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NEUROSURGICAL ANESTHESIA

The Effects of Dexmedetomidine on Myogenic Motor Evoked Potentials in Rabbits

From the Department of Anesthesiology, Nara Medical University, Nara, Japan.

Address correspondence and reprint requests to Masahiko Kawaguchi, MD, Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. Address e-mail to drjkawa{at}naramed-u.ac.jp.

	Abstract

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BACKGROUND: Dexmedetomidine is used in the perioperative management of patients, including as an intraoperative adjuvant. The effects of dexmedetomidine on myogenic motor evoked potentials (MEPs) remain undetermined. We conducted the present study to investigate the effects of dexmedetomidine on myogenic MEPs in rabbits.

METHODS: New Zealand white rabbits were used for the studies. First, to determine appropriate doses of dexmedetomidine as an adjunct for anesthesia in rabbits, the level of anesthesia was evaluated by testing the palpebral and limb withdrawal reflexes, and the reactions to ear pinching and tail clamp at 5, 25, 50, 100 µg/kg/h. Second, in 10 rabbits under ketamine and fentanyl anesthesia, myogenic MEPs in response to single pulse and a train-of-five pulses were recorded from the soleus muscle before, during, and after the administration of dexmedetomidine at 5, 25, and 50 µg/kg/h.

RESULTS: At 50 µg/kg/h of dexmedetomidine, palpebral reflex, limb reflex, and reaction to ear pinching were inhibited in >50% of animals, but the reaction to tail clamp was not reduced. Dexmedetomidine suppressed myogenic MEPs in a dose-dependent manner, but when multipulses were used for stimulation, myogenic MEPs could be recorded in all animals at 50 µg/kg/h.

CONCLUSIONS: As long as multipulse is used for stimulation, the recording of myogenic MEPs is feasible in rabbits under ketamine and fentanyl anesthesia during the administration of dexmedetomidine at doses that are an adjunct to anesthesia.

	Introduction

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Intraoperative monitoring of myogenic motor evoked potentials (MEPs) in response to transcranial electrical stimulation of the motor cortex provides a method for monitoring the functional integrity of descending motor pathways during operations in which the brain and spinal cord are at a risk for injury. However, a number of investigators have shown that the elicited myogenic MEP responses are very sensitive to suppression by most anesthetics (1). Although recently developed stimulators using multipulse have made intraoperative recording of myogenic MEPs possible, myogenic MEPs induced by such stimulation paradigms are still affected by anesthetics (2–5). Therefore, monitoring of MEPs during anesthesia remains a clinical challenge and further improvements in anesthetic techniques are desirable.

Dexmedetomidine, a highly selective ₂-adrenoreceptor agonist, is used in perioperative management. It produces sedation, anxiolysis, and analgesia without respiratory depression, reduces anesthetic requirements and, because of its sympatholytic properties, provides hemodynamic stability (6–8). In addition, in vivo and in vitro studies have indicated a neuroprotective effect (9–11). Since these characteristics make this IV drug a potentially attractive adjunct for neuroanesthesia, monitoring of myogenic MEPs may be required during the administration of dexmedetomidine. Furthermore, by adding dexmedetomidine as an adjunct for anesthesia, the doses of other anesthetics with suppressive effects on myogenic MEPs may be reduced. However, to our knowledge, there are no data regarding the effects of dexmedetomidine on myogenic MEPs. The present study was therefore conducted to investigate the effects of dexmedetomidine on myogenic MEPs in rabbits under ketamine/fentanyl anesthesia. The appropriate doses of dexmedetomidine as an adjunct for anesthesia in rabbits were also investigated.

	METHODS

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New Zealand white rabbits weighing 2.7–3.5 kg were used in this study. They were housed and maintained on a 12-h light–dark cycle with free access to food and water. The study was approved by the Animal Experiment Committee of Nara Medical University.

