Anesth Analg 2000;91:1282-1288
© 2000 International Anesthesia Research Society
GENERAL ARTICLES
Isoflurane Depresses Electroencephalographic and Medial Thalamic Responses to Noxious Stimulation via an Indirect Spinal Action
Joseph F. Antognini, MD*,
E. Carstens, PhD
,
Makoto Sudo, MD
, and
Satoko Sudo, MD
*Department of Anesthesiology and Pain Medicine,
Section of Neurobiology, Physiology and Behavior, University of California, Davis, California; and
Department of Anesthesiology and Resuscitology, Ehime University, Ehime, Japan
Address correspondence to Joseph F. Antognini, MD, Department of Anesthesiology, TB-170, University of California, Davis, CA 95616. Address e-mail to jfantognini{at}ucdavis.edu
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Abstract
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Anesthetics such as isoflurane act in the spinal cord to suppress movement in response to noxious stimulation. Spinal anesthesia decreases hypnotic/sedative requirements, possibly by decreasing afferent transmission of stimuli. We hypothesized that isoflurane action in the spinal cord would similarly depress the ascending transmission of noxious input to the thalamus and cerebral cortex. In six isoflurane-anesthetized goats, we measured electroencephalographic (EEG) and thalamic single-unit responses to a clamp applied to the forelimb. Cranial bypass permitted differential isoflurane delivery to the torso and cranial circulations. When the cranial-torso isoflurane combination was 1.3% ± 0.2%–1.0% ± 0.4% the noxious stimulus did not evoke significant changes in the EEG or thalamic activity: 389 (153–544) to 581 (172–726) impulses/min, (median, 25th–75th percentile range, P > 0.05). When the cranial-torso isoflurane combination was 1.3% ± 0.2%–0.3% ± 0.2%, noxious stimulation increased thalamic activity: 804 (366–1162) to 1124 (766–1865) impulses/min (P < 0.05), and the EEG "desynchronized": total EEG power decreased from 25 ± 20 µV2 to 12 ± 8 µV2 (P < 0.05). When the cranial-torso isoflurane was 1.7% ± 0.1%–0.3% ± 0.2%, the noxious stimulus did not significantly affect thalamic: 576 (187–738) to 1031 (340–1442) impulses/min (P > 0.05), or EEG activity. The indirect torso effect of isoflurane on evoked EEG total power (12.6 ± 2.7 µV2/vol%, mean ± SE) was quantitatively similar to the direct cranial effect (17.7 ± 3.0 µV2/vol%; P > 0.05). These data suggest that isoflurane acts in the spinal cord to blunt the transmission of noxious inputs to the thalamus and cerebral cortex, and thus might indirectly contribute to anesthetic endpoints such as amnesia and unconsciousness.
Implications: Isoflurane action in the spinal cord diminished the transmission of noxious input to the brain. Because memory and consciousness are likely dependent on the "arousal" state of the brain, this indirect action of isoflurane could contribute to anesthetic-induced amnesia and unconsciousness.
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Introduction
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The spinal cord is now recognized as an important site of anesthetic action. In particular, anesthetics produce immobility (in response to noxious stimulation) via action in the spinal cord (1,2). Other critical endpoints of anesthesia (amnesia, unconsciousness) are thought to be the result of anesthetic action in the brain. Spinal anesthesia, however, decreases hypnotic/sedative requirements, possibly by decreasing afferent transmission of stimuli and the "arousal" level of the brain (3,4). Some have argued that general anesthetics might alter the transmission of noxious input from the spinal cord to the brain, and thereby indirectly affect memory and consciousness (5). Indeed, we have recently reported that isoflurane and propofol action in the spinal cord blunted the electroencephalographic (EEG) and midbrain reticular formation (MRF) responses to noxious stimulation (6,7). One limitation of our previous study (6) was that we were unable to determine the extent of the spinal cord action of isoflurane to blunt EEG activation, relative to isoflurane’s direct effect.
