Anesth Analg 2007; 105:1272-1277
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000281075.77316.98
ANESTHETIC PHARMACOLOGY
The Effect of Dexmedetomidine on Electrocorticography in Patients with Temporal Lobe Epilepsy Under Sevoflurane Anesthesia
Yutaka Oda, MD, PhD*,
Sumiko Toriyama, MD*,
Katsuaki Tanaka, MD, PhD*,
Tadashi Matsuura, MD*,
Naoya Hamaoka, MD, PhD*,
Michiharu Morino, MD, PhD
, and
Akira Asada, MD, PhD*
From the Departments of *Anesthesiology and Intensive Care Medicine and Neurosurgery, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Address correspondence and reprint requests to Yutaka Oda, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan. Address e-mail to odayou{at}msic.med.osaka-cu.ac.jp.
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Abstract
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BACKGROUND: Although dexmedetomidine is often used in neuroanesthesia and neuronal critical care practice, its effect on cerebral electrical activity in those with an abnormal electroencephalogram is not known. The electrocorticogram (ECoG), a sensitive method for examining the effect of drugs on cerebral electrical activity and surgical treatment for epilepsy, is usually guided by monitoring of the ECoG. We investigated the effect of dexmedetomidine on ECoG in patients with epilepsy undergoing surgery with sevoflurane.
METHODS: Patients with medically intractable temporal lobe epilepsy undergoing resection of the epileptic foci (n = 11) were enrolled. Under general anesthesia with 2.5% sevoflurane and end-tidal carbon dioxide tension at 30 mm Hg, ECoG was recorded by strip electrodes with eight contacts placed on the mesial temporal lobe ipsilateral to the epilepsy foci. Dexmedetomidine was given as a computer-controlled infusion to achieve target plasma concentrations of 0.5 and 1.5 ng/mL. Each concentration was maintained for 20 min and ECoG was recorded before infusion of dexmedetomidine and between the 10th and 20th min after starting infusion. The median frequency of ECoG, spectral power density of each spectral band, and number of spikes at each concentration of dexmedetomidine were compared by Kruskal–Wallis test, followed by Student–Newman–Keuls test.
RESULTS: The median frequency of ECoG in 88 leads from all leads from all patients was significantly decreased by 1.5 ng/mL of dexmedetomidine compared with those at baseline and 0.5 ng/mL (P = 0.003 and 0.03, respectively); however, spectral power densities in the frequency bands: 
(<4 Hz), 
(
4 and <8 Hz), 
(8 and <13 Hz), and ß (13 Hz), were not changed. Neither the number of leads with spikes nor the number of spikes in all leads and in the lead with highest number of spikes at baseline was affected by dexmedetomidine.
CONCLUSIONS: Dexmedetomidine at plasma concentrations of 0.48 and 1.60 ng/mL decreased the median frequency of ECoG, but did not affect spike activity in patients with temporal lobe epilepsy anesthetized with 2.5% sevoflurane.
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Introduction
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Surgical treatment is an option for patients with medically intractable epilepsy. During surgery for treatment of epilepsy, such as cortical resection, temporal lobectomy, and amygdalohippocampectomy, monitoring the subdural electrocorticogram (ECoG) is a common procedure to identify the location and the extent of epileptogenic zone, as well as to guide the extent of resection. As the ECoG records the electrical potential close to the cortical focus, but without being affected by the dampening effect of the skull and scalp (1), it is a sensitive method for detecting interictal spikes of short duration and high frequencies, and thereby allows investigation of the effects of drugs on interictal epileptiform activity (2–4).
Dexmedetomidine, a selective 2-adrenergic agonist with sedative and analgesic effects, is increasingly used in intensive care practice. Coupled with potential neuroprotective properties (5), the sympatholytic effect of dexmedetomidine associated with a decrease in plasma catecholamine levels suggests that it may be suitable for sedation of patients with acute confusional status caused by brain injury, intracranial hypertension, and other central nervous system (CNS) disorders (6). However, there are few reports examining its effect on patients with CNS disorders with abnormal electroencephalography (EEG) (7). To our knowledge, there have been no studies investigating the effect of dexmedetomidine on cerebral cortical electrical activity in patients with refractory epilepsy. Examining the effect of dexmedetomidine on cerebral electrical activity in patients with CNS disorders is crucially important for establishing its safety for these patients or after a neurosurgical operation. In the present study, we evaluated the effect of dexmedetomidine on the ECoG in patients with temporal lobe epilepsy during sevoflurane anesthesia.
