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The Shivering Threshold in Rabbits with JM-1232(–), a New Benzodiazepine Receptor Agonist

Taishi Masamune, MD^*, Hiroaki Sato, MD^*, Katsumi Okuyama, MD, PhD, Yusuke Imai, MD, Hironobu Iwashita, MD, PhD^*, Tadahiko Ishiyama, MD, PhD^*, Takeshi Oguchi, MD, PhD, Daniel I. Sessler, MD, and Takashi Matsukawa, MD, PhD

From the *Operating Theater, Yamanashi University Hospital, Yamanashi, Japan; Department of Anesthesiology, University of Yamanashi, Japan; Department of Anesthesia, Kanoiwa General Hospital, Yamanashi, Japan; and Department of Outcomes Research, The Cleveland Clinic, Cleveland, Ohio.

Address correspondence and reprint requests to Taishi Masamune, MD, Operating Theatre, Yamanashi University Hospital. 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. Address e-mail to ezn00202{at}nifty.ne.jp or www.or.org.

Abstract

Background: JM-1232(–) is a novel isoindoline derivative which shows sedative and hypnotic activities through the benzodiazepine site of -aminobutyric acid type A (GABA_A) receptors. Typical doses of midazolam, another GABA_A receptor agonist, slightly reduce the shivering threshold in humans. We thus determined the extent to which JM-1232(–) decreases the shivering threshold.

Methods: Eighteen rabbits, lightly anesthetized with isoflurane 0.2 minimum alveolar anesthetic concentration (MAC), were randomly assigned to infusions of 1) saline (control), 2) 0.01 mg · kg^–1 · min^–1 JM-1232(–), or 3) 0.1 mg · kg^–1 · min^–1 JM-1232(–). Body temperature was reduced at a rate of 2–3°C/h by perfusing water at 10°C though a U-shaped plastic tube positioned in the colon. Cooling continued until shivering was observed by an investigator blinded to treatment, or until core temperature reached 34°C. Core temperatures were recorded from the distal esophagus, and core temperature at the onset of shivering defined the threshold. Data were analyzed by one-way analysis of variance with Student-Newman-Keuls tests. Results are presented as means ± sd; P < 0.05 was considered statistically significant.

Results: The rabbits given a saline infusion shivered at 36.5 ± 0.3°C. Five of the six rabbits given JM-1232(–) at a rate of 0.01 mg · kg^–1 · min^–1 shivered at 35.7 ± 0.8°C, and one of these rabbits failed to shiver at 34.0°C. None of the rabbits given JM-1232(–) at a rate of 0.1 mg · kg^–1 · min^–1 shivered before reaching the 34.0°C cutoff temperature.

Conclusion: A low dose of JM-1232(–) reduced the shivering threshold in rabbits approximately 0.8°C which is similar to the effects in humans given premedication doses of midazolam. In contrast, a 10-fold larger dose reduced the threshold more than 2.5°C. This is a substantial decrement and might facilitate induction of therapeutic hypothermia.