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NEUROSURGICAL ANESTHESIA

Isoflurane Reduces N-Methyl-D-Aspartate Toxicity In Vivo in the Rat Cerebral Cortex

Hideki Harada, MD, Paul J. Kelly, BS^*,*, Daniel J. Cole, MD, John C. Drummond, MD, FRCPC^*,*, and Piyush M. Patel, MD, FRCPC^*,*

*Departments of Anesthesiology, University of California; *Department of Veterans Affairs, Veterans Affairs Medical Center, San Diego, California; Department of Anesthesiology, Kurume University School of Medicine, Kurume, Japan; and Department of Anesthesiology, Loma Linda University, Loma Linda, California

Address correspondence and reprint requests to Piyush M. Patel, Anesthesia Service 9125, VA Medical Center, 3350 La Jolla Village Dr., San Diego, CA 92161. Address e-mail to ppatel{at}ucsd.edu

Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known. We conducted the present study to evaluate the effect of isoflurane on injury produced by cortical injection of NMDA in vivo and to compare it with dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were anesthetized with isoflurane. NMDA 50 nmoles (5-µL volume) were stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane groups, the end-tidal concentration of isoflurane was maintained at either electroencephalogram (EEG)-burst suppression (BS) doses (2.2%–2.3%, n = 12) or a 1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before the NMDA injection. In the awake group and the dizocilpine group, anesthesia was discontinued on completion of the NMDA injection, and the animals were allowed to awaken. In the animals in the control group (n = 10), 20 µL of artificial cerebrospinal fluid was injected into the cortex. Injury to the cortex was evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses, isoflurane reduced the injury produced by a cortical NMDA injection compared with the awake state (1.74 ± 0.49 and 0.96 ± 0.46 vs 2.34 ± 0.56 mm³; P = 0.02). Dizocilpine reduced cortical injury (0.56 ± 0.27; P = 0.01) compared with the awake state. Injury in the control group was limited to the trauma produced by cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury was not different from the control group.

Implications: Isoflurane can reduce N-methyl-D-aspartate–mediated cortical injury in vivo in a dose-dependent manner. These data are consistent with the previously demonstrated ability of isoflurane to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.

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