Study 1: Appropriate Doses of Dexmedetomidine as an Adjunct for Anesthesia
Eight rabbits were anesthetized in a plastic box with 5% isoflurane in oxygen, a 24-gauge catheter was placed in the left marginal ear vein, and isoflurane was discontinued. Thereafter, a continuous infusion of dexmedetomidine 5, 25, 50, 100 µg/kg/h was initiated. For each dose, an equilibration period of 30 min was allowed, and the level of anesthesia was evaluated by testing the palpebral reflex, the front and hindlimb withdrawal reflexes, and the reactions to ear pinching and tail clamp. The tail was always stimulated proximal to a previous test. Gross movements of the head, extremities or body were taken as a positive sign, whereas no movement or small movements such as grimacing, swallowing, chewing, or tail flicking were considered negative (12). The number of animals with positive responses for the palpebral reflex, the front and hindlimb withdrawal reflexes, and the reactions to ear pinching and tail clamp in each dose of dexmedetomidine were evaluated.

Study 2: The Effects of Dexmedetomidine on Myogenic MEPs
Ten rabbits were given 50 mg/kg of ketamine IM, and a 24-gauge catheter was placed in the left marginal ear vein. Thereafter, a continuous infusion of ketamine 17 mg/kg/h and fentanyl 33 µg/kg/h in lactated Ringer’s solution was initiated. Another 24-gauge catheter was inserted in the right marginal ear vein for the infusion of dexmedetomidine. The trachea was intubated via a tracheotomy, and the lungs were ventilated mechanically to maintain end-tidal carbon dioxide at 35–40 mm Hg (Harvard model 510, Summit Medical, MA). Rabbits’ lungs were ventilated with air containing 30% oxygen. The exhaled gas was recirculated through a carbon dioxide absorber. The right femoral artery was exposed and cannulated for arterial blood pressure monitoring and blood gas analysis. Blood gases, pH, and hematocrit were measured with a blood gas analyzer (GEM permier, Mallinckrodt, Ann Arbor, MI). Esophageal temperature was continuously monitored with a thermometer (Mon-a Therm, Mallinckrodt, St Louis, MO) and maintained between 39.0°C and 39.5°C.

MEPs recording was performed as reported previously (13,14). Briefly, the rabbits were turned prone, and the head was fixed in a stereotactic frame. The scalp was infiltrated with 1% lidocaine and reflected laterally to expose the calvarium. Two small craniotomies were performed with an air drill. A point 0.5 mm lateral to the sagittal suture and 14.5 mm rostral from the lambdoid suture on the right hemisphere was chosen as an anodal stimulating site. A point 0.5 mm lateral to the right of the sagittal suture at the level of lambdoid suture was used for the cathode. Silver ball electrodes (1 mm diameter) were placed epidurally via the holes, into which mineral oil was administered. Two standard recording needle electrodes were inserted in the left soleus muscle. A ground electrode was set at the tail. Constant voltage anodal stimulation was delivered through an electrical stimulator (SEN-3301, Nihon Kohden, Tokyo, Japan). The strength of the epidural electrical stimulus was gradually increased until the MEPs amplitude no longer increased. The recording device (SYNAX 1100, NEC Medical Systems, Tokyo, Japan) was triggered by the stimulating device. Low-cutoff and high-cutoff filters were set at 30 Hz and 3 kHz, respectively. Amplitude was defined as the voltage from the most negative component to the most positive component of the evoked electromyographic activity. Values were averaged from three individual responses. MEPs in response to single-pulse and a train-of-five pulses stimulations were recorded. The duration of each pulse was 200 µs. The interpulse interval during train-pulse stimulations was set at 2 ms. The interval between each stimulation was set at 30–60 s.

