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© 1999 International Anesthesia Research Society
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Abstract |
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The sedative and anesthetic-sparing ability of the
2-adrenergic agonist dexmedetomidine is well documented. In this study, we identified the effects of halothane, with and without dexmedetomidine, on hemodynamic and electroencephalographic (EEG) variables and quantified the concentration of halothane resulting in various anesthetic depth indices mediated through the central nervous system (CNS) in chronically instrumented cats. Halothane was given alone or after dexmedetomidine (15 µg/kg PO). In both groups, four indices of anesthetic depth—minimum alveolar anesthetic concentration (MAC; no movement to noxious stimuli), MACBAR (no autonomic response to noxious stimuli), MACBS (EEG burst suppression), and MACISOELECTRIC (EEG isoelectricity)—were determined. Halothane decreased arterial blood pressure, heart rate, and higher frequency components of the EEG before the onset of burst suppression and isoelectricity. Dexmedetomidine pretreatment augmented the actions of halothane on arterial pressure, heart rate, and the EEG. Dexmedetomidine reduced the halothane concentrations resulting in MAC (from 1.22% ± 0.06% to 0.89% ± 0.08%) and MACBAR (from 1.81% ± 0.05% to 1.1% ± 0.10%), but not those resulting in MACBS (3.01% ± 0.17% vs 3.14% ± 0.10%) or MACISOELECTRIC (4.39% ± 0.26% vs 4.65% ± 0.12%). These results suggest that dexmedetomidine does not alter various CNS-mediated indices of anesthetic action to equivalent degrees and that there are dissimilar degrees of an anesthetic-sparing action at different levels of the neuraxis. Implications: The anesthetic adjuvant dexmedetomidine seems to differentially alter central nervous system-mediated indices of anesthetic action. Lower brainstem or spinal determinants of anesthetic depth (movement and hemodynamic responses) are more attenuated than those of higher brain functions, such as the electroencephalogram.
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Introduction |
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The anesthetic-sparing action of the
2-adrenergic agonists, including dexmedetomidine, has been the subject of animal and clinical investigations (1–3). Sedative, hypnotic, and perhaps minimum alveolar anesthetic concentration (MAC) reduction actions of dexmedetomidine may be modulated by actions within the central nervous system (CNS) at the locus coeruleus (4–6). However, evidence suggests that classic behavioral end points of MAC (7) and antinociceptive actions of 2-adrenergic agonists (8,9) may be mediated primarily at spinal levels.
The attenuation of hemodynamic alterations as an indicator of a lack of autonomic response to a noxious stimulus is analogous to the MAC required to block the adrenergic response to skin incision (MACBAR) (10). Because normal cardiovascular regulation occurs at caudal brainstem levels and the 2-adrenergic agonists may partially produce their hemodynamic stabilizing effects at such caudal nuclei (11–13), the anesthetic-sparing action of 2-adrenergic agonists, as determined hemodynamically, may also be mediated at this level. However, dexmedetomidine has significant effects on cardiovascular control mechanisms at more rostral CNS levels (14), and diencephalic cardiovascular control centers may be more susceptible to volatile anesthetic-induced disruption than more caudal CNS sites (13). Therefore, the anesthetic-sparing action of 2-adrenergic agonists may be dependent on the CNS level involved. Previous studies suggest that burst suppression or isoelectricity in the electroencephalogram (EEG) may document deep levels of anesthesia (15,16).
The purpose of this investigation was to examine the effects of halothane, with and without dexmedetomidine, on MAC, MACBAR, and the MAC producing burst suppression (MACBS) and isoelectricity (MACISOELECTRIC) of the EEG in chronically instrumented cats. We hypothesized that dexmedetomidine would equivalently reduce all four indices of volatile anesthetic action.
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Methods |
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All studies were approved by the Animal Use and Care Committee of the Medical College of Wisconsin, and all experimental procedures and protocols used conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and the National Institutes of Health guidelines (Guide for the Care and Use of Laboratory Animals). Fifteen male and female cats (2.6–4.7 kg, mean 3.5 kg) anesthetized with halothane in oxygen were prepared for surgery, as described by Farber and Schmeling (14). The right carotid artery and right external jugular vein were cannulated. The catheters were subsequently tunneled subdermally to a lateral thoracic exit site, and the wounds were closed.