The thalamus is considered critical to consciousness (8). Furthermore, the medial thalamus transmits nociceptive information from the periphery and spinal cord to higher cerebral structures (9–11). Isoflurane has been shown to have an indirect effect on depth recordings in the thalamus (6), but these depth recordings were limited because they likely included electrical activity of other nearby areas. Demonstration of effects on single-unit activity would be more compelling evidence that spinal cord action of isoflurane indirectly affects thalamic responses. We hypothesized that isoflurane would have a similar indirect depressant effect on single-unit recordings from the medial thalamus, and that the magnitude of the indirect effect on the EEG response to noxious stimulation would be similar to the direct effect. We tested these hypotheses in the present study.
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Materials
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The local animal care and use committee approved this study. Six goats (four female and two male) weighing 65 ± 13 kg were anesthetized with isoflurane via a mask. The trachea of each goat was intubated, and a tube was passed via the esophagus to drain rumen contents. Bilateral neck dissections were performed to access the jugular veins and carotid arteries on each side. The occipital arteries were ligated to isolate the cerebral circulation as previously reported (Figure 1) (2,12). A catheter was placed into a peripheral vein for the administration of lactated Ringer’s solution. Isoflurane 2%–3% was administered during the surgical procedures. Rectal and nasopharyngeal temperatures were measured and maintained at 37.3° ± 0.7 °C and 37.3° ± 1.1 °C, respectively, by using a heating lamp and, during bypass, the heat exchanger of the oxygenator.
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Figure 1. Diagram of cranial bypass preparation. Cannulae were placed into the jugular veins to drain cranial venous blood either into the systemic circulation or into the bypass oxygenator. Opening Clamps 1–3 and closing Clamp 4 permitted drainage of blood into the oxygenator and infusion of arterialized blood into the cranial circulation. An isoflurane vaporizer was placed in line with the gas flow to the oxygenator thereby permitting differential delivery of isoflurane to the cranial circulation as compared with the systemic circulation. Cranial ("stump") blood pressure was measured from a catheter placed in a carotid artery. Note that in the present study a Y cannula was placed in each jugular vein. Reproduced with permission from Antogini JF, Schwartz K; Exaggerated anesthetic requirements in the preferentially anesthetized brain; Anesthesiology 1993;79:1244–9.
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A craniotomy was performed to access the brain. The head was secured to a stereotaxic frame with ear bars and a mouthpiece. Pancuronium was administered (initial dose 0.15 mg/kg, 0.1 mg/kg every 2–3 h). A tungsten microelectrode (F. Haer, Brunswick, ME; tip diameter 25-µ, impedance approximately 10 M
) was advanced to the medial thalamus by using a hydraulic microdriver (D. Kopf, Inc, Tujunga, CA). The coordinates were 15 mm rostral to the interaural line, 3–4 mm lateral to midline, and 32–36 mm below the brain surface (13). Action potentials were isolated from single neurons. In brief, the signal was amplified and entered into a personal computer in which a custom program stored each action potential (14). The signal-to-noise ratio was generally at least 5-to-1 and often exceeded 10-to-1, based on visual inspection. Action potentials that had low signal-to-noise ratios were not studied further. Thalamic cells were sought that increased their activity in response to a noxious mechanical clamp (ViseGripTM; Petersen Manufacturing Company, Dewitt, NE) applied to the hoof of the forelimb for 1 min. These neurons received input from large areas of the body, in that they often responded to noxious stimuli applied to the face, tongue, and hindlimb. Neuronal discharges were counted for the successive 1-min periods before and during clamp application. In virtually all cases, the clamp was applied at least twice, with an interstimulus interval of 5 min.