After the set up was completed and control MEPs were recorded, continuous infusions of dexmedetomidine of 5, 25, 50 µg/kg/h were administered. At each dose, an equilibration period of 30 min was allowed. After the recording of MEPs at each dose, administration of dexmedetomidine was discontinued and 90 min later MEPs were recorded again (Re0). During the experimental periods, administration of phenylephrine was used if arterial blood pressure decreased by more than 10% of control. At the end of the experiment, the animals were killed by an injection of propofol and potassium chloride, which caused cardiac arrest.

All values are expressed as mean ± sd. All values were assessed using two-way analysis of variance with repeated-measurements followed by Student–Newman–Keuls test. P < 0.05 was considered to be significant.

	RESULTS

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Study 1: Appropriate Doses of Dexmedetomidine as an Adjunct for Anesthesia
During the administration of dexmedetomidine, no respiratory assistance was required at any dose. The results of the palpebral reflex, the front and hindlimb withdrawal reflexes, and the reactions to ear pinching and tail clamp during the administration of dexmedetomidine are shown in Figure 1. At 5 µg/kg/h, the level of sedation was very light, and spontaneous movements were never diminished. At 25 µg/kg/h, good sedation was produced with eyes closed but arousal posture was kept, all rabbits easily transitioned from sleep to wakefulness, and all reflexes were positive. At 50 µg/kg/h, almost all rabbits lay down, and palpebral reflex, limb reflex, and reaction to ear pinching occurred in <50% of animals, but reaction to tail clamp was still present. At 100 µg/kg/h, all rabbits lay down, but spontaneous breathing was kept, and reaction to tail clamp only occurred in 37.5% of animals, while the other reflexes were all absent. Therefore, 100 µg/kg/h of dexmedetomidine seemed to be a dose which could be used for anesthesia by itself, and an appropriate dose as an adjunct for anesthesia was considered about 25–50 µg/kg/h. In study 2, 100 µg/kg/h of dexmedetomidine was not therefore included.

View larger version (24K): [in this window] [in a new window]   Figure 1. Percentage of animals with positive responses for the palpebral reflex, front and hindlimb withdrawal reflexes, and reactions to ear pinching and tail clamp for each dose of dexmedetomidine.

Study 2: The Effects of Dexmedetomidine on Myogenic MEPs
Physiologic variables are shown in Table 1. There were no significant differences in esophageal temperature, mean arterial blood pressure, hematocrit, pH, arterial partial pressure of oxygen and carbon dioxide throughout the administration of dexmedetomidine. Heart rate was significantly reduced during the administration of dexmedetomidine compared with the baseline values (P < 0.05).

The changes in MEPs amplitudes in response to single pulse and train-of-five pulses stimulation are shown in Figures 2a and b, respectively. There were no significant differences in MEPs amplitudes at the baseline and Re0. MEPs amplitudes were suppressed in a dose-dependent manner. Amplitudes of MEPs in response to single and five pulse stimulations at 50 µg/kg/h were significantly lower than those at baseline. Although success rates of MEPs in response to single pulse stimulations at 50 µg/kg/h were 80% (8 of 10), reliable MEPs could be recorded in all animals (success rate of 100%) when train-of-five pulses were used for stimulation. Representative MEPs in response to stimulation with single and train-of-five pulses are shown in Figure 3. The changes in MEPs latencies in response to single and train-of-five pulses stimulation are shown in Table 2. At 50 µg/kg/h, latencies of MEPs in response to train stimulation were significantly longer compared with those at baseline.

View larger version (20K): [in this window] [in a new window]   Figure 2. Changes in amplitudes of motor evoked potentials in response to single pulse stimulation (a) and train-pulse stimulation (b). Data are expressed as mean ± sd *P < 0.05 vs control.

View larger version (7K): [in this window] [in a new window]   Figure 3. Representative motor evoked potentials (MEPs) in response to single pulse stimulation (a) and train-pulse stimulation (b) during the administration of dexmedetomidine (DEX).