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METHODS
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Experimental Protocol
After approval from the Osaka City University Hospital Ethics Committee (Osaka, Japan) and obtaining written informed consent, 11 patients (20–40 yr, mean 31 yr; 6 males, 5 females) with medically intractable temporal lobe epilepsy scheduled for elective surgical resection of epileptic foci were included in this study (Table 1). Patients with hypertension, ischemic heart disease, arrhythmia, respiratory, or renal dysfunction were excluded from the study. Patients received their regular anticonvulsant medication until the day before surgery, and no premedication was used before surgery.
Anesthesia was induced with vital capacity breaths of 5% sevoflurane in oxygen (8), and vecuronium (0.15 mg/kg) was administered before tracheal intubation. No IV anesthetics were used. Anesthesia was maintained with sevoflurane in air and oxygen (fraction of inspired oxygen [Fio2] = 0.3) while the lungs were mechanically ventilated maintaining end-tidal carbon dioxide tension (PAco2) at 30 mm Hg and sevoflurane concentration at 2.5%, corresponding to 1.5 times the minimum alveolar anesthetic concentration (MAC) (9). These conditions were chosen based on previous studies not to suppress the spike activity (10), and maintained until the end of ECoG recording. Vecuronium was continuously administered at 3–5 mg/h during anesthesia. Intraoperative monitoring included electrocardiogram, noninvasive arterial blood pressure measurement, pulse oximetry, bladder temperature, and capnometer (Capnomac Ultima, Datex Instrumentarium, Helsinki, Finland), which was calibrated before each anesthetic. An intraarterial catheter was inserted for continuous monitoring of mean arterial blood pressure (MAP) and blood sampling. For maintaining body temperature, a water blanket was placed under each patient with a polyurethane-formed pad covered with a cotton sheet to protect the patient from direct contact with the water blanket.
After bilateral frontotemporal craniotomy and exposure of the temporal lobe, a slender trapezoid-shaped four-contact strip electrode with four basal contacts (total number of contacts [electrodes] in a patient is 8), was inserted and placed under the temporal lobe ipsilateral to the seizure focus with the basal electrodes approximately on the mesial temporal structure as previously reported (11 (Fig. 1). Baseline ECoG was recorded using Neurofax EEG-5532 (Nihon Kohden, Tokyo, Japan) for 10 min with measurement of MAP and heart rate (HR), and then infusion of dexmedetomidine was started. Dexmedetomidine was administered by a target-controlled infusion (TCI) system using the STANPUMP software1 operated based on a pharmacokinetic parameter shown by Dyck et al. (12) to maintain the plasma concentration at 0.5 ng/mL. Ten minutes after starting the dexmedetomidine infusion, MAP and HR were measured and recorded, and arterial blood samples were withdrawn for measuring the plasma concentration of dexmedetomidine, and then recording of ECoG was started and lasted for 10 min. After completion of recording ECoG, the target concentration of dexmedetomidine was increased to 1.5 ng/mL. Ten minutes later, MAP and HR were measured while blood samples were obtained and recording of ECoG was started. Plasma samples were stored at –70°C until analysis. Arterial blood gas was measured within 60 min after tracheal intubation and within 30 min before recording ECoG.
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Figure 1. Location of the trapezoid-shaped electrode. A slender trapezoid-shaped four-contact strip electrode with four basal contacts (total number of electrode in a patient is 8) was inserted and placed under the temporal lobe ipsilateral to the seizure focus with the basal electrodes approximately on the mesial temporal structure.
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Analysis of ECoG
ECoG signals were obtained from the cerebral hemisphere ipsilateral to the epileptic foci, referred to a scalp electrode placed on the mandible, and were recorded on a personal computer (ThinkPad G40, IBM, New Orchard Road, Armonk, NY) via low-pass filter (50 Hz) and analog-digital converter at 512 Hz sampling rate. Recorded ECoG signals were subjected to Fast Fourier Transformation with 2-s epochs and its power spectral densities in frequency bins with 0.125 Hz band width were calculated using computer software (BIMUTAS II, Kissei Comtec, Co., Ltd., Nagano, Japan). Median frequency, and the spectral power density in the following bands were calculated as the sum of power in the single frequency bins; (<4 Hz), (4 and <8 Hz), (8 and <13 Hz), and ß (13 Hz). To assess the extent of areas with spike activity, the number of leads with at least one spike per min during the 10-min recording interval was counted. The number of spikes in all leads and in the most active lead was counted for the 10-min recording period. A spike was defined as a clearly outstanding transient sharp activity with duration of 20–200 ms and amplitude of higher than 200 µV (13). ECoG was analyzed by one of the authors (NH) who was not involved in the anesthesia of the patient and was unaware of the dose of dexmedetomidine.