In five goats, EEG activity was also recorded (electrical interference problems prevented recording adequate data in the sixth goat). Platinum needle electrodes (E-2; Grass Instruments, West Warwick, RI) were placed in the skull periosteum in the frontal and occipital regions bilaterally, permitting the recording of EEG activity of four sites: bifrontal, bioccipital, and right and left hemispheric. Electrode impedances were <2–3 kOhms. The signals were amplified by using a GrassTM model 8-10E EEG machine (Grass Instruments), with filter settings at 0.3–35 Hz. The signals were relayed to a personal computer where they were digitized (200 Hz) and stored for off-line analysis. Because each site responded similarly to the noxious stimulus as previously reported (6,16), we only analyzed the data from the bifrontal recording site. By using a commercial program (PolyViewProTM; Grass Astro-Med, Inc, Braintree, MA), the EEG data were subjected to a Hanning window and fast fourier transform to determine total power in the 0.3–35-Hz range. The raw EEG tracing was visually inspected and artifacts were deleted (<4% data). The total power was determined from the average of 4-s epochs in the 1-min period before and 1-min period during application of the noxious stimulus.
Heparin (4 mg/kg, 1–2 mg/kg every 2–3 h IV) was administered. Y cannulae were placed into the jugular veins to permit drainage of blood either into a bubble oxygenator (B-10Plus; American Edwards, Irvine, CA) or back into the systemic circulation (2,12). One of the carotid arteries was permanently ligated, and a cannula was placed into the artery to permit oxygenator blood to be infused into the cerebral circulation. A small catheter was placed into this carotid artery and directed toward the heart for withdrawal of blood for hematocrit, glucose, and acid-base analysis and to measure systemic blood pressure. An 18-gauge catheter was placed into the other carotid artery and directed toward the head to measure cranial blood pressure during bypass (Figure 1).
The oxygenator was primed with blood (500 mL) withdrawn from the animal. Bypass was initiated by draining the cranial venous blood into the oxygenator and reinfusing the arterialized blood into the carotid cannula at flows of 300–600 mL/min. Gas flow to the oxygenator was 95% O2 and 5% CO2 at 6–8 L/min. An isoflurane vaporizer was placed in line with the gas flow. Complete bypass was achieved by placing a loop ligature around the remaining carotid artery that transmitted systemic blood to the cerebral circulation. Isoflurane concentration in the cranial arterial blood was estimated by measuring, with a calibrated agent analyzer, the isoflurane concentration in the oxygenator exhaust (2,12). In a previous study (12), the correlation between the oxygenator exhaust and arterial concentrations of halothane was quite good (r = 0.82). Because isoflurane has a lower blood-gas solubility coefficient than halothane, we expected the correlation to be better with isoflurane. The torso isoflurane was measured by analysis of end-tidal gases, by using a calibrated agent analyzer. During bypass, the cranial and torso (systemic) blood pressures were 61 ± 13 mm Hg and 107 ± 25 mm Hg, respectively. The initiation of cranial bypass often resulted in EEG activation, then EEG depression, followed by reversion to the prebypass EEG pattern. The bypass flows and cranial blood pressures were sufficient to ensure stable EEG recordings over the course of each experiment.
To determine the effect of isoflurane action in the torso on thalamic activity, cranial isoflurane concentration was maintained at 1.3% ± 0.2%, while torso isoflurane concentration was alternated between 1.0% ± 0.4% and 0.3% ± 0.2%. In each animal, the cranial isoflurane concentration was always maintained at the same concentration (or within 0.1%) when the torso isoflurane was changed. At least 15 min elapsed at any new cranial-torso isoflurane concentration combination before neuronal and EEG responses were determined. Responses were also determined at a cranial-isoflurane combination of 1.7% ± 0.1%–0.3% ± 0.2% (n = 6). To determine the relative impact of torso and cranial actions of isoflurane on EEG activity, EEG responses were determined at other cranial and torso isoflurane concentrations. Combinations were sought that permitted and prevented changes in EEG activity in response to the noxious stimulus. The cranial isoflurane concentration ranged from 0.7% to 1.8%, and the torso concentration ranged from 0.2% to 1.8%.
