Electroencephalography and clinical Neurophysiology, 84 (1992) 180-187 0 1992 Elsevier Scientific Publishers Ireland, Ltd. 0168-5597/92/$05.00

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EVOPOT 90243

A comparative analysis of enflurane anesthesia on primate motor and somatosensory evoked potentials James L. Stone a, Ramsis F. Ghaly a,b,Walter J. Levy ‘, Radha Kartha b, Lisa Krinsky b and Peter Roccaforte a Departments of a Neurological Surgery and b Anesthesiology, Cook County and University of Illinois Hospitals, and Hektoen Institute for Medical Research, Chicago, IL 60612 (U.S.A.), and ’ Department of Neurological Surgery, Cleveland Clinic Florida, Fort Lauderdale, FL (U.S.A.)

(Accepted for publication: 6 September 1991)

The effect of increasing enflurane concentration on magnetic-induced myogenic cranial (0) and peripheral (Pr) motor evoked Summary potentials (MEPs), and electrically induced median (MN) and posterior tibia1 (PTN) somatosensory evoked potentials (SEPs) was studied in 10 monkeys. MEP, recorded from abductor pollicis brevis and abductor hallucis muscles, and SEP (short- and long-latency scalp recorded potentials) variables were examined at 0.25, 0.5, 0.75, 1.0 MAC enflurane concentrations. Cr-MEPs progressively attenuated (P < 0.01) with 0.25 MAC and were abolished (2 0.75 MAC) by graded enflurane concentration. Stimulation threshold for Cr-MEP was progressively elevated (P < O.Ol), and eventually reliable responses were lost ( 2 0.75 MAC). Marked scalp zone reduction to obtain Cr-MEP responses was noted with increasing enflurane concentration. Pr-MEPs and most SEP peaks maintained good replicability but showed significant amplitude reduction (P < 0.01). MEP and SEP latency values were not significantly delayed as long as the wave form remained identifiable. We conclude that enflurane has a differential influence on Cr-MEPs and SEPs. Administration of enflurane should be discouraged while monitoring myogenic Cr-MEPs since even a subanesthetic concentration is profoundly detrimental. Key words: Enflurane; Motor evoked potentials; Somatosensory evoked potentials; Transcranial magnetic stimulation; (Monkeys)

Since successful introduction of non-invasive transcranial motor stimulation (electrical by Merton and Morton 1980 and magnetic by Barker and Jalinous 1985) to assess motor functional integrity in awake subjects, the intraoperative extension of this technique to anesthetized patients has been hampered by the influence of anesthetics (Tung et al. 1988; Schonle et al. 1989; Zenter 1989). Recently, the technique of transcranial magnetic stimulation (TMS) has shown considerable promise towards clinical application (Cohen and Hallett 1988; Levy 1988; Maccabee et al. 1988; Cracco et al. 1989; Schriefer et al. 1989; Chokroverty et al. 1989; Zenter 1989; Dvorak et al. 1990; Pascual-Leone et al. 1991). The potential use of TMS in the operating room may expand from not only monitoring of descending motor pathways but also to non-invasive mapping of functional brain areas (Cohen and Hallett 1988; Katayama et al. 1988; Cracco et al. 1989; Pascual-Leone et al. 1991). The latter testing has

Correspondence to: Drl James L. Stone, Department of Neurosurgery, Cook County Hospital, 1835 W. Harrison Street, Chicago, IL 60612 (U.S.A.). Tel.: (312) 633-6328; Fax: (312) 633-8410.

been made possible in awake subjects by the development of magnetic coils capable of inducing more focal stimulation (figure-of-8 or butterfly coil) (Cohen and Hallett 1988; Cracco et al. 1989; Epstein et al. 1991). Further refinement of TMS equipment is currently underway. Both MEP and somatosensory (SEP) recordings complement each other in reflecting the descending and ascending nervous pathways; respectively (Grundy 1983; Fehlings et al. 1988; Levy 1988). Unlike MEPs, SEPs can usually be reliably recorded under acceptable anesthetic levels (Grundy 1983). The following experiment was conducted in monkeys to test the effect of the general anesthetic, enflurane on MEPs and SEPs. Forelimb and hind limb MEPs, and median and posterior tibia1 nerve SEPs (short- and long-latency potentials) were studied as a function of end-tidal enflurane concentration. Enflurane, isoflurane, and halothane are the 3 potent, florinated volatile agents commonly used in clinical practice (Koblin 1990). The anesthetic concentration delivered to the brain can indirectly be estimated by measuring the end-tidal concentration after equilibration (Koblin 1990). The MAC value is the minimum alveolar concentration of an inhaled anesthetic at 1 atmosphere, which prevents skeletal

ENFLURANE EFFECTS ON MEPs AND SEPs

muscle movement in response to a noxious stimulus (e.g., surgical skin incision) in 50% of subjects (Koblin 1990).