Measurement of Plasma Concentration of Dexmedetomidine
The plasma concentration of dexmedetomidine was measured by high performance liquid chromatography– mass spectrometry as previously reported with small modifications (14). Briefly, dexmedetomidine was extracted with solid-phase column (Oasis HLB, 30 mg/mL Waters, MA) and measured with tandem mass spectrometry using 100 ng of midazolam as an internal standard (4000 Qtrap, Analytical Biosystems, Foster City, CA). Coefficient of within-day and day-to-day variance were 7.5% and 8.2%, respectively, at 0.1 ng/mL and 3.5% and 4.2%, respectively, at 1.0 ng/mL. Limit of detection was 0.02 ng/mL.
Statistics
Statistical analysis was performed using SigmaStat 3.0 (Systat Software Inc., Richmond, CA). Hemodynamic data are expressed as mean ± sd and compared using analysis of variance, followed by Student–Newman– Keuls test for multiple comparisons. Regarding ECoG, median frequency, and spectral power density of each spectral band, the number of leads with spikes, average number of spikes in eight leads, and the number of spikes in the most active lead in 11 patients were analyzed by Kruskal–Wallis test, followed by Student– Newman–Keuls test. A probability value <0.05 was considered statistically significant.
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RESULTS
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Patients' characteristics are described in Table 1. During anesthesia, bladder temperature was maintained at 36.5°C–37.2°C. Blood gas data within 30 min before recording ECoG were pH: 7.50 ± 0.02, Paco2: 30 ± 2 mm Hg, Pao2: 179 ± 27 mm Hg, Base Excess: 1.2 ± 1.5 mmol/L. Blood hemoglobin content was 13.2 ± 1.5 g/dL (n = 11). Plasma concentrations of dexmedetomidine were 0.48 ± 0.12 and 1.60 ± 0.45 ng/mL corresponding to the target concentrations of 0.5 and 1.5 ng/mL, respectively (n = 11). There were no differences in MAP among baseline, with dexmedetomidine at target concentrations of 0.5 and 1.5 ng/mL (72 ± 8, 71 ± 9, and 80 ± 10 mm Hg, respectively, P = 0.08). MAP was not decreased below 60 mm Hg; accordingly, no vasopressors or catecholamines were used. Although HR was not changed by 0.5 ng/mL of dexmedetomidine compared with baseline (92 ± 11 vs 91 ± 11 bpm), it was significantly decreased by 1.5 ng/mL (80 ± 11 bpm, P = 0.02).
A typical ECoG obtained from a patient (patient no. 5) is shown in Figure 2. Dexmedetomidine at 1.5 ng/mL significantly decreased the median frequency of ECoG compared with those at baseline and at 0.5 ng/mL (P = 0.003 and 0.03, respectively); however, it did not affect the spectral power density of any spectral bands (Figs. 2 and 3). Before starting the infusion of dexmedetomidine, spikes were present in all (8) leads in nine patients, in five and six of eight leads in the other two patients. The number of spikes in leads with the largest number of spikes and the average number of spikes in eight leads in each individual at baseline, with 0.5 and 1.5 ng/mL of dexmedetomidine are shown in Table 2. There were no differences in these values among baseline and at each concentrations of dexmedetomidine (P = 0.4 and 0.9, respectively). The leads with spikes were completely identical with and without dexmedetomidine. The number of spikes was increased, decreased, or not changed by dexmedetomidine in the same individuals. No differences were detected in the effect of dexmedetomidine on spike activity in mesial or basal temporal cortex.
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Figure 2. Electrocorticogram (ECoG) from bilateral cerebral hemisphere at baseline, with 0.48 and 1.58 ng/mL, corresponding to target concentrations of 0.5 and 1.5 ng/mL of dexmedetomidine under 2.5% sevoflurane and end-tidal carbon dioxide tension at 30 mm Hg in patient no. 5. Arterial blood gas data were pH: 7.50, Paco2: 28 mm Hg, Pao2: 207 mm Hg, base excess: 0 mmol/L. Blood hemoglobin content was 15.7 g/dL. ECoG was recorded by trapezoid-shaped four-contact strip electrode with four basal contacts (total number of electrode is 8) placed on the temporal lobe. MTC = mesial temporal cortex; BTC = basal temporal cortex.
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DISCUSSION
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We have shown that dexmedetomidine does not affect the number of leads with spikes or number of spikes in the ECoG in patients with temporal lobe epilepsy during anesthesia with 2.5% sevoflurane and with Paco2 30 mm Hg.
