Anesth Analg 2003;97:1784-1788
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Propofol Suppresses the Cortical Somatosensory Evoked Potential in Rats
Helene G. Logginidou, MD,
Bai-Han Li, MD,
De-Pei Li, MD,
Jeffrey S. Lohmann, MS CCC-A,
H. Gregg Schuler, BA,
Nicole A. DiVittore, BS,
Sarah Kreiser, BS, and
Arthur J. Cronin, MD
Department of Anesthesiology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center
Address correspondence and reprint requests to Arthur J. Cronin, MD, 500 University Dr., H187, Hershey, PA 17033. Address e-mail to acronin{at}psu.edu
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Abstract
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The dose-response curve for the effect of volatile anesthetics on the somatosensory evoked potential (SEP) is well described, but for propofol, the large dose segment of the curve is undefined. We describe the effect of increasing plasma concentrations of propofol on cortical SEPs in 18 rats. After surgical preparation under ketamine anesthesia, a remifentanil infusion was begun at 2.5, 5, or 10 µg · kg-1 · min-1. After 20 min, the propofol infusion was initiated at 20 mg · kg-1 · h-1 and was increased to 40, 60, and 80 mg · kg-1 · h-1 at 20-min intervals. SEP was recorded before remifentanil infusion, before propofol infusion rate changes, and 30 min after discontinuing propofol infusion. In six additional rats, the plasma concentrations of propofol after each 20-min infusion were measured using gas chromatography. Remifentanil did not have a significant effect, but propofol significantly depressed the SEP amplitude and prolonged the latency at infusion rates of 40 mg · kg-1 · h-1 and more. Propofol’s effect was dose-dependent, but even at 80 mg · kg-1 · h-1 with an estimated plasma concentration of 31.6 ± 3.4 µg/mL (10.8 50% effective concentration), a measurable response was present in 44.5% of rats. These results suggest that even at large doses, propofol and remifentanil provide adequate conditions for SEP monitoring.
IMPLICATIONS: Rats demonstrate dose-dependent somatosensory evoked potential (SEP) suppression with propofol but not with remifentanil. However, SEP suppression by 50% occurred only at large (1.5 EC50) concentrations of propofol, and a measurable SEP was present in 8 of 18 rats, even at 10.8 EC50.
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Introduction
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In many medical centers, somatosensory evoked potential (SEP) monitoring has replaced the "wake-up" test during spinal surgery (1). Although SEPs monitor the function of only some sensory pathways, they offer the ability to repeatedly assess neurological function throughout a surgical procedure in an objective and quantifiable manner (2). However, correct interpretation of these data requires understanding the effect of the patient’s anesthetic drugs on neuroelectric responses. Volatile anesthetics have a dose-dependent suppressive effect (3,4), whereas ketamine (5) and etomidate (6) increase cortical SEP amplitude. Propofol (7) and opioids (8), especially remifentanil (9), have been reported to have relatively minor effects on the cortical SEP, but the information regarding propofol’s effect is incomplete.
For correct intraoperative interpretation, an understanding of the entire dose-response curve of an anesthetic’s effect on SEPs is required. Volatile anesthetics, for example, at 1 minimum alveolar anesthetic concentration (MAC) normally create adequate conditions for SEP monitoring but abolish the response at 2 MAC (4). Propofol titrated to achieve bispectral index (BIS) electroencephalographic values between 25 and 55 normally creates even better conditions for intraoperative monitoring (7), but the effect of large plasma concentrations is unknown. This gap in information is especially concerning because clinicians have no means of reliably and rapidly determining the blood concentration of propofol. The purpose of this study is to fill this information gap so that clinicians can make more informed interpretations of SEP changes that occur during propofol anesthesia.
The primary aim of this study was to quantify, in a rat model, the effect of a wide range of plasma concentrations of propofol on the cortical SEP. Because infusion of propofol and opioid is a frequently used technique for surgical cases that require intraoperative SEP monitoring, this study describes the propofol-SEP dose-response curve during infusion of remifentanil at three different infusion rates. Studies of the effect of an intentional overdose of propofol cannot be performed in humans. However, the results obtained from this study, performed in a rat model, may provide useful information for the interpretation of SEPs in humans.
