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ANESTHETIC PHARMACOLOGY

Sevoflurane and Propofol Increase ¹¹C-Flumazenil Binding to Gamma-Aminobutyric Acid_A Receptors in Humans

Turku PET Centre, University of Turku and the Department of Anesthesiology and Intensive Care, Turku University Hospital, Turku, Finland.

Address correspondence to Elina Salmi, MD, Turku PET Centre, PO Box 52, FIN-20521 Turku, Finland. Address email to elina.salmi{at}utu.fi

Based on in vitro studies and animal data, most anesthetics are supposed to act via -aminobutyric acid type A (GABA_A) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied ¹¹C-flumazenil binding to GABA_A receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with ¹¹C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 ± 3.0 (mean ± SD) µg/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of ¹¹C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 ± 6 in the sevoflurane group and 28 ± 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of ¹¹C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABA_A receptors in the mechanism of action of both anesthetics in humans.

IMPLICATIONS: Both sevoflurane and propofol enhanced gamma-aminobutyric acid (GABA)_A receptor binding in the living human brain as assessed with ¹¹C-labeled flumazenil and positron emission tomography, thus supporting the involvement of GABA_A receptors in the mechanism of action of both volatile anesthetics and propofol.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999