The effects of sedatives used intraoperatively on convulsions have been infrequently assessed except barbiturates, propofol, and benzodiazepines (15–17). Dexmedetomidine is a highly selective 2-adrenoceptor agonist and acts via different receptors and brain areas than do benzodiazepines and propofol. Bolus injection of high-dose dexmedetomidine (100 µg/kg) exerts proconvulsant effects during anesthesia with a volatile anesthetic, probably resulting from a markedly increased plasma concentration (18). On the other hand, dexmedetomidine administered in a target-controlled manner increased the threshold for local anesthetics-induced convulsions at 0.5 and 1.5 ng/mL (14). Although studies examining the effect of dexmedetomidine on human EEGs have been documented (19,20), its effect on EEG in patients with convulsions secondary to acute onset disorders, such as trauma and hemorrhage as well as temporal lobe epilepsy, have not been investigated. In the present study, we examined the effect of dexmedetomidine on EEG frequency and spectral power as well as spike activity. Under 1.5 MAC sevoflurane, baseline ECoG predominantly consisted of slow () waves and dexmedetomidine further decreased the median frequency, which is consistent with previous studies using dexmedetomidine in combination with alfentanil (19). Since the median frequency of ECoG was <4 Hz and classified as waves, a decrease of median frequency would not have affected the spectral power density.
After TCI, we determined the plasma concentration of dexmedetomidine 10 min after starting the infusion. Despite a relatively short equilibration time, there was good agreement between the target and measured concentrations. Previous studies using the same computer software have also shown good agreement between dexmedetomidine concentration measured 15 and 40 min after starting TCI with the target concentrations between 0.6 and 2.4 ng/mL (20), suggesting that TCI is a useful tool for establishing a stable plasma concentration of dexmedetomidine in a short period. However, it is not clear whether concentrations of dexmedetomidine in plasma and the target organs also equilibrated in such a short period. The lower concentration used in the present study (0.5 ng/mL) is a typical level used for sedation in surgical intensive care units. The higher one (1.5 ng/mL) is regarded as the highest therapeutic or even supratherapeutic level. Viewed together with results reporting no abnormal EEG during infusion in awake subjects (19), our results suggest that dexmedetomidine could be safely used in patients with epilepsy.
Dexmedetomidine induced no hemodynamic changes; occasionally, however, HR was decreased by approximately 12% at a concentration of 1.5 ng/mL compared with baseline. The hemodynamic effect of dexmedetomidine might have been modulated by the relatively high concentration of sevoflurane. Without sevoflurane, the hemodynamic changes induced by a rapid increase of its plasma concentration should be carefully monitored, since it exhibits a direct vasoconstrictive effect (21). Conversely, the pharmacokinetics of dexmedetomidine could be influenced by the hemodynamic effects of sevoflurane. We used a vital capacity induction technique with sevoflurane, which is effective for rapid loss of consciousness with small hemodynamic changes (8). Although MAP is influenced by cardiac output, which affects the clearance of dexmedetomidine (22), it was not significantly changed during the experiments, suggesting that hemodynamic change should not have affected the pharmacokinetics of dexmedetomidine and ECoG.
One of the major limitations of our study is that dexmedetomidine was used during anesthesia with sevoflurane, which may not be the common practice. Second, because of its known ability to induce interictal spikes, a high concentration (1.5–2.0 MAC) of sevoflurane with hyperventilation has been used for eliciting epileptic foci in subjects with refractory epilepsy (10,23,24). The effect of dexmedetomidine on ECoG was evaluated only during anesthesia with 2.5% sevoflurane. The effect of dexmedetomidine on ECoG in patients with temporal lobe epilepsy at different concentrations of sevoflurane still remains unclear. Another limitation is that only median frequency and spectral power densities were examined, and other EEG parameters, such as bispectral index or 95% spectral edge frequency, were not evaluated in our study. This is because those EEG parameters would not contribute to the investigation of spike activity and, therefore, could not meet the major purpose of our study.
In conclusion, we have shown that dexmedetomidine slowed the frequency, but did not affect the spike activity, of ECoG in patients with temporal lobe epilepsy during anesthesia with sevoflurane. Further studies in awake patients and at different sevoflurane concentrations are required for establishing its safety in patients with temporal lobe epilepsy.
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ACKNOWLEDGMENTS
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The authors thank Mrs. K. Hironaka for technical assistance.
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Footnotes
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1STANPUMP. Available at: http://anesthesia.stanford.edu/phpd. Assessed December 6, 2006. 
Accepted for publication July 3, 2007.
Supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan, no. 17791051 and 18791097.
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Abstract
Introduction
