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ANESTHETIC PHARMACOLOGY

Doxapram Produces a Dose-Dependent Reduction in the Shivering Threshold in Rabbits

Katsumi Okuyama, MD^*, Takashi Matsukawa, MD^*, Makoto Ozaki, MD, Daniel I. Sessler, MD, Tomoki Nishiyama, MD, Makoto Imamura, MD^*, and Teruo Kumazawa, MD^*

Departments of Anesthesia, *University of Yamanashi, Faculty of Medicine, Yamanashi; Tokyo Women’s Medical University, and Tokyo University School of Medicine, Tokyo, Japan; and Outcomes Research^TM Institute and Departments of Anesthesiology, University of Louisville, Louisville, Kentucky

Address correspondence and reprint requests to Dr. Takashi Matsukawa, Department of Anesthesia, University of Yamanashi, Faculty of Medicine, Tamaho, Yamanashi 409-3898, Japan. Address e-mail to takashim{at}res.yamanashi-med.ac.jp

Dopamine is a thermoregulatory neurotransmitter that provokes hypothermia when injected in or near the hypothalamus. Doxapram stimulates release of dopamine from carotid bodies, but is known to have central effects that are probably, at least in part, similarly mediated. We thus tested the hypothesis that doxapram produces a substantial, dose-dependent reduction in the shivering threshold in rabbits. Twenty-four rabbits, anesthetized with isoflurane, were randomly assigned to 1) saline (control), 2) 0.25 mg · kg^-1 · h^-1 doxapram, or 3) 0.50 mg · kg^-1 · h^-1 doxapram. These doses are within the recommended range for humans. Body temperature was reduced at a rate of 2° to 3°C/h by perfusing water at 10°C through a U-shaped thermode positioned in the colon. Core temperatures were recorded from the distal esophagus. A blinded observer evaluated shivering. Core temperature at the onset of shivering defined the threshold. Data were analyzed with a one-way analysis of variance; P < 0.05 was considered statistically significant. Hemodynamic and respiratory responses were comparable in the groups. The control rabbits shivered at 36.3° ± 0.3°C, those given 0.25 mg · kg^-1 · h^-1 doxapram shivered at 34.8° ± 0.5°C, and those given 0.50 mg · kg^-1 · h^-1 shivered at 33.7° ± 0.6°C. All the shivering thresholds significantly (P < 0.001) differed from one another. The magnitude of this inhibition, if similar in humans, would be clinically important.

IMPLICATIONS: Doxapram produced a substantial and dose-dependent reduction in the shivering threshold. The magnitude of this inhibition, if similar in humans, would be clinically important. Clinical studies are thus indicated to determine whether the drug might help defeat thermoregulatory defenses during induction of therapeutic hypothermia.

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