Differential effects of prolonged isoflurane anesthesia on plasma, extracellular, and CSF glutamate, neuronal activity, 125I-Mk801 NMDA receptor binding, and brain edema in traumatic brain-injured rats

Background. Volatile anesthetics reduce neuronal excitation and cerebral metabolism but can also increase intracellular water accumulation in normal and injured brains. While attenuation of neuronal excitation and glutamate release are beneficial under pathological conditions, any increase in edema formation should be avoided. In the present study we investigated duration-dependent effects of the commonly used isoflurane/nitrous oxide (N2O) anesthesia on EEG activity, specific NMDA receptor binding, extracellular, CSF, and plasma glutamate, and cerebral water content in brain-injured rats subjected to short (30 minutes) or prolonged (4 hours) anesthesia. Methods. Before controlled cortical impact injury (CCI), during prolonged (4-8 hours) or short anesthesia (7.5-8 hours after CCI), and before brain removal, changes in neuronal activity were determined by quantitative EEG analysis and glutamate was measured in arterial plasma. Brains were processed to determine acute and persisting changes in cerebral water content and I-125-Mk801 NMDA receptor binding at 8 and 32 hours after CCI, i.e., immediately or 24 hours after short or prolonged anesthesia. During prolonged anesthesia glutamate was measured via microdialysis within the cortical contusion. CSF was sampled before brain removal. Findings. Prolonged isoflurane (1.8 vol%) anesthesia significantly increased EEG activity, plasma, cortical extracellular, and CSF glutamate, cortical and hippocampal I-125-Mk801 NMDA receptor binding, and cerebral water content in brain-injured rats. These changes were partially reversible within 24 hours after prolonged anesthesia. At 24 hours, CSF glutamate was significantly reduced following long isoflurane anesthesia compared to rats previously subjected to short anesthesia despite an earlier significant increase. Conclusions. The partially reversible increases in EEG activity, I-125-Mk801 NMDA receptor binding, cerebral water content, plasma and CSF glutamate appear important for physiological, pathophysiological, and pharmacological studies requiring prolonged anesthesia with isoflurane. Increases in extracellular cortical and plasma glutamate could contribute to acute aggravation of underlying tissue damage.