	DISCUSSION

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The results of the present study show that the appropriate doses of dexmedetomidine as an adjunct for anesthesia in rabbits were 25–50 µg/kg/h, and that these doses reduced MEPs amplitudes in a dose-dependent manner. When single-pulse stimulation was applied, a reduction in MEPs amplitudes was prominent, and at 50 µg/kg/h, the success rate was reduced to 80%. By contrast, when multipulse stimulation was applied, the amplitudes of MEPs were increased at all doses and even at 50 µg/kg/h, MEPs were adequately elicited. These results suggest that MEPs recording may be feasible when dexmedetomidine is used as an adjunct to anesthesia if multipulse is used for stimulation.

In the present study, the level of sedation was evaluated by testing the palpebral reflex, the front and hindlimb withdrawal reflexes and the reactions to ear pinching and tail clamp. At 25 µg/kg/h, the rabbits closed their eyes but were easily aroused. At 50 µg/kg/h, the palpebral reflex, limb reflex, and reaction to ear pinching were inhibited in >50% of animals but reaction to tail clamp was not diminished. Therefore, we considered that 25–50 µg/kg/h may be an appropriate dose of dexmedetomidine as an adjunct for anesthesia. Maier et al. (10) used a computer-controlled infusion of dexmedetomidine to maintain a steady-state plasma concentration of 4.0 ng/mL in rabbits because their previous study indicated that a plasma dexmedetomidine concentration of 4.0 ng/mL reduced anesthetic requirements by 50%. In their study, the rate of dexmedetomidine infusion ranged from 10.35 to 38.19 µg/kg/h. These doses of dexmedetomidine are comparable with those used in the present study (10).

To our knowledge, there have been no reports on the effects of dexmedetomidine on myogenic MEPs. However, there have been several reports on the effects of dexmedetomidine on other neurophysiological monitors in animals and humans. Li et.al. investigated the effects of dexmedetomidine on the cortical somatosensory evoked potential (SEP) in rats and demonstrated that increasing plasma concentrations of dexmedetomidine, to more than the clinical and supraclinical range for the rat, did not significantly change the amplitudes and latencies of cortical SEP (15). A study in volunteers demonstrated that dexmedetomidine decreased SEP amplitudes dose-dependently, but SEP could still be recorded even at high doses. Bloom et al. reported that although dexmedetomidine could affect the later cortical peaks of SEPs, consistent and reproducible potentials could be recorded (16). These results are consistent with the results obtained in the present study, in which dexmedetomidine suppressed myogenic MEPs, but the reliable MEPs recordings were still feasible during the administration of dexmedetomidine.

There are several limitations that merit comment. First, we did not measure the concentration of dexmedetomidine, so it is unclear whether an appropriate concentration was maintained during each infusion rate. However, as mentioned previously, the infusion rates of dexmedetomidine were similar to those in a previous study in which target-controlled infusion was used. Second, it is possible that the background anesthetics might have affected the results. In the present study, ketamine and fentanyl were used as background anesthetics because they have been shown to have little effect on myogenic MEPs compared with other anesthetics. Since the doses of ketamine and fentanyl remained unchanged, anesthetic depth might have increased during the administration of dexmedetomidine. This might have affected the results. An increase in the plasma levels of ketamine and fentanyl over time does not seem to have occurred, because the amplitude of Re0 MEPs was the same as baseline. Finally, in the present study we did not compare the suppressive effects of dexmedetomidine with other anesthetics. Further study may be required.

In summary, we investigated the effects of dexmedetomidine on myogenic MEPs in rabbits under ketamine and fentanyl anesthesia. The results indicated that dexmedetomidine suppressed myogenic MEPs in a dose-dependent manner, but when multipulses were used for stimulation, myogenic MEPs could be recorded even with 50 µg/kg/h of dexmedetomidine.

	Footnotes

 
Accepted for publication February 13, 2007.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamamoto, Y. Articles by Furuya, H. Search for Related Content PubMed Articles by Yamamoto, Y. Articles by Furuya, H. Related Collections Neuroanesthesia Pharmacology