Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan*Corresponding author
Accepted for publication: 14 September, 2000
Abstract
The effect of nitrous oxide on myogenic motor evoked potentials (MEPs) after multipulse stimulation is controversial. We investigated the effects of propofol in this paradigm. MEPs were elicited electrically by a single pulse and by trains of three and five pulses in rabbits anaesthetized with ketamine and fentanyl. Nitrous oxide 3070% was given and MEPs were recorded. After washout of nitrous oxide, propofol was given as a bolus of 10 mg kg1 followed by 0.8 (n=9) or 1.6 mg kg1 min1 (n=8) as a continuous infusion. Nitrous oxide was then readministered and MEPs were recorded. Without propofol, nitrous oxide significantly reduced the amplitude of MEPs dose-dependently, but this effect was reversed by multipulse stimulation. Administration of low-dose propofol enhanced nitrous oxide-induced suppression, and this effect was reversed by five-pulse stimulation. However, high-dose propofol produced a greater increase in suppression, such that even five-pulse stimulation did not overcome the suppression. The results suggest that the degree of reversal of nitrous oxide-induced MEP suppression produced by multipulse stimulation is affected by the administration of propofol.
Br J Anaesth 2001; 86: 395402
Keywords: anaesthetics i.v., propofol; anaesthetics, gases, nitrous oxide; monitoring; spinal cord
Intraoperative monitoring of myogenic motor evoked potentials (MEPs) in response to transcranial 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.13 However, the clinical and experimental use of these techniques with a single pulse as the stimulus has shown that the potentials elicited are very sensitive to suppression by most anaesthetic agents.47 Recently, to overcome anaesthetic-induced depression of myogenic MEPs, multiple-stimulus setups with paired or a train of pulses for stimulation of the motor cortex have been proposed.813 The advent of multipulse stimulation for intraoperative monitoring of myogenic MEPs may allow a wider choice and dose range of anaesthetic agents.
Nitrous oxide has been used commonly during MEP monitoring as a supplementary anaesthetic,2 3 6 8 1214 although a number of investigators have shown that it suppresses MEPs elicited by single-pulse stimulation.1518 However, the effect of nitrous oxide on myogenic MEPs in response to stimulation with paired pulses or a train of pulses is still controversial.1921 One report demonstrated that 50% nitrous oxide did not affect the amplitude of MEPs under fentanyl/low-dose propofol anaesthesia when paired-pulse stimulation was applied.19 By contrast, other reports have shown that, even with a train of six pulses, increasing the concentration of nitrous oxide to 60% resulted in reduced MEP amplitude.21 These controversial results suggest that the reversing effect of multipulse stimulation on nitrous oxide-induced suppression of MEPs may be overcome by adding more anaesthetic in the form of propofol. However, there has been no report confirming this hypothesis, probably because many permutations of nitrous oxide concentration, propofol infusion rate and stimulus train size would make this difficult to study in surgical patients.
The present study was conducted to investigate the effects of nitrous oxide on myogenic MEPs when multipulse stimulation was applied in rabbits under ketamine/fentanyl anaesthesia, which produces minimal depression of MEP.4 14 21 Furthermore, we infused propofol at two rates (low- and high-dose regimens) with nitrous oxide to elucidate the above controversy about the reversing effect of multipulse stimulation on nitrous oxide-induced MEP suppression.
Materials and methods
The study was approved by the Animal Experiment Committee of Nara Medical University. Seventeen male New Zealand White rabbits weighing 2.02.5 kg (mean 2.3 kg) were used. They were housed and maintained on a 12 h lightdark cycle with free access to food and water.
Each rabbit was given ketamine 50 mg kg1 i.m. and a 24-gauge catheter was placed in the right marginal ear vein. Thereafter, continuous infusion of ketamine 25 mg kg1 h1 and fentanyl 30 µg kg1 h1 in lactated Ringer solution was initiated at the rate of 4 ml kg1 h1. Another 24-gauge catheter was inserted in the left ear vein for the administration of propofol. The trachea was intubated via a tracheostomy and the lungs were ventilated mechanically to maintain end-tidal carbon dioxide at 3035 mm Hg. End-tidal concentrations of carbon dioxide and nitrous oxide were monitored continuously with a gas analyser (Hewlett Packard, Andover, MA, USA). The left femoral artery was exposed and cannulated to monitor arterial blood pressure and for blood gas analysis. Blood gases, pH and haematocrit were measured periodically with a blood gas analyser (GEM Premier; Mallinckrodt, Ann Arbor, MI, USA). Oesophageal temperature was monitored continuously with a thermometer (Mon-a-Therm, Mallinckrodt, St Louis, MO, USA) and maintained at 40°C with a warm blanket.