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Methods
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The study protocol was approved by the Institutional Animal Care and Use Committee of the Pennsylvania State University, College of Medicine. Eighteen male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 350–450 g were anesthetized with an intraperitoneal injection of ketamine (50 mg/kg). Subsequent doses of ketamine (25 mg/kg) were administered as required when the rat responded to surgical stimulation (maximum total dose of 150 mg/kg). After local tissue infiltration with 1% lidocaine, a tracheostomy was performed, and the trachea was cannulated with a 14-gauge intracatheter. The lungs were mechanically ventilated with room air. The tidal volume was set at 1 mL/100 g body weight with an adjustable respiratory rate of 55–60 breaths/min maintaining an end tidal carbon dioxide tension between 35–40 mm Hg. The right femoral vein and artery were exposed and cannulated with PE50 tubing for IV drug and fluid administration and arterial blood pressure monitoring. Mean blood pressure less than 70 mm Hg was treated with a 1-mL boluses of normal saline and phenylephrine (7 µg/kg). Body temperature was monitored with a rectal probe and was kept at 36.5°C–37°C with heating lamps. After the experiment, rats were killed with a 100-mg/kg IV dose of pentobarbital.
After surgical preparation under ketamine anesthesia, an IV remifentanil HCL (Ultiva, Abbott Laboratories, North Chicago, IL) infusion was started at 2.5, 5, or 10 µg · kg-1 · min-1, with six rats in each treatment group. Twenty minutes after initiating the remifentanil infusion, an IV propofol (Diprivan, Astra Zeneca Pharmaceuticals, Wilmington, DE) infusion was begun at 20 mg · kg-1 · h-1 with stepped increases to 40, 60, and 80 mg · kg-1 · h-1 every 20 min.
Six additional male Sprague-Dawley rats weighing 300–400 g were used for the plasma propofol concentration measurements. Animals were anesthetized in a PlexiglasTM chamber using 4% isoflurane and underwent endotracheal intubation, mechanical ventilation, and placement of arterial (tail artery) and jugular venous catheters. Isoflurane was discontinued. After the end-tidal isoflurane had decreased to less than 0.3%, the same stepped incremental propofol infusion was administered. After 20 min at each propofol infusion rate, a 0.5-mL sample of blood was withdrawn from the arterial catheter, and an equal amount of normal saline was administered. The infusion rate was then increased, and this sequence was repeated at 40, 60, and 80 mg · kg-1 · h-1. All blood specimens were collected in heparinized syringes. The blood was centrifuged for 10 min at 3000 rpm to separate cells from the plasma. The plasma samples were stored at -70°C until all the samples were available to be analyzed as a batch. The propofol was extracted into chloroform and measured using gas chromatography (5890 Series 2 Gas Chromatograph, Hewlett Packard, Paris, France) (10). Analysis was performed in duplicate on each sample, and the mean value was recorded. If the values differed by more than 10%, a third value was obtained and included in the formulation of the mean value.
Subdermal stainless steel needle electrodes were percutaneously placed overlying the median nerve in the left upper forelimb and in the scalp overlying the frontal and parietal cortex (Fz-Cz). The median nerve was stimulated (Nicolet Bravo EP system, Nicolet Biomedical Inc, Madison, WI) at supramaximal intensity (15–20 mA) using 0.2-ms biphasic impulses delivered at a frequency of 4.7 Hz. The signal recorded from the scalp was filtered to exclude frequencies higher than 1.5 KHz and lower than 30 Hz and was averaged over 300 repetitions. The recordings were stored on the computer and were analyzed as a batch by an investigator blinded to the treatment condition. The SEP amplitude was measured as the difference in microvolts between the peak and trough deflections (Fig. 1). The latency was measured as the time elapsed between stimulation and the first peak. SEPs were recorded before the remifentanil infusion (pre-remi), before the propofol infusion (remi), and after 20 min at each propofol infusion rate (P20, P40, P60, and P80). Additionally, SEPs were recorded 30 min after the propofol infusion was discontinued (washout).
