Anesth Analg 2006;102:1715-1721
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000208992.83093.5c
ANESTHETIC PHARMACOLOGY
The Effects of Xenon on Myogenic Motor Evoked Potentials in Rabbits: A Comparison with Propofol and Isoflurane
Yuri Yamamoto, MD,
Masahiko Kawaguchi, MD,
Meiko Kakimoto, MD,
Masahiro Takahashi, MD,
Satoki Inoue, MD,
Takahisa Goto, MD, and
Hitoshi Furuya, MD
Department of Anesthesiology, Nara Medical University, Nara, Japan; Department of Anesthesia, Teikyo University, School of Medicine, Tokyo, Japan
Address correspondence and reprint requests to Masahiko Kawaguchi, MD, Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Nara, Japan. Address e-mail to drjkawa{at}naramed-u.ac.jp.
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Abstract
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We compared the effects of xenon on myogenic motor evoked potentials (MEPs) with those of propofol and isoflurane in rabbits under ketamine/fentanyl anesthesia. Thirty animals were randomly allocated to one of 3 groups (n = 10 in each group). In the propofol group, propofol was administered at a rate of 0.4 mg · kg–1 · min–1 (small) and 0.8 mg · kg–1 · min–1 (large). In the isoflurane group, isoflurane was administered at 0.8% (small) and 1.6% (large). In the xenon group, xenon was administered at 35% (small) and 70% (large). Myogenic MEPs in response to stimulation with single pulse and a train of 5 pulses were recorded from the soleus muscle before, during (at small and large doses), and after the administration of each anesthetic. With single-pulse stimulation, MEPs were recorded in 90% and 50% of animals at small and large doses of xenon, respectively, and MEP amplitudes in the xenon and isoflurane groups were significantly lower compared with those in the propofol group. With train pulse stimulation, MEPs were recorded in 100% and 90% of animals at small and large doses of xenon, respectively, and a reduction in MEP amplitudes by xenon was more prominent than by propofol but less than isoflurane at large doses. These results suggest that MEP recording may be feasible under xenon anesthesia if multipulse stimulation is used, although xenon has suppressive effects on myogenic MEPs.
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Introduction
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Intraoperative monitoring of myogenic motor evoked potentials (MEPs) to transcranial electrical stimulation of the motor cortex provides a method for monitoring the functional integrity of descending motor pathways during invasive manipulation of the spine or thoracoabdominal aortic replacement surgery. However, clinical and experimental use of these techniques has shown that the elicited responses are very sensitive to suppression by most anesthetics (1). Although advances in multipulse stimulation setups made intraoperative recording of myogenic MEPs possible, myogenic MEPs induced by such stimulation paradigms are still affected by anesthetics (2–5). Therefore, the development of proper anesthetic techniques during intraoperative monitoring of myogenic MEPs remained an important clinical challenge.
Xenon, an inert gas with anesthetic properties, has recently attracted renewed interest because it has many of the characteristics of an ideal anesthetic (6–8). In addition, recent evidence from in vivo and in vitro studies has indicated that xenon has neuroprotective efficacy (9–12). Homi et al. (9) demonstrated that xenon administration improved both functional and histological outcome in mice subjected to transient middle cerebral artery occlusion. Petzelt et al. (10) reported that xenon prevented neurotoxicity in hypoxic cortical neurons. It is therefore expected that xenon may be used for the prevention of spinal cord injury during monitoring of myogenic MEPs, although the effects of xenon on spinal cord injury remain undetermined. There have been no data regarding the effects of xenon on myogenic MEPs. We therefore hypothesized that the monitoring of myogenic MEPs may be feasible under xenon anesthesia. The present study was conducted to compare the effects of xenon on myogenic MEPs with those of propofol and isoflurane in rabbits under ketamine/fentanyl anesthesia.
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Methods
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Thirty male New Zealand White rabbits weighing 2.5–3.5 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.