The animals were placed 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 to the lamboid suture on the left hemisphere was chosen as the anodal stimulating site.22 A point 0.5 mm to the right of the sagittal suture at the level of the lamboid suture was used for the cathode. Silver ball electrodes (1 mm in diameter) were placed epidurally via holes, in which mineral oil was placed. Two standard recording needle electrodes were inserted in the left soleus muscle. A ground electrode was placed 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 increased gradually until MEP amplitude no longer increased. The recording device (Neuropack Sigma, Nihon Kohden) was triggered by the stimulating device. Low- and high-cutoff filters were set at 30 Hz and 3 kHz respectively. Peak-to-peak amplitude was determined from the average of three to five individual responses. After the MEPs in response to a single-pulse stimulation had been recorded, a train of three or five pulses was applied. The duration of each pulse was 200 µs. The interstimulus interval of each pulse was set at 2 ms. The interval between each stimulation was set at 30 s.
After control MEPs had been recorded, nitrous oxide was administered at a concentration of 30, 50 or 70%. The order of concentrations was randomized to eliminate time-course bias. At least 10 min was allowed to elapse between each targeted concentration, and the end-tidal concentration of nitrous oxide was confirmed with a gas analyser. At each concentration of nitrous oxide, MEPs in response to a single pulse and a train of three or five pulses were recorded. After completion of all recordings at the three concentrations of nitrous oxide, administration of nitrous oxide was discontinued. MEPs were again recorded when the end-tidal concentration of nitrous oxide was 0%, as assessed by the gas analyser.
After the complete elimination of nitrous oxide, all animals were allocated randomly to one of two groups. In one group (Propofol 0.8, n=9), a bolus of propofol 10 mg kg1 was administered, followed by a continuous infusion of propofol at 0.8 mg kg1 min1. In the other group (Propofol 1.6, n=8), a bolus of propofol 10 mg kg1 was followed by a continuous infusion of propofol at 1.6 mg kg1 min1. Thirty minutes after administration of the bolus of propofol, nitrous oxide was administered at 30, 50 or 70% and MEPs were recorded in the same fashion as described above. During administration of propofol, a continuous infusion of phenylephrine was given if arterial blood pressure decreased by more than 10% of control. At the end of the study, the animals were killed with an injection of potassium chloride, which caused cardiac arrest.
Statistical analysis
All values are expressed as mean (SEM). Parametric methods were used for the analysis of all variables, as a normal distribution was confirmed with the KolmogorovSmirnov test. For comparisons of physiological variables and MEP amplitudes between the two experimental groups, we used two-way analysis of variance with repeated measures followed by Fishers protected least significant difference test for multiple comparisons. To compare values within groups, we used multiple analysis of variance with repeated measures followed by Fishers protected least significant difference test for multiple comparisons. Differences were considered significant when P<0.05.
Results
Physiological variables are shown in Tables 1 and 2. There were no significant differences between the two experimental groups in mean arterial pressure (MAP), heart rate, oesophageal temperature, pH, PaCO2 and PaO2 before the administration of propofol. With the exception of heart rate, all variables were similar in the two groups during the administration of propofol. Heart rate was significantly reduced during the administration of propofol 1.6 mg kg1 min1 (P<0.01). MAP, heart rate and oesophageal temperature did not change significantly before, during or after the administration of nitrous oxide. Phenylephrine was used in all animals in both groups during propofol infusion; the doses were approximately 0.050.7 (mean 0.33) mg h1 for the Propofol 0.8 group and 0.11.5 (mean 0.6) mg h1 for the Propofol 1.6 group.