At the end of each study, an electrolytic lesion was made at the thalamic recording site. The animal was killed with potassium chloride, and the brain was removed and fixed in formalin. Sections (50-microns thick) were made with a microtome, counterstained, and the lesions observed under light microscopy to confirm the location of the electrode site.
Data were presented as the median and 25th–75th percentile range or as mean ± SD or mean ± SE as noted. A log transformation of the thalamic neuronal activity was performed because of the large variance in the data. Changes in the EEG and thalamic neuronal activities at the high and low torso isoflurane concentrations were analyzed by using repeated measures analysis of variance, followed by a paired t-test. In addition, multiple regression was performed on the evoked total power data of all of the cranial-torso isoflurane combinations (15). This analysis permitted a comparison of the relative roles of the torso and cranial actions of isoflurane on the evoked EEG activity. When the stimulus was applied more than once at a given cranial-torso isoflurane combination, the data were averaged for that combination, except for the multiple regression analysis of the EEG, where each individual response was used. Significance was achieved with P < 0.05.
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Results
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Thalamic single-unit activity data were obtained from seven neurons in six goats. The receptive fields were generally large, involving the face as well as the limbs. Two individual examples are shown in Figure 2, demonstrating the indirect depressant effect of isoflurane on thalamic neuronal and EEG activity. When the cranial-torso isoflurane was 1.3% ± 0.2%–1.0% ± 0.4%, the noxious stimulus did not evoke a significant neuronal response: 389 (153–544) to 581 (172–726) impulses/min, P > 0.05. When the torso isoflurane was decreased to 0.3% ± 0.2%, thalamic activity increased significantly when the clamp was applied: 804 (366–1162) to 1124 (766–1865) impulses/min, P = 0.0024. In six of seven thalamic neurons, the spontaneous activity increased when the torso isoflurane concentration was decreased to 0.3% ± 0.2%. When the cranial-torso isoflurane was 1.7% ± 0.1%–0.3% ± 0.2%, the noxious stimulus evoked increased neuronal activity in four of six neurons, but no significant effect was found when the data from all six neurons were pooled: 576 (187–738) to 1031 (340–1442) impulses/min, P > 0.05. Log transformed data are shown in Figure 3. Only four recording sites were recovered; these were located in the medial thalamus (Figure 3).
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Figure 2. These individual examples demonstrate the depressant effect of isoflurane on thalamic single-unit and electroencephalographic (EEG) responses to noxious stimulation. The arrows indicate when the noxious clamp was applied. A, When the cranial-torso isoflurane combination was 1.3%–0.8% (first panel), application of the noxious clamp stimulus had no significant effect on the thalamic single-unit activity; the EEG response (desynchronization) was minimal, with a small change from high-amplitude, slow-wave activity to low-amplitude, fast-wave activity (tracing at top). When the torso isoflurane was decreased to 0.3% (second panel), the EEG response to the noxious stimulus was more robust. The thalamic neuronal spontaneous activity was increased, as was the stimulus-evoked activity. Increasing the cranial isoflurane to 1.8%, while maintaining the torso isoflurane at 0.2%, depressed the responses (third panel). The far-right panel shows 10 consecutive action potentials recorded from the thalamic neuron of this animal. B, Thalamic neuronal and EEG activity from another animal demonstrated that decreasing the torso isoflurane resulted in significantly increased thalamic activity. The EEG response was less affected than the EEG response in A.
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Figure 3. A, Pooled log-transformed data for the thalamic responses demonstrated that decreasing the torso isoflurane from 1.0% ± 0.4% to 0.3% ± 0.2% resulted in a significant increase in the evoked response (*P = 0.0024 compared with prestimulus value and P = 0.0086 compared with value at 1.3/1.0 isoflurane combination). When the cranial isoflurane was 1.7% ± 0.1%, the pre- and poststimulus values were not significantly different from each other or from the values at the 1.3% ± 0.2%–0.3% ± 0.2% combination. B, Representative section of thalamus 15 mm rostral to the interaural line (13). The recording sites that were recovered were located in the medial thalamus. The sites are indicated by black dots. PUL = pulvinar, CM = central medial nucleus.
