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The Effectiveness and Stability of a 20% Emulsified Sevoflurane Formulation for Intravenous Use in Rats

Morohashi, Toru MD; Itakura, Sayako MD; Shimokawa, Ken-ichi PhD; Ishii, Fumiyoshi PhD; Ikeda, Takehiko MD, PhD; Kazama, Tomiei MD, PhD

doi: 10.1213/ANE.0000000000001070
Anesthetic Pharmacology: Research Report

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.

Published ahead of print December 3, 2015

From the *Department of Anesthesiology, National Defense Medical College, Tokorozawa, Japan; and Department of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.

Accepted for publication September 14, 2015.

Published ahead of print December 3, 2015

Funding: The Department of Anesthesiology, National Defense Medical College.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Toru Morohashi, MD, Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Address e-mail to a13030ndmchosp@ndmc.ac.jp.

© 2016 International Anesthesia Research Society