The 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–1 · h–1 and fentanyl 33 µg · kg–1 · h–1 in lactated Ringer's solution was initiated. Another 24-gauge catheter was inserted in the right marginal ear vein for the addition of ketamine or administration of propofol. The trachea was intubated via a tracheostomy, and the lungs were ventilated mechanically to maintain end-tidal carbon dioxide at 35–40 mm Hg (Harvard Respirator 510; Summit Medical, MA). Rabbits 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 premier; 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–39.5°C.
MEP 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 applied. 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 electrical stimulus was gradually increased until the MEP 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. MEPs in response to single-pulse and train of 5 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 60 s. MEP 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. MEP responses were defined as "no response," when average MEP amplitudes were <50 µV.
After the setting was completed and control MEPs were recorded, animals were randomly allocated to one of the following 3 groups: propofol (n = 10), isoflurane (n = 10), or xenon (n = 10). In the propofol group, a bolus of propofol 2 mg/kg was administered followed by a continuous infusion of propofol at a rate of 0.4 mg · kg–1 · min–1 (small) and 0.8 mg · kg–1 · min–1 (large). These doses were determined based on the data in a previous study, in which a mean propofol infusion rate of 0.876 mg · kg–1 · min–1 produced a light plane of anesthesia in which the palpebral reflex, the reaction of ear pinching, and the front and hindlimb withdrawal reflexes were not abolished in rabbits (15). In the isoflurane group, isoflurane was administered at the end-tidal concentrations of 0.8% (small) and 1.6% (large). In the xenon group, xenon was administered at the end-tidal concentrations of 35% (small) and 70% (large). Minimal alveolar concentrations (MAC) of isoflurane and xenon in rabbits are 2.0% and 85%, respectively (16,17). Therefore, the concentrations of isoflurane 0.8% (0.4 MAC) and 1.6% (0.8 MAC) correspond to those of xenon at 35% (0.4 MAC) and 70% (0.8 MAC). The end-tidal concentrations of isoflurane were continuously monitored by a gas analyzer (Hewlett Packard, Andover, MA). End-tidal concentration of xenon was monitored by the gas analyzer (Thermomat; ZAFFZ603-ZABAY-Y, Fuji electrical systems, Tokyo, Japan). In each group, an equilibration period of 30 min was allowed at each infusion rate or concentration. After the recording of MEPs at small and large doses of each anesthetic, administration of each drug was discontinued and 60 min later MEPs were recorded again. During the experimental periods, a continuous 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 value <0.05 was considered to be significant.
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Results
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Physiologic variables are shown in Table 1. There were no significant differences in body weight, esophageal temperature, mean arterial blood pressure, hematocrit, pH, Pao2, and Paco2 among the three groups. Heart rate was significantly reduced during the administration of propofol and large doses of isoflurane compared with the baseline values (P < 0.05). During anesthetic administration, heart rate was significantly slower in the propofol group compared with the isoflurane and xenon groups (P < 0.05). Doses of phenylephrine were significantly lower in the xenon group compared with those in the propofol and isoflurane groups.
The changes in success rate of MEP recording are shown in Table 2. With single-pulse stimulation, MEPs were recorded in 9 and 5 of 10 animals at small and large doses of xenon, respectively. Success rates of MEP recording were significantly reduced after the administration of large doses of xenon and isoflurane compared with those at baseline (P < 0.05). Success rates of MEP recording in the isoflurane group were significantly less than those in the xenon group.
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Table 2. Success Rate of Myogenic Motor Evoked Potentials (MEPs) Recording in Response to Single Pulse or Train Pulse Stimulation During the Administration of Propofol, Xenon, and Isoflurane
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The changes in MEP amplitudes in response to single pulse stimulation are shown in Figure. 1a. There were no significant differences in MEP amplitudes at baseline and Re0 among the three groups. MEP amplitudes were significantly reduced in a dose-dependent manner in all three groups. At small doses, MEP amplitudes in the xenon group were significantly lower compared with those in the propofol group, and were significantly higher compared with those of isoflurane (P < 0.05). At large doses, MEP amplitudes in the isoflurane and xenon groups were significantly lower compared with those in the propofol group (P < 0.05).