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EEG activity responded similarly to the changes in the torso isoflurane. When the torso isoflurane was 1.0% ± 0.4%, total power was unchanged during application of the clamp (25 ± 16 to 24 ± 19 µV2, P > 0.05). Total power decreased significantly during clamp application when the torso isoflurane was 0.3% ± 0.2% (25 ± 20 to 12 ± 8 µV2, P < 0.05). When the cranial-torso isoflurane was 1.7% ± 0.1%–0.3% ± 0.2%, the noxious stimulus did not significantly affect total power: (26 ± 13 to 21 ± 11 µV2, P > 0.05). Multiple regression analysis of all cranial-torso combinations demonstrated a significant relationship among total power evoked by the noxious stimulus, cranial isoflurane, and torso isoflurane (Figure 4). The total power of the spontaneous EEG before stimulation was not significantly affected within the range of isoflurane concentrations studied. A plane was fitted to the data by using multiple regression: 
where IsoC = cranial isoflurane concentration and IsoT = torso isoflurane concentration, both in vol%. The torso and cranial actions of isoflurane had similar quantitative effects on evoked total power, as shown by the coefficients for the cranial (17.7 ± 3.0 µV2/vol%, mean ± SE) and torso (12.6 ± 2.7 µV2/vol%) isoflurane concentrations in the planar equation that best described the data (Figure 4; P > 0.05, unpaired t-test). Hematocrit, glucose, and blood gas analyses demonstrated no significant physiological changes during the bypass period (Table 1).
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Figure 4. Three different scattergram views show the relationship among the evoked total power (µV2) during the noxious stimulus, cranial isoflurane concentration, and torso isoflurane concentration (66 cranial-torso isoflurane combinations from five animals). The total power of the spontaneous electroencephalogram (i.e., before stimulation) was not significantly affected by changes in the cranial or torso isoflurane concentrations. When analyzed by using multiple regression (lower right figure), a plane was fitted to the data: total evoked power = -15.3 µV2 + 17.7 µV2 · vol%-1 · (IsoC) + 12.6 µV2 · vol%-1 · (IsoT) where IsoC = cranial isoflurane concentration and IsoT = torso isoflurane concentration, both in vol%. The adjusted r2 value was 0.44, P < 0.001. The cranial (17.7) and torso isoflurane (12.6) coefficients were not significantly different from each other (P > 0.05, unpaired t-test).
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Discussion
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Our results indicate that isoflurane action in the torso indirectly affects medial thalamic single-unit and cortical EEG activities. This indirect effect is significant, as seen in the EEG data, where the indirect effect appeared to be as strong as the direct (cranial) effect of isoflurane. Although not directly proven in this study, we believe that this blunting effect is a result of the action of isoflurane to depress nociceptive transmission in the spinal cord. Action at peripheral sites seems unlikely to have impacted our results. For example, volatile anesthetics sensitize, not depress, peripheral nociceptors (17,18), so we would have expected thalamic activity to increase, not decrease, when the torso isoflurane was increased. In fact, we found the opposite. Because volatile anesthetics have no significant effect on peripheral nerves (e.g., axons), it is unlikely that isoflurane would have exerted its effect by a peripheral action (19). An effect on synaptic transmission within the spinal cord is more likely. Volatile anesthetics depress dorsal horn neuronal responses to innocuous and noxious stimuli (20,21). Although these earlier studies (20,21) did not identify whether the recorded neurons projected to supraspinal targets, our present data and previous work (6) suggest that spinoreticular and spinothalamic projection neurons would be inhibited by volatile anesthetics. Further work is required to determine what specific spinal cord sites are affected by isoflurane and can account for the current findings.