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Figure 1. Somatosensory evoked potential (SEP) traces obtained from one representative animal after each treatment condition. Note the lack of effect of remifentanil, the dose-dependent suppression by propofol, and the recovery of SEP amplitude during the washout period.
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For descriptive purposes, the actual SEP amplitude and latency at each time point are presented, but for statistical analysis, the raw data from each rat were first transformed using a z-transformation. To evaluate the effect of propofol and of remifentanil on the SEP amplitude or latency, two-way repeated-measures analysis of variance using propofol dose and remifentanil dose as explanatory factors was performed with post hoc Dunnett test to detect significant differences from baseline (remi) at each propofol infusion rate. To quantify the effect of remifentanil alone, paired t-tests were performed comparing the transformed SEP values obtained at pre-remi to the values obtained after 20 min of remifentanil infusion (remi).
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Results
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All animals survived the experiment. Reproducible cortical SEPs with a mean ± SD amplitude of 15.8 ± 12.5 µV and latency of 5.88 ± 0.47 ms at the baseline (remi) measurement were obtainable from all of the rats (Fig. 2)
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Figure 2. Effects of increasing propofol infusion rates on the amplitude and latency of the cortical somatosensory evoked potential (SEP). The y axes depict the mean + SEM of the SEP amplitude in microvolts (µV) and the latency in milliseconds (ms). The x axes depict the treatment conditions. *Significantly different from baseline (remi).
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In the six rats in which the arterial plasma propofol concentrations were measured, the concentrations progressively increased (Table 1). The mean ± SD plasma concentrations ranged from 1.2 ± 0.7 µg/mL at 20 mg · kg-1 · h-1 to 31.6 ± 3.4 µg/mL at 80 mg · kg-1 · h-1. These concentrations represent a range of 0.4–10.8 50% effective concentration (EC50) (response to tail clamp) for rats (11).
Propofol had a dose-dependent suppressive effect on the SEP amplitude (F-ratio = 19.8; P < 0.0001) (Fig. 1). This suppression did not reach statistical significance until the infusion rate was 40 mg · kg-1 · h-1. At this point, the estimated mean propofol plasma concentration was 4.4 µg/mL (1.5 tail clamp EC50). At the 80-mg · kg-1 · h-1 propofol infusion rate estimated (plasma concentration of 31.6 µg/mL, corresponding to 10.8 EC50), the SEP response was obliterated in 10 of 18 rats (Table 2). In 16 of 18 rats, the SEP returned after the 30-min propofol washout period, and the amplitude of this response was significantly more than the response during the 80 mg · kg-1 · h-1 infusion (P < 0.01; Fig. 2). The SEP amplitude and latency had parallel responses to propofol (Fig. 2), with a dose-dependent increase in latency (F-ratio = 37.5; P < 0.0001) that became statistically significant during the 40-mg · kg-1 · h-1 infusion, and that demonstrated statistically significant resolution after the washout period (P < 0.01).
Remifentanil did not affect the SEP amplitude or latency when administered alone or when co-administered with propofol (Fig. 3).
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Figure 3. Effects of remifentanil doses on somatosensory evoked potential (SEP) amplitude and latency. The mean + SEM of cortical SEP amplitude and latency before (pre-remi) and during (remi) infusion of remifentanil at 2.5 (R2.5), 5 (R5), and 10 (R10) µg · kg-1 · min-1 are displayed.
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Discussion
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The principle finding of this study was a dose-dependent suppression of the amplitude and latency of cortical SEPs by propofol. This finding is consistent with a previous report (7,12) and extends it by correlating the SEP responses to a wide range of measured plasma propofol concentrations. Even at 10.8 EC50, which should exceed the propofol plasma concentration achieved in any clinical setting, a measurable SEP response was present in 44.5% of the rats.