Cats were placed in a stereotaxic restraint, and surgical exposure of the skull was accomplished. Stainless steel recording electrodes were placed epidurally through calvarium burr holes. Electrodes were situated bilaterally over the frontal cortex and the occipital cortex. All wounds were closed in layers, and animals recovered for 7–10 days. After surgery, each animal was fitted with a jacket (Alice King Chatham, Los Angeles, CA) to prevent instrumentation damage, and each received antibiotics and analgesics as previously described (14). During the postoperative recovery period, cats were trained to stand quietly in a restraining sling, and the catheters were flushed daily with small volumes of heparinized saline.
On the day of experimentation, each animal was placed in the sling within a Faraday cage, and arterial pressure, heart rate, core body temperature (by rectal thermistor), and right and left channels of hemispheric EEG activity were recorded on a polygraph. The EEG signals were amplified 20,000 times, analog-filtered between 0.1 and 100 Hz, displayed on a Techtronix (Beaverton, OR) oscilloscope, and recorded on a Vetter (Rebersburg, PA) VHS FM tape recorder for computer-assisted analysis of the EEG power and frequency distribution, hemodynamic variables, and EEG burst suppression and isoelectric determination. Experiments were conducted in a darkened room without auditory stimuli and with minimal motion activity.
MAC was determined by using a modification of the "up-down method" (17). A hemostat was applied to the first ratchet position, two-thirds from the base of the tail (60 s). Muscular movement of the head or extremities was evaluated. Coughing, bucking, chewing, swallowing, twitching, and shivering were not considered gross purposeful movement. MACBAR was defined as <10% alteration in arterial pressure and heart rate after the same nociceptive stimuli as used with MAC.
EEG data were analyzed by using a DASH-16 A-D converter (Metrabyte Instruments, Tauton, MA) coupled to a microcomputer using software specifically developed in this laboratory. Each channel of EEG activity was digitized at 256 Hz, digitally Hanning-filtered, corrected for DC voltage offset, and subjected to fast Fourier transform and power spectral analysis. A 48-s sample of the EEG was digitized, and 24 consecutive 2-s epochs were analyzed for spectral activity and averaged. Separate 2-s epochs were analyzed to minimize the effects of brief variations in EEG activity. Resultant power spectra were normalized before determination of the percent frequency and power bandwidth distributions calculations by subtracting the standard error of the absolute total voltage mean of the entire spectral array from each point in the array. The average EEG power distributions in the delta (0–4 Hz), theta (5–8 Hz), alpha (9–12 Hz), and beta (13–20 Hz) bands were calculated for the 24 epochs of each channel. The spectral frequency corresponding to the mean (50%) and 80% and 95% of the power spectrum from 0 to 25 Hz was also determined.
Calculation of burst suppression and isoelectricity used a determination of the EEG voltage isoelectrical noise for each hemispheric channel. The absolute value of this voltage noise plus the absolute value of the standard error of this noise determination was then used as the threshold for EEG burst suppression and isoelectric calculations. EEG activity that exceeded this threshold voltage was determined as nonisoelectric activity. Points for both EEG traces that simultaneously exceeded this isoelectric level for >0.5 s were assigned as electrical activity. When the simultaneous activity of both channels did not exceed the isoelectric activity for >0.5 s, a period of isoelectric and/or burst suppression was determined. Each 48-s epoch was evaluated for the number of bursts, burst duration, number of periods of isoelectric activity, and isoelectric duration. The burst suppression ratio was defined as time of isoelectric activity/time burst activity within each 48-s EEG epoch. The MACBS, or end-tidal concentration of anesthetic resulting in burst suppression, was the equilibrated concentration first producing an isoelectric pause. The MACISOELECTRIC was the concentration of halothane producing a >10-s pause in the electrical activity in both hemispheres with a >80% burst suppression ratio for the epoch. After determination of the MACBS, 5–10 epochs (48 s) before and after the MACBS epoch were quantified for the burst suppression ratio and corresponding end-tidal concentration of halothane. After the experiments and analyses, the end-tidal concentration of halothane was converted to a MAC multiple for each individual animal, and a linear regression of the burst suppression ratio versus this MAC multiple was accomplished.
Two experimental protocols (halothane and dexmedetomidine plus halothane) were completed on different days with animals assigned from a Latin square design. Seven to 10 days were allowed between experiments. After an overnight fast and fluid replacement with saline, baseline recordings of EEG activity, deep core temperature, and hemodynamics were obtained.