The present data extend and complement our previous study reporting an indirect depressant effect on isoflurane on EEG and MRF single-unit responses to noxious stimulation (6). For a noxious stimulus to "activate" the brain and cause arousal, noxious inputs must be transmitted through the spinal cord, to the MRF and thalamus, and then on to the cerebral cortex. In previous studies, we found that there appeared to be diffuse activation in response to noxious stimulation; that is, all areas of the cerebral cortex responded similarly with a change to a low-amplitude, high-frequency EEG pattern (6,16), and our present results are consistent with these findings. Others have similarly determined that noxious stimuli are associated with diffuse cerebral activation, as determined by using positron emission tomography (22).
Increasing the torso isoflurane concentration (from approximately 0.3 to 1.0) depressed the spontaneous and evoked activity of the thalamic neurons. We previously found that increasing the torso isoflurane concentration depressed the spontaneous and evoked activity of lumbar dorsal horn neurons (23,24). These studies are consistent with the present results insofar as direct depression of spinothalamic dorsal horn neurons that project to the thalamus could indirectly depress thalamic neurons.
We were unable to directly test memory and consciousness and used EEG and thalamic single-unit activity as surrogate measures of cerebral function. The thalamus and MRF are critically involved in consciousness and generation of the EEG (8). Furthermore, in humans, bispectral EEG analysis correlates with amnesia and unconsciousness during anesthesia (25). We therefore believe that thalamic and EEG activities are reasonable measures of central nervous system arousal.
The action of isoflurane in the spinal cord to blunt the EEG response to noxious stimulation is not insignificant, and approaches, and may even exceed, the power of isoflurane to directly depress the response (via cranial action). Thus, intraoperatively, isoflurane could contribute to amnesia and unconsciousness by both direct and indirect mechanisms. We have recently determined that propofol also has indirect depressant effects on MRF neuronal and EEG activity responses (7). Whether this is generally true for other anesthetics requires further study. Spinal and epidural anesthesia decreases sedative and anesthetic requirements, suggesting that brain arousal is less when afferent impulses are decreased (3,4).
We used simple multiple regression to describe the relationship among EEG power and cranial-torso isoflurane concentrations. However, the resulting equation is only valid for the data range presently obtained and fails to adequately account for very small concentrations (which erroneously predict negative total power) or very large concentrations (where total power should be zero at isoelectricity). When a simple curved surface was used to describe the data of Figure 4, the fit was only marginally better. Despite these limitations, our data nonetheless indicate approximately equivalent direct (cranial) and indirect (torso) effects of clinically relevant concentrations of isoflurane on EEG responses to noxious stimulation. In fact, our data suggest that the spinal cord action of isoflurane might be more important than the cranial action regarding suppression of thalamic responses to noxious stimulation. When the cranial isoflurane was 1.7% (torso isoflurane = 0.3%), the noxious stimulus still evoked a significant response in four of six neurons; in the other two neurons, the activity was inhibited by the stimulus.
In conclusion, isoflurane has indirect effects on thalamic and EEG responses to noxious stimuli. Regarding the EEG response, the impact of the indirect action approaches that of the direct cranial action. These indirect effects are likely the result of actions within the spinal cord, although the specific neural circuits involved have not yet been identified.
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Acknowledgments
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Supported in part by National Institutes of Health Grant R01 57970 and the Foundation for Anesthesia Education and Research.
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Accepted for publication June 15, 2000.
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C. Vahle-Hinz and O. Detsch
What can in vivo electrophysiology in animal models tell us about mechanisms of anaesthesia?
Br. J. Anaesth.,
July 1, 2002;
89(1):
123 - 142.
[Abstract]
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J. F. Antognini and E. Carstens
In vivo characterization of clinical anaesthesia and its components
Br. J. Anaesth.,
July 1, 2002;
89(1):
156 - 166.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