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During the administration of propofol 1.6 mg kg1 min1, MEPs could be recorded in only three of eight animals after single-pulse stimulation. By contrast, MEPs could be recorded in all animals after stimulation with a train of three or five pulses, and MEP amplitudes were significantly higher than after single-pulse stimulation (P<0.01). The amplitudes of MEPs after stimulation with a single pulse or a train of three or five pulses were significantly reduced during propofol administration (P<0.01).
For later analysis of the effects of nitrous oxide and number of pulses, data on MEPs before the administration of propofol in both groups were pooled as group Propofol().
Effects of nitrous oxide on MEPs
Propofol()
Without administration of propofol, the amplitudes of MEPs in response to stimulation with a single pulse or a train of three pulses were significantly reduced after the administration of 50% (P<0.01) or 70% (P<0.01) nitrous oxide and after 70% (P<0.05) nitrous oxide, respectively (Fig. 2). By contrast, the amplitudes of MEPs induced by a stimulation with a train of five pulses did not change significantly during the administration of nitrous oxide (Fig. 3). The amplitudes of MEPs in response to a stimulation with a train of three pulses during 70% nitrous oxide and a train of five pulses during administration of 30, 50 or 70% nitrous oxide were significantly higher than those after single-pulse stimulation.
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Propofol 1.6
During the administration of propofol 1.6 mg kg1 min1, MEPs in response to a single pulse could be recorded only in the absence of nitrous oxide. MEPs in response to stimulation with a train of three pulses could be recorded in eight, five and four of eight animals during the administration of 30, 50 and 70% nitrous oxide respectively. MEPs could be recorded in all animals in response to stimulation with a train of five pulses. During the administration of nitrous oxide, the amplitudes of MEPs in response to stimulation with a train of three or five pulses were significantly reduced in a dose-dependent manner (Figs 2 and 4). The amplitudes of MEPs in response to stimulation with a train of three pulses during 30 or 50% nitrous oxide or with a train of five pulses during the administration of nitrous oxide were significantly higher than those after single-pulse stimulation.
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Results obtained in the present study show that nitrous oxide dose-dependently reduced the amplitudes of MEPs in response to single-pulse stimulation in rabbits anaesthetized with ketamine and fentanyl, and that this effect was reversed by the application of a train of pulses. After the administration of propofol 0.8 mg kg1 min1, significant nitrous oxide-induced suppression was observed in the amplitudes of MEPs in response to stimulation with a single pulse or a train of three pulses, but not with a train of five pulses. However, after the administration of propofol 1.6 mg kg1 min1, significant nitrous oxide-induced suppression was noted even after a train of five pulses. These results suggest that the reversing effect of multipulse stimulation on nitrous oxide-induced suppression of MEPs was overcome by high-dose administration of propofol.
In previous work that investigated the effects of nitrous oxide on myogenic MEPs,1518 the dose-dependence of the suppressive effect of nitrous oxide on MEPs in response to single-pulse stimulation has often been demonstrated,1518 regardless of differences in combined anaesthetic regimens. These reports are compatible with the present results, which were obtained with ketamine/fentanyl anaesthesia. However, there have been few reports on the effect of nitrous oxide on myogenic MEPs when paired pulses or a train of pulses were used for stimulation, and the results are controversial.1921 Van Dongen et al.19 compared MEPs in response to a six-pulse train of transcranial electrical stimuli when 20, 40 or 60% nitrous oxide was given in 10 patients anaesthetized with fentanyl and low-dose propofol. Compared with 20% nitrous oxide, 40 or 60% nitrous oxide significantly reduced MEP amplitude. Pechstein et al.20 also reported that 60% nitrous oxide significantly reduced the amplitude of MEPs induced by transcranial stimulation with a train of five pulses in four patients anaesthetized with alfentanil and propofol. By contrast, in another report by van Dongen et al., 21 it was noted that 50% nitrous oxide did not affect the amplitude of MEPs induced by transcranial electrical stimulation with paired pulses during fentanyl and low-dose propofol anaesthesia in 10 patients. The reasons for the different results are unknown. However, it is possible that co-administration of propofol with nitrous oxide affected the results.