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Figure 1. 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. In the propofol group, a bolus of propofol 2 mg/kg was administered followed by a continuous infusion of propofol at a rate of 0.4 mg · kg–1 · min–1 (small) and 0.8 mg · kg–1 · min–1 (large). In the isoflurane group, isoflurane was administered at the end-tidal concentrations of 0.8% (small) and 1.6% (large). In the xenon group, xenon was administered at the end-tidal concentrations of 35% (small) and 70% (large). *P < 0.05 versus baseline.
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The changes in latencies of MEPs in response to single-pulse stimulation are shown in Table 3. With single-pulse stimulation, MEP latencies at small dose in the isoflurane group were significantly longer than those in the other two groups (P < 0.05).
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Table 3. Changes in Latencies of Myogenic Motor Evoked Potentials in Response to Single Pulse or Train Pulse Stimulation During the Administration of Propofol, Xenon, and Isoflurane
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With train pulse stimulation, MEPs were recorded in 10 and 9 of 10 animals at small and large doses of xenon, respectively (Table 2). Success rates of MEP recording did not significantly change during the administration of xenon. At large dose, the success rate of MEP recording in the isoflurane group was significantly less than that in the xenon group (P < 0.05).
The changes in MEP amplitudes in response to train pulse stimulation are shown in Figure 1b. There were no significant differences in MEP amplitudes at baseline and Re0 among the three groups. At small doses, MEP amplitudes in the xenon group were significantly higher than those in the isoflurane group and there were no significant differences in MEP amplitudes between the propofol and xenon groups. At large doses, MEP amplitudes in the xenon group were significantly lower than those in the propofol group and were significantly higher than those in the isoflurane group (P < 0.05). Representative MEPs in response to train pulse stimulation are shown in Figure 2.
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Figure 2. Representative motor evoked potentials (MEPs) in response to a train of five pulses stimulation. In the propofol group, a bolus of propofol 2 mg/kg was administered followed by a continuous infusion of propofol at a rate of 0.4 mg · kg–1 · min–1 (small) and 0.8 mg · kg–1 · min–1 (large). In the isoflurane group, isoflurane was administered at the end-tidal concentrations of 0.8% (small) and 1.6% (large). In the xenon group, xenon was administered at the end-tidal concentrations of 35% (small) and 70% (large). Note that MEP recording was feasible under 70% xenon (large) as long as a train of pulses are used for the stimulation of motor cortex.
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With train pulse stimulation, MEP latencies in the isoflurane group were significantly longer than those in the other two groups and those at baseline, and MEP latencies at large dose in the xenon group were longer than those at baseline (Table 3; P < 0.05).
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Discussion
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The results of the present study show that xenon, propofol, and isoflurane reduced MEP amplitudes in a dose-dependent manner. When single-pulse stimulation was applied, a reduction in MEP amplitudes by xenon was more prominent than propofol, but less than isoflurane. When train pulse stimulation was applied, MEP amplitudes were increased in all anesthetic statuses. At small dose, a reduction in MEP amplitudes was similar between xenon and propofol. At large dose, a reduction in MEP amplitude by xenon was more prominent than propofol, but myogenic MEPs could be recorded in 90% of animals receiving xenon. These results suggest that MEP recording may be feasible under xenon anesthesia if multipulse stimulation is used, although xenon has suppressive effects on myogenic MEPs.