Methods and materials

Ten normal adult monkeys (Macaca fuscata) weighing 5-8.5 kg were entered in the study. Following an anesthetic dose of 15-20 mg/kg methohexitone i.m., the trachea was orally intubated using an endotracheal tube with a monitoring lumen (Mallinckrodt, Glens Falls, NY) to allow sampling of alveolar gas for analysis. Both lungs were ventilated (Siemens-Elema Servo Ventilator 900-D, Schaumburg, IL, U.S.A.) with FIO 2 (fraction of inspired oxygen) 0.5. A peripheral intravenous catheter was inserted and lactated Ringer's solution administered at a rate of 15-20 m l / k g / h . Electrocardiogram, rectal and peripheral limb temperature (Mallinckrodt, Mon-A-Therm Inc., St Louis, MO, U.S.A.), arterial oxygen saturation (Ohmeda Biox 3700 Pulse Oximeter, Boulder, CO, U.S.A.), and end-tidal CO 2 and gas concentrations (Datex Capnomac, Tewksbury, MA, U.S.A.) were continuously monitored. Arterial blood pressure (automatic Dianamp, Critikon, Tampa, FL) was recorded every 3 min. Respiratory parameters were adjusted to maintain the end-tidal CO 2 at 35-40 mm Hg. Oxygen saturation was maintained > 98%. A heating lamp was applied to maintain core and peripheral body temperature 36.5-37.5°C. Mean arterial blood pressure was maintained > 55 mm Hg (a bolus of crystalloid infusion was given if needed).

MEP recording MEP monitoring was carried out by using the Novametrix Mag-Stim 200 coil (Wallingford, CT) producing maximum output of 1.5 Tesla (100%). The TMSMEP methodology used in this study was repeated from previous experiments in our laboratory (Ghaly et al. 1990a,b,c). Pulsed (110 /zsec duration) magnetic fields were delivered, by the circular magnetic coil with clockwise current direction, to the scalp and lower cervical and lumbosacral spine posteriorly to produce cranial (Cr-) and peripheral (Pr-) MEPs, respectively. For Cr-MEPs, the standard coil was placed tangentially, lightly touching the left MEP scalp zone as described previously (Ghaly et al. 1990a,b). The coil center was used as a reference point. Our previous studies demonstrated that reproducible forelimb and hind limb MEPs could be obtained when the coil was centered over Cz (center vertex). Contralateral highly reproducible MEPs were also obtained if the coil was moved over the scalp in an area extending approximately 2 cm lateral and 4 cm posterior to Cz (MEP scalp zone). For upper extremity Pr-MEPs, the coil was

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centered over the C7 spinous process, and for lower extremity stimulation over the lumbosacral spinous processes at the level of an imaginary line connecting the superior border of both iliac crests. Evoked compound muscle action potentials were recorded from right abductor pollicis brevis (APB) and abductor hallucis brevis (AHB) muscles. Subdermal platinum electrodes (Grass Medical Instruments, Quincy, MA) were inserted subcutaneously over the muscle belly (active electrode) and distally along the tendon (reference electrode). MEPs were recorded, stored and printed using a Nicolet Pathfinder II unit (Nicolet Biomedical, Madison, WI, U.S.A.). Filter settings were 150 Hz-8 kHz and sweep time was 40 msec. MEP responses were displayed with negativity reflected by an upward deflection (Figs. 1 and 2). Stimulation thresholds for cranial and peripheral APB and AHB excitation were determined by applying 0.15 Tesla increments until a recordable response was obtained. A triplicate of Cr- and Pr-MEPs were taken in response to 1.5 Tesla magnetic intensity. The best response, regarding superior wave form amplitude and clarification, was selected in the present study. Peak latency (msec) was measured from stimulus onset to the peak of the prominent negativity. The amplitude (mV) response was determined as the voltage difference between the prominent negative peak and the following positive peak. We have found in our laboratory that measurement of peak latency, peak-to-peak amplitude, and stimulation threshold provided a reliable and reproducible way to assess the response changes induced by deepening anesthetic agents. About 0.3 to 0.6-0.7 Tesla was sufficient to evoke a response. MEP wave forms occurred with peak latency 8.2 _+ 1.3 and 14.2 + 0.9 msec and 9.0 + 0.8 and 21.3 _+ 1.0 msec post stimulus (1.5 Tesla) for Pr- and Cr-APB and AHB. A stimulus of 1.5 Tesla elicited a large potential: 7.2 + 5.3 and 6.6 _+4.1 mV for Pr- and CrAPB and 12.0+7.2 and 6.5+3.6 mV for Pr- and Cr-AHB, respectively. In contrast to lumbosacral magnetic stimulation, cervical stimulation was technically difficult in eliciting reproducible Pr-APB in the smaller animals.