In the present study, the degree of reversal of the effect of nitrous oxide-induced suppression of multipulse stimulation was affected by propofol. In the absence of propofol, nitrous oxide-induced suppression could be reversed after the application of a train of five pulses. A similar tendency was also observed during the administration of propofol at 0.8 mg kg1 min1 (low dose). However, when the propofol infusion rate was increased to 1.6 mg kg1 min1 (high dose), even a train of five pulses was unable to reverse the nitrous oxide-induced suppression of MEPs. These findings may be important for the determination of the optimal combination of anaesthetics during intraoperative MEP monitoring. Our data in a rabbit model suggest that, when nitrous oxide is used as a supplement, high-dose propofol is probably better avoided. In contrast, when multipulse stimulation is used the effect of nitrous oxide on MEPs may be minimal during low-dose administration of propofol in the rabbit MEP model.
For ethical reasons, a baseline anaesthetic was necessary. We selected ketamine and fentanyl because both drugs have minimal effects on MEPs,4 13 14 23 24 although Thees et al. 25 have recently reported a dose-dependent suppressive effect of fentanyl. However, the dosage of fentanyl used in the present experiment was much lower than that used in their study. Moreover, there was evidence that, with this regimen, multipulse stimulus resulted in maximal MEP amplitudes, suggesting near-maximal recruitment of cortical and spinal motor neurones.
Our propofol regimen comprised a bolus of 10 mg kg1 followed by continuous infusion at 0.8 or 1.6 mg kg1 min1. These doses were selected on the basis of the results of a preliminary study that we made (unpublished), in which the basic procedure was identical to that used in the present study. Infusion rates after a bolus of propofol 10 mg kg1 were doubled from 0.1 to 3.2 mg kg1 min1 in a step-wise manner. Amplitudes of MEPs in response to single-pulse stimulation were recorded 30 min after each step. On the basis of the results obtained, in the present study we chose 0.8 mg kg1 min1 as the low-dose regimen, which resulted in a mild reduction in MEP amplitude, and 1.6 mg kg1 min1 as the high-dose regimen, which produced a severe reduction in MEP amplitude. These doses were similar to those used in a previous study in which a mean propofol infusion rate of 0.876 mg kg1 min1 produced a light plane of anaesthesia in which the palpebral reflex, the reaction to ear pinching, and the front and hind limb withdrawal reflexes were abolished in rabbits.26
Ma et al. 27 measured the blood concentration of propofol when propofol was infused at 0.8 mg kg1 min1 in rabbits. They demonstrated that the blood concentration remained constant from 15 min after starting the infusion until the withdrawal of propofol at 105 min. In our study, MEP recording began 30 min after the propofol infusion and was completed within 120 min. Therefore, we believe that blood concentration was constant during the administration of propofol 0.8 mg kg1 min1. By contrast, regarding propofol 1.6 mg kg1 min1, we cannot exclude the possibility that the variation in blood propofol concentration observed during the administration of propofol 1.6 mg kg1 min1 affected the results obtained in the present study. In order to avoid time-course bias, the order of administration of the different nitrous oxide concentrations was randomized. Moreover, we measured MEP amplitudes again after nitrous oxide had been discontinued, and did not find any differences between the values obtained before and after the administration of nitrous oxide. Therefore, we believe that the influence of variation in propofol concentration on MEPs was minimal.
In summary, we have investigated the influence of stimulation paradigm and the administration of propofol on the nitrous oxide-induced suppression of myogenic MEPs in rabbits anaesthetized with ketamine and fentanyl. We have demonstrated that the application of a train of five pulses reverses nitrous oxide-induced suppression of MEPs in the absence of propofol infusion and during the administration of low- but not high-dose propofol. These results suggest that nitrous oxide-induced suppression of MEPs can be modified by the use of multipulse stimulation and the administration of propofol. Further clinical investigations are required to determine optimal anaesthetic regimens for intraoperative MEP monitoring.
Acknowledgements
The authors thank Professor Shuji Dohi and Dr Hiroki Iida, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, and Dr Katsuyasu Kitaguchi, Department of Anesthesiology, Nara Medical University, for help in preparing the experimental protocol. The authors also thank Dr Masahiro Takahashi for technical support. This work was supported by Grants in Aid for Scientific Research (10671439 and 11470326) from the Ministry of Education, Science and Culture of Japan.
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