effective dose (ED50) for the loss of righting reflex and the median lethal dose (LD50) were determined. ED50 and LD50 values were calculated using nonlinear regression, and data were fitted with a cumulative Gaussian model using GraphPad Prism. Measurements of vital signs and evaluation of the presence of adverse effects associated with continuous infusion of emulsions were verified. Stability of the emulsion was assessed by measuring particle size at 365 days and sevoflurane concentrations after opening the vial at 180 minutes.
  
  
  RESULTS
  The ED50 and LD50 were 0.47 mL/kg (95% confidence interval [CI], 0.46-0.48) and 1.13 mL/kg (95% CI, 1.07-1.18), respectively. The therapeutic index (LD50/ED50) was 2.41 (95 CI%, 2.23-2.59), which compares favorably with therapeutic index of a fluoropolymer-based emulsion of sevoflurane, propofol, and thiopental. There were no adverse effects associated with the continuous infusion of emulsions. Particle size of the emulsion at 365 days after preparation was 78.9 ± 3.8 nm (±SD), and sevoflurane concentration at 180 minutes after opening the vial was 19.0% ± 0.6% (±SD).
  
  
  CONCLUSIONS
  We prepared a 20% sevoflurane lipid emulsion using caprylic triglyceride (i.e., medium-chain triglyceride). In rats, this emulsion was an effective anesthetic and was not associated with adverse events. The emulsion was stable after consecutive evaluation for 365 days and for 180 minutes after the vial was opened.
authors.affiliation: From the Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan; and Department of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Morohashi
authors.forename: Sayako
authors.initials: S
authors.lastname: Itakura
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Shimokawa
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Ishii
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Tomiei
authors.initials: T
authors.lastname: Kazama
mesh_terms: D000707:Anaphylaxis / Q000503:physiopathology; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000503:physiopathology; D004355:Drug Stability; D005217:Fat Emulsions, Intravenous; D007928:Lethal Dose 50; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D014280:Triglycerides / Q000737:chemistry
chemical_list: D018686:Anesthetics, Intravenous; D005217:Fat Emulsions, Intravenous; D008738:Methyl Ethers; D014280:Triglycerides; D000077149:Sevoflurane