SEP recording SEP monitoring was obtained in response to electrical stimulation of left median nerve (MN) at the wrist and posterior tibial nerve (PTN) at the ankle via bipolar Grass subdermal electrodes. The anode was placed on the ventral surface of the forearm 1 cm above the wrist for MN stimulation and on the medial surface of the ankle behind the medial malleolus for PTN stimulation. The cathode was located 2 cm proximal to the anode. The stimulating current was 5.7/sec constantcurrent square pulses of 200 /.~sec duration. The current intensity used was 2-fold that required to elicit

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visible digit twitch which was increased to 3-fold under enflurane. The scalp generated subcortical and cortical MNand PTN-SEPs were recorded with subdermal Grass electrodes. For MN SEPs, the active electrode was placed subcutaneously over the monkey's parietal somatosensory hand area contralateral to the stimulated nerve (approximately C4'). For PTN SEPs, the electrode was placed at the midline (Cz' just behind central vertex). The reference electrode was placed at the midline forehead. The ground electrode was placed subcutaneously over the contralateral shoulder. Electrode impedance was maintained < 9 kO. Bandpass was 30-3000 Hz and sensitivity was 50 /xV. The SEP averages (600 stimuli) were obtained in duplicate, stored on floppy disk, and plotted on paper using a Nicolet Pathfinder II averager (Nicolet Biomedical, Madison, WI). Artifactual signals were automatically rejected by the computer. Negativity (N) was reflected by an upward deflection (Fig. 5). The first 4 negative SEP peaks analyzed were numbered sequentially N~ (4.6 + 0.4 and 9.0 + 0.3 msec for MN and PTN), N 2 (8.1 + 0.4 and 12.3 + 0.3 msec), N 3 (18.7 + 2.1 and 22.7 + 2.1 msec), N 4 (45.3 + 1.1 and 49.5 + 2.1 msec) (Fig. 5). N t , N 2, N 3, and N 4 presumably indicate subcortical and early, middle and late cortical generated potentials, respectively (Arezzo et al. 1979, 1981; Allison and Hume 1981). SEP peak latency (msec) was measured from stimulus onset to each negative peak. The amplitude (/~V) was measured as the voltage difference between the negative peak and immediately following positive peak (Fig. 5). Baseline MN- and PTN-SEP amplitude values were 2.5 + 1.4 and 1.1 + 0.6 /~V, 7.1 + 4.6 and 4.4 + 2.2 /zV, 10.6 + 7.3 and 6.4 + 3.4 ~V, and 2.0+ 1.5 and 1.7+ 0.8 /zV for N]/P1, N2/P 2, N3/P3, and N4/P 4, respectively (Figs. 5 and 6). A minimum of 45 min elapsed before obtaining baseline values. With the animal still under residual ketamine effect, baseline MEP and SEP tracings were taken. MEPs were recorded when there were no visible extremity movements. Each animal was then allowed to inhale 0.25 (0.48 vol%), 0.5, 0.75, and 1.0 end-tidal MAC enflurane (Tinker et al. 1977). Each alveolar concentration was held constant for at least 15 min before stimulation. Samples of end-tidal gas were drawn from a commercially available side catheter passed down the endotracheal tube. Fifteen to 25 min were required for complete data acquisition. Complete MEP and SEP recordings were obtained at each concentration. MEP recordings were obtained before SEPs. All data were stored on floppy disk and printed on paper. Data are presented as means + 1 S.D. One-way analysis of variance (ANOVA) with repeated measures was used to study MEP and SEP variables as a function of increasing enflurane concentrations. Statistical significance was considered for P values < 0.05. If

J.L. STONE ET AL.

ANOVA demonstrated significance, a Tukey's HSD post-hoc test was performed to determine differential values.

Results

The physiological parameters were well controlled throughout the experiment. Well-defined MEP and SEP wave forms were obtained prior to enflurane inhalation in all animals (Figs. 1-3). TMS to evoke Cr-MEPs averaged 62.0-t-11.8 TMS repetitions. Peripheral stimulation to evoke Pr-MEPs averaged 43 + 4.5 repetitions. Various MEP and SEP variables (mean + 1 S.D.) are presented graphically in Figs. 4-8. SEP and Pr-MEP wave forms were obtained with good replicability at baseline and following increments of enflurane (Figs. 1 and 3). However Cr-MEPs manifested dramatic attenuation by 0.25-0.5 MAC which were progressively lost by > 0.5 MAC (Fig. 2). Consequently, statistical analysis for Cr-MEP data was only possible for enflurane concentrations < 0.5 MAC. Discontinuation of enflurane and ventilation with 100% 0 2 resulted in reappearance of Cr-MEPs in 6.4 + 4.0 min (Fig. 2). Due to lack of animal cooperation, it was impractical to examine the SEP-MEP response changes over time in the awake state. Pr-MEPs Following peripheral stimulation, replicable APB and AHB responses were recorded under various enMEPs

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flurane concentrations (Fig. 1). Visible contractions of the target muscles were always seen in response to magnetic stimulation. However, evoking Pr-AHB was technically easier than Pr-APB. Enflurane produced slight response alterations observed with inconsistent significance (Figs. 4-6). Incremental enflurane doses caused mean APB amplitude depression between 35% and 58%, while AHB amplitude diminished from 43% to 59% (P < 0.05) compared to control values (Fig. 4). Mean threshold elevation for APB and AHB responses ranged from 19% to 63% (P < 0.05) and from 14% to 36% of the pre-enflurane values (Fig. 5). No significant latency change was noted (Fig. 6). Cr-MEPs

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