In Group I, nine animals underwent an inhaled induction with halothane in oxygen via a mask. Their tracheas were intubated, and the lungs were ventilated with halothane in oxygen using a semiclosed circle system. End-tidal gas concentrations were monitored using a mass spectrometer (Marquette Electronics, Milwaukee, WI). Arterial blood samples were obtained in all experiments for arterial gas tensions. Ventilation was adjusted and/or sodium bicarbonate was administered to adjust gas tensions and pH to control conditions (pH 7.39–7.43, PCO2 32–38 mm Hg, HCO3 20–24 mEq/L). The end-tidal concentration of halothane was increased to 0.9%, and equilibration was accomplished for 15 min. The nociceptive stimuli for MAC determination were applied as above; if purposeful movement occurred, the halothane concentration was increased to 1.1%, and 10 min was allowed for equilibration. If purposeful movement was then observed, the anesthetic was further increased to 1.3%. However, if no movement was observed, the anesthetic concentration was decreased to 1.0%. If no movement was observed at 1.3%, the anesthetic concentration was decreased to 1.2%. If movement was observed at 1.3%, the end-tidal concentration was altered in 0.1% increments, yielding a resolution of 0.05%. Ten minutes was allowed for each equilibration period for halothane after the initial equilibration at 0.9%.
The volatile anesthetic level was altered, and a similar protocol was used for the determination of MACBAR, MACBS, and MACISOELECTRIC by using an analogous up-down method, with quantification of EEG parameters at each equilibrated end-tidal anesthetic level and at 0.5 MAC at the end of the protocol. The determinations of MACBAR, MACBS, and MACISOELECTRIC were performed in a randomized fashion. After determining that the above anesthetic depth variables were present, systemic hemodynamic variables were also quantified.
In Group II, dexmedetomidine (15 µg/kg) was administered orally to nine animals. Twenty minutes after receiving dexmedetomidine, the animals were anesthetized with halothane, in the same fashion as for Group I. The concentration of halothane resulting in MAC, MACBAR, MACBS, and MACISOELECTRIC was determined, and hemodynamics were quantified. In selected experiments in both groups, phenylephrine was used to maintain mean arterial pressure before determination of MACBS (at 55 mm Hg) and MACISOELECTRIC (at 50 mm Hg). After the experiments, halothane was discontinued, the animals were allowed to recover, and their tracheas were extubated.
Statistical analysis of data within and between groups during the conscious control state, at various halothane anesthesia depths, and during halothane after dexmedetomidine pretreatment was performed by using analysis of variance with repeated measures, followed by Student’s t-tests with Duncan’s correction. Comparison of linear regression analysis between the groups was accomplished using an overall test of coincidence. Changes from control within and between the groups were considered statistically significant when P < 0.05. All data are expressed as the mean ± SEM.
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Results |
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Six cats experienced instrument failure or postoperative surgical complications, and their data were not included in the analyses. The effects of halothane (Group I) and halothane after dexmedetomidine pretreatment (Group II) are listed in Tables 1 and 2, respectively. At all indices of anesthetic depth, halothane resulted in significant decreases in heart rate and arterial pressures. Dexmedetomidine resulted in significant decreases in heart rate, systolic arterial pressure, and the rate-pressure product, but not in diastolic and mean arterial pressures. The decreases in heart rate at all anesthetic depths during the administration of halothane after dexmedetomidine pretreatment, compared with halothane alone, did not reach statistical significance. Higher arterial pressures at 1.0 MAC in the dexmedetomidine group were also not statistically significant. Other hemodynamic variables were similar between the two groups at MACBAR, MACBS, and MACISOELECTRIC. Three animals in each group received phenylephrine during determination of MACBS and MACISOELECTRIC. The MAC determinations for these animals were not different from those whose arterial pressure was not controlled. The hemodynamic data for each subgroup were thus combined.
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The effects of halothane (Group I) and halothane after dexmedetomidine pretreatment (Group II) on EEG activity were similar between the right and left hemispheres. For the sake of simplicity, only the left hemispheric data are presented. Halothane administration resulted in decreases in the percentage of activity in the highest frequency range (12–20 Hz) of the EEG as anesthetic depth increased (36% ± 3% for control to 34% ± 5% for MAC, 22% ± 7% for MACBAR, 17% ± 6% for MACBS, and 12% ± 4% for MACISOELECTRIC) (Table 3, Figure 1A). This decrease in beta activity was significantly different from conscious control at MACBAR, MACBS, and MACISOELECTRIC, but not at MAC. Concurrently, the percentage of activity in the lowest frequency range (delta; 0–4 Hz) increased in both hemispheres (28% ± 2% for control to 35% ± 4% for MAC, 32% ± 4% for MACBAR, 33% ± 6% for MACBS, and 44% ± 2% for MACISOELECTRIC) (Table 3, Figure 1B). Halothane administration resulted in variable changes in both alpha and theta activity and generally decreased the spectral edge frequencies (Table 3, Figure 2).