Propofol and isoflurane have been shown to suppress myogenic MEPs after single and train pulse stimulation (1). However, if multipulse stimulation is applied, myogenic MEPs could be recorded under clinical doses of propofol. Propofol-based anesthesia is therefore considered to be the standard anesthetic regimen for intraoperative monitoring of myogenic MEPs. In a rabbit model, Sakamoto et al. (18) investigated the effects of propofol at a dosage of 0.8 mg · kg–1 · min–1 on myogenic MEPs and demonstrated that, although MEP amplitudes in response to single-pulse stimulation were significantly reduced during propofol administration, MEP amplitudes in response to train pulse stimulation did not decrease significantly. In contrast, because the suppressive effects of isoflurane on myogenic MEPs are more marked compared with propofol, the use of isoflurane during monitoring of myogenic MEPs has been avoided. In a rat model, Kawaguchi et al. (2) demonstrated that MEP amplitudes after single and train pulse stimulation were significantly reduced to approximately 0.9% and 7% of control, respectively, at 0.5 MAC. Clinically, Ubags et al. (3) demonstrated that, although isoflurane significantly suppressed myogenic MEPs after multipulse stimulation, its monitoring was feasible in the presence of up to 0.6% isoflurane in patients anesthetized with nitrous oxide and sufentanil. These findings are consistent with the results obtained in the present study, in which reliable MEPs could be recorded after train pulse stimulation at small and large doses of propofol and at small doses (0.4 MAC), but not at large doses (0.8 MAC), of isoflurane.
The results of the present study indicate that the suppressive effects of xenon on myogenic MEPs seem to be between those of propofol and isoflurane. Even at 0.8 MAC of xenon, MEPs could be recorded in 90% of animals. This is the first report to investigate the effects of xenon on myogenic MEPs. However, there have been a few reports on the effects of xenon on somatosensory evoked potentials (SEPs) (19,20). Utsumi et al. (19) investigated the effects of 70% xenon on SEPs in cats and reported that xenon suppressed the amplitudes of SEPs more than nitrous oxide. Lorenz et al. (20) also investigated the effects of 33% xenon/oxygen mixture on SEPs in 8 patients and demonstrated that 33% xenon decreased the amplitude of SEPs and there were no significant changes in the latencies of SEPs during xenon administration. They suggested that the xenon effect of SEPs rather resembles alterations caused by volatile anesthetics than by IV anesthetics. Propofol has less influence on SEPs compared with inhaled anesthetics (21). These results on SEPs are consistent with the results in the present study, in which the suppressive effects of xenon on myogenic MEPs were more prominent than propofol. However, as long as small dose xenon is used as a supplement, its influence on myogenic MEPs seems to be modest if multipulse is used for stimulation.
There are several limitations of the study that merit comment. First, although we compared the same levels of isoflurane and xenon (0.4 MAC and 0.8 MAC), it is not known whether the doses of propofol used in our study are equivalent to those of isoflurane and xenon. Based on data from previous studies, we chose the dose of propofol that seemed to be similar to anesthetic levels in the isoflurane and xenon groups. Although it is difficult to compare the depth of anesthesia between volatile and IV anesthetics, it might be better to use monitors for the assessment of anesthetic depth. Second, there is a possibility that background anesthetics might have affected our 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. In addition, the influence of an accumulation of ketamine and fentanyl seemed to be little because the amplitude of MEPs at Re0 was the same as that at baseline in the present study. Finally, it is unknown whether the propofol concentration was kept constant during the experimental period because we did not measure propofol concentrations. Ma et al. (22) measured the blood concentration of propofol when propofol was infused at 0.8 mg · kg–1 · min–1 in rabbits and demonstrated that the blood concentration remained constant from 15 minutes after starting the infusion until the withdrawal of propofol at 105 minutes. In our study, MEP recording began 30 minutes after the propofol infusion and was completed within 90 minutes. Therefore, we believe that the alterations of propofol concentration seem to be modest.
In summary, we investigated the effects of xenon on myogenic MEPs in rabbits under ketamine and fentanyl anesthesia. The results indicated that the suppressive effects of xenon on myogenic MEPs were more prominent than those of propofol but less than those of isoflurane. However, when multipulse is used for stimulation, myogenic MEPs can be recorded even under 0.8 MAC of xenon. Although further investigations of the neuroprotective efficacy of xenon are required, the use of xenon at a small dose as a supplement or in combination with other anesthetics can be one alternative during the monitoring of myogenic MEPs during operations in which there is a risk of intraoperative spinal cord injury.
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Footnotes
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Accepted for publication January 19, 2006.
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Abstract
Introduction