Suppression of cortical SEPs is expected because propofol decreases neural transmission in both the spinal cord and the brain. In the spinal cord, propofol depresses spinal neuron excitability by suppressing L-type calcium channel plateau potentials as a result of potentiating the activity of gamma aminobutyric acid (GABA)A receptors (13,14). In the brain, as well, propofol potentiates the inhibitory activity of GABAA (15,16) and decreases intracellular sodium currents in a concentration-dependent manner.
The new information added by this study is the plasma concentration of propofol at which the SEP suppression might interfere with interpretation of intraoperative SEP monitoring. As a rule of thumb in clinical intraoperative neurophysiologic monitoring, a 50% decrease in SEP amplitude is the threshold for making a call of possible neurological insult (17). In this study, the threshold of a 50% suppression of SEP amplitude was crossed in 9 of the 18 rats at the end of the 40-mg · kg-1 · h-1 infusion (Table 2). This corresponded to an estimated plasma concentration of propofol of 4.4 ± 0.6 µg/mL, which is 1.5 EC50 (tail clamp) for propofol in the rat (11). In 50% of humans, loss of consciousness occurs at propofol blood concentrations of 3.4 µg/mL, but there is great variability in the concentration required for surgical anesthesia (18). The concomitant use of remifentanil should decrease the propofol requirement, thereby suggesting that the results presented here overestimate the SEP suppression by propofol.
Compared with volatile anesthetics, propofol has a more gradually sloped dose-response curve. Desflurane, for example, decreases the rat cortical SEP by 33% at 1 MAC and obliterates the response at 2 MAC (19). In humans, 0.5 MAC of isoflurane in 60% nitrous oxide decreases the SEP amplitude by 54%, and 1.5 MAC isoflurane in 60% nitrous oxide decreases the SEP amplitude by 95% (4). Despite their SEP suppressive effect, volatile anesthetics usually provide adequate conditions for intraoperative SEP monitoring, but our finding of relative stability in the SEP over a wide range of plasma propofol concentrations suggests that propofol might provide a more predictable anesthetic effect on intraoperative SEP monitoring.
Whereas clinical studies comparing the effects of propofol and volatile anesthetics on cortical SEPs cannot provide the same degree of control over study conditions as this rat study, the conclusions are similar. A retrospective report by Taniguchi et al. (20) describes 185% (tibial nerve) to 191% (median nerve) larger amplitude cortical SEP responses after changing the standard anesthetic practice in their institution from an inhaled technique to an IV technique using propofol and alfentanil. A randomized prospective study using three ranges of BIS as target levels of anesthesia found a direct relationship between BIS and SEP amplitude during sevoflurane anesthesia, but during propofol anesthesia there was no suppression of SEP amplitude over the same range of BIS values (7).
Because propofol is often administered in combination with an opioid during intraoperative SEP monitoring, this study evaluated the effect of propofol on the SEP over a range of opioid doses. Consistent with the results from the current study, opioids have been found to have only a modest effect on the SEP (8,9). Administration of 53.2 ± 9.1 µg/kg of fentanyl to humans decreased the amplitude of the cortical SEP by 36% and had little effect on the SEP recorded from the cervical spine (8). Rat studies also demonstrate a modest opioid effect with morphine-induced dose-dependent suppression of amplitude occurring at the thalamic component of the SEP (21,22).
A limitation of this study is the use of ketamine during the surgical preparation of the rats. Because ketamine increases SEP amplitude (5), the amplitude of the pre-remi SEPs obtained in this study might be ketamine-enhanced relative to the SEP responses obtained subsequently without additional administration of ketamine. Even if this effect is significant, our conclusions are not altered because this ketamine effect would lead to overestimation of the suppressive effect of propofol and remifentanil.
In summary, this study demonstrates that the dose-response curve of propofol suppression of the cortical SEP has a gradual slope. Even at estimated plasma concentrations of 10.8 EC50, there was a measurable SEP response in 8 of 18 rats. The clinical implication of this finding is that propofol is unlikely to be the cause of large changes in the SEP response in patients receiving intraoperative neurophysiologic monitoring.
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Acknowledgments
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The authors thank Garry Russell, MD, for his guidance.
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References
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Accepted for publication July 21, 2003.
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Abstract
Introduction