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As with halothane alone, pretreatment with dexmedetomidine tended to produce a shift to lower EEG frequencies during the administration of halothane. EEG alterations were similar between the two groups. However, there was a significant decrease in beta activity and an increase in delta activity at MACBS after dexmedetomidine pretreatment, compared with halothane alone (Table 4).
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The regression analysis of epochs around the burst suppression determination and corresponding end-tidal concentrations of halothane for Groups I and II are shown in Figure 3. Dexmedetomidine pretreatment resulted in a significant decrease of the slope of the linear regression analysis with a concurrent increase in the scatter of the MAC multiples versus burst suppression ratios.
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The end-tidal concentrations of halothane resulting in the indices of anesthetic depth for MAC, MACBAR, MACBS, and MACISOELECTRIC were 1.22% ± 0.06%, 1.81% ± 0.05%, 3.01% ± 0.17%, and 4.39% ± 0.26%, respectively (Figure 4). Pretreatment with dexmedetomidine (Group II) reduced the percentage of halothane resulting in MAC and MACBAR by 27% and 39%, respectively (from 1.22% ± 0.06% to 0.89% ± 0.8% and from 1.81% ± 0.05% to 1.1% ± 0.10%, respectively). In contrast, the halothane concentrations resulting in MACBS and MACISOELECTRIC after dexmedetomidine pretreatment were not significantly different from those required in the absence of dexmedetomidine (3.01% ± 0.17% vs 3.14% ± 0.10% and 4.39% ± 0.26% vs 4.65% ± 0.12%, respectively).
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Discussion |
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Pretreatment with dexmedetomidine produced a significantly greater action on the concentration of halothane resulting in MAC and MACBAR than those concentrations producing EEG burst suppression or isoelectricity. These findings suggest that anesthetic sparing by dexmedetomidine is dependent on the type of indices used to determine anesthetic depth, which, in turn, varies with the neuraxial level. In the present study, modulations in halothane-induced changes in heart rate, arterial pressure, and EEG activities by dexmedetomidine corresponded to times at which the anesthetic depth indices (MAC, MACBAR, MACBS, and MACISOELECTRIC) were measured, rather than at specific concentrations of halothane.
The autonomic actions of dexmedetomidine may be predominantly mediated at CNS nuclei, including the nucleus tractus solitarius, the rostral and caudal ventrolateral medulla, the locus coeruleus, and the dorsal motor nucleus of the vagus (18). At these caudal brainstem sites, 2-adrenoreceptor activation results in direct vagal activation to the heart and inactivation of descending projections to sympathetic preganglionic cell bodies in the intermediolateral cell column (18,19). These 2-adrenoreceptor sites also modulate projections to supraoptic and supraventricular hypothalamic nuclei attenuating various endocrine cardiovascular mechanisms and partially mediating stress responses (20).
Studies have suggested that the anesthetic-sparing action of dexmedetomidine may lie in the locus coeruleus (4,5). The specific antinociceptive action produced by 2-adrenergic agonists may be mediated primarily at a caudal CNS site of action (8,9). However, studies have demonstrated that a microinjection of 2-adrenergic agonists into the brainstem does not result in significant analgesia and that spinal transection does not alter the analgesic action after systemic administration (21–23). Using decerebrate rats, Rampil et al. (7) demonstrated that MAC does not depend on cortical or forebrain structures but perhaps in the caudal CNS. Other studies have suggested that different concentrations of isoflurane are required to suppress motor responses to different types of nociceptive stimuli (24). Volatile anesthetics alter the activity of the ascending reticular activating system through significant actions at the pons and mesencephalon. These areas of the brainstem reticular system modulate the activity of spinal cord centers and alter motor and sensory spinal reflexes. There are multiple interactions between monoaminergic systems within the CNS and volatile anesthetic requirements. Indeed, cortical consciousness, central autonomic regulation, and response to nociceptive stimuli are often closely linked through reciprocal ascending and descending systems, with monoaminergics as the putative neurotransmitters. Thus, 2-adrenergic agonists may specifically modulate volatile anesthetic requirements at various CNS levels. The anxiolytic, antinociceptive, and antihypertensive effects of 2-adrenergic agonists may be mediated through specific actions at a variety of locations, as there are specific binding sites in noradrenergic and adrenergic brainstem visceral nuclei, the periaqueductal gray column, substantia gelatinosa, locus ceruleus, the intermediolateral cell column, and various limbic areas (23,25). Specific descending catecholaminergic pathways modulate motoneuron activity from both rostral CNS centers and spinal segmental loci. Thus, the ability of dexmedetomidine to decrease MAC, as determined by the response to nociceptive stimuli, may represent an interaction of the continuing modulation of such sensory and motor systems at the brainstem or spinal sites.
MACBAR, as introduced by Roizen et al. (10), represents the anesthetic concentration required to block the adrenergic response to skin incision. The ability of dexmedetomidine to reduce the halothane requirement for MACBAR may represent a decrease in the capacity of the CNS to mount a strong sympathetic response to nociceptive stimuli.
The ability of halothane and dexmedetomidine to alter various EEG parameters has been well documented (14,26). However, no single EEG parameter may reliably predict anesthesia, perhaps reflecting the complex genesis of the EEG. Although the EEG generally reflects cortical activity beneath the recording sites, the cortex is highly dependent on reticulocortical activation and intralaminar and associational thalamic nuclei modulation. Afferent and nociceptive stimulation results in significant EEG activation and desynchronization, whereas anesthesia generally results in widespread cortical rhythmicity before the production of burst suppression and isoelectricity. Adrenergic pathways seem to modulate subcortical processing and autonomic regulation to a significantly greater extent than cortical activity (25). The distribution of 2-adrenergic receptors is consistent with this pattern. Therefore, the failure of dexmedetomidine to reduce the cortical indices of anesthetic action on the CNS may reflect such a distribution of 2-adrenergic receptors.
Electrical stim ulation of reticular formation sites alters the EEG in a way similar to that of arousal after painful stimulation during anesthesia with volatile drugs (27). Removing the arousal influence of the reticular system and depressing synaptic transmission may underlie the EEG effects of general anesthesia. The various derived parameters of the processed EEG that have been used to describe anesthetic action do not all seem to respond to increasing depths of anesthesia in a linear fashion among various anesthetics.1 Anesthetics such as isoflurane and desflurane may produce burst suppression before achieving MACBAR. Indeed, lack of a motor response during isoflurane anesthesia is not an accurate predictor of this drug’s ability to suppress hemodynamic responses to either central (1) or peripheral (28) noxious stimulations. Halothane produces a pattern of anesthetic depth, as measured by the indices of MAC, MACBAR, MACBS, and MACISOELECTRIC, in a linear fashion. In the present investigation, dexmedetomidine did not reduce the anesthetic concentrations of halothane resulting in burst suppression or isoelectricity of the EEG, but it did result in a greater variability at burst suppression levels, perhaps reflecting subcortical modulation (23).
In summary, dexmedetomidine produced a differential anesthetic-sparing action on caudal CNS cardiovascular control centers (decreased MAC and MACBAR) versus telencephalic indices of anesthetic depth (MACBS and MACISOELECTRIC). Such differential actions may reflect the distribution of 2-adrenergic receptor activation within the CNS or differences in the ability of dexmedetomidine to bind to specific 2-adrenoceptor subtypes with diverse distributions within the central nervous system. Results of studies involving the assessment of anesthetic depth and anesthetic-sparing action of 2-adrenergic agonists may depend on the specific index under investigation. Because various anesthetics result in differential effects on various reported indices of anesthetic action within the CNS, care must be used when assessing anesthetic depths when an 2-adrenergic agonist is used in combination with an anesthetic.
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Acknowledgments |
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Supported in part by an Anesthesiology Young Investigator Award from the Foundation for Anesthesiology Education and Research, Ohmeda, and the Society for Pediatric Anesthesia (NEF); by National Institutes of Health Grant R01 GM56398–01 (NEF); and by Research Funds from the Department of Veterans Affairs
We extend our appreciation to David Schwabe for superb technical assistance and to Angela M. Barnes for preparation of the manuscript.
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Footnotes |
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1 Farber NE, Scwabe D, Kampine JP, Schmeling WT. Differential potencies of desflurane on adrenergic responses and the electroencephalogram (EEG): a comparison with halothane and isoflurane [abstract]. Anesthesiology 1994;81:A1484.
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