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Abstract |
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Halothane attenuates the alterations in arterial pressure (BP) and heart rate (HR) produced by central nervous system (CNS) stimulation. We examined the effects of the
2-adrenergic agonist dexmedetomidine, with and without halothane, on cardiovascular regulation during CNS pressor site stimulation in chronically instrumented cats. Stimuli trains via bipolar stimulating electrodes in the hypothalamus and reticular formation elicited pressor responses. Dexmedetomidine-induced (15 µg/kg PO) bradycardia was greater in the presence of halothane. CNS stimulation increased BP and HR, which were dose-dependently attenuated by halothane (hypothalamic stimulation 71 ± 9 mm Hg at control, 25 ± 5 and 15 ± 3 mm Hg at 1.0% and 1.5% halothane, respectively). Although dexmedetomidine alone did not alter pressor responses, halothane plus dexmedetomidine attenuated pressor responses in a potentially synergistic fashion (hypothalamic stimulation 67 ± 8 mm Hg at control, 2 ± 1 and 1 ± 0.4 mm Hg at 1.0% and 1.5% halothane, respectively). These results suggest differences in the disruptive effects of CNS-mediated cardiovascular responses by halothane and dexmedetomidine, and that dexmedetomidine has an anesthetic-sparing effect on these CNS-mediated cardiovascular control mechanisms, potentiating the depressant effect of halothane. Implications: A new potential anesthetic adjunct, dexmedetomidine, does not attenuate brain-mediated increases in blood pressure, but the combination of dexmedetomidine and the anesthetic halothane acts to modulate central cardiovascular responses.
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Introduction |
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Halothane alters normal cardiovascular homeostatic mechanisms through changes in cardiac, vascular, ganglionic, and peripheral autonomic function. Halothane also disturbs the regulation of cardiovascular hemodynamics via alterations within the central nervous system (CNS), including disruption of baroreflex function (1), tonic vagal efferent activity (2), and modulation of either central neuronal processing or the generation of appropriate efferent responses (3). Previous studies from this laboratory (3–5) have demonstrated that the volatile anesthetics isoflurane and halothane attenuate the hemodynamic alterations that occurred after electrical stimulation of several CNS pressor sites in both acute and chronically instrumented animals. These results suggest that volatile anesthetics alter hemodynamic stability, at least in part, by disruption of cardiovascular control centers.
The 2-adrenergic agonists, including dexmedetomidine and clonidine, are useful as anesthetic adjuvants in producing analgesia and sedation, decreasing anesthetic requirements, reducing postanesthetic shivering, and improving hemodynamic stability (6–8). These effects may result from decreased CNS sympathetic outflow mediated by 2-adrenoceptor stimulation in medullary bulbar vasomotor and cardiac centers (6,8). Peripheral receptors contribute to blood pressure-decreasing actions of 2-agonists. However, the predominant mechanism for the hypotensive actions seems to be mediated by adrenergic neurons involved in cardiovascular and vasomotor control mechanisms within brainstem CNS control centers. Significant differences in hemodynamic responses to anesthetics are evident after 2-adrenergic pretreatment. Whether the anesthetic-sparing action of dexmedetomidine also extends to other CNS-mediated cardiovascular control mechanisms is unknown.
The purpose of the present investigation was to examine a potential modulatory action of dexmedetomidine on halothane-induced alterations in heart rate (HR) and systemic arterial pressure (BP) responses to electrical stimulation of CNS cardiovascular control sites in chronically instrumented cats.
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Methods |
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Experimental procedures were reviewed and approved by the Medical College of Wisconsin Animal Use and Care Committee, and protocols were completed in accordance with the Guiding Principles in the Care and Use of Laboratory Animals of the American Physiological Society and with National Institutes of Health guidelines. Animals were housed in animal facilities at the Medical College of Wisconsin, which is accredited by the American Association for the Accreditation of Laboratory Care.
Twenty-three cats were used for these experiments; successful experiments were performed in nine animals. Not all animals completed all protocols because of instrument failures. Animals were fasted overnight before experimentation. Saline 0.9% was used as fluid replacement. Animals were anesthetized by inhaled halothane, their tracheas were intubated, and their lungs were mechanically ventilated with halothane in oxygen. All procedures were performed under aseptic conditions. The right carotid artery and external jugular vein were cannulated for measurement of arterial pressure and for fluid and drug administration, respectively. Arterial blood samples were determined for measurements of gas tensions. Ventilation was adjusted to maintain normal PaCO2. Catheters were tunneled subdermally to a lateral thoracic exit site. While in a stereotaxic restraint, the skull was exposed through a midline incision. Burr holes were created through the calvarium, and 23-gauge coaxial stimulating electrodes (resistance 60–80 k
) were stereotaxically placed in target sites in the right ventrolateral hypothalamus (anterior 10.0 mm, lateral 2.5 mm, depth -3.0 to -5.0 mm) and left mesencephalic reticular formation (anterior 2.0 mm, lateral 2.0 mm, depth 0.0 to -2.0 mm) (9). The electrodes were advanced toward the target depths in 500-µm increments, with stimulation at each depth, to determine the optimal position for eliciting pressor responses. The pressor stimulus was a 10-s train of 0.05- to 0.1-ms square-wave pulses delivered at 100 Hz through a constant current unit using digital stimulators (WPI Electronics, New Haven, CT).
Electrodes were then connected to a miniature headplate anchored to the skull, and tissue layers were closed. Animals were allowed to recover for a minimum of 7 days. Animals were fitted with a jacket (Alice King Chatham, Los Angeles, CA) that housed the arterial and venous catheters and were trained to rest quietly in a restraining sling.
On experimental days, each cat was placed in the sling, and BP, HR, respiratory rate, and temperature were monitored and recorded on a Grass polygraph and FM tape (AR Vetter, Rebersburg, PA). Stimulation trains (100 Hz, 0.1–0.3 ms, 10.0 s) were delivered to either the hypothalamic or reticular formation site to elicit a small (5–10 mm Hg) and consistent increase in BP (threshold current). Threshold and 2x and 4x threshold current were then administered at 3- to 5-min intervals, and a series of two to three sequential responses to stimuli was obtained before the administration of halothane or dexmedetomidine.
Halothane (n = 8), dexmedetomidine (n = 6), or halothane with dexmedetomidine pretreatment (n = 7) was administered on separate days to each animal in random order. In the first set of experiments, halothane, administered in oxygen, was randomly administered at 0.7%, 1.0%, and 1.5% end-tidal concentrations as measured by a mass spectrometer and 1.0 minimum alveolar anesthetic concentration (MAC) (1.2% ± 0.05%) (10). A minimum of 30 min elapsed between each change in anesthetic concentration and stimulus presentation. Stimulisequences were randomized, and graded pressor responses were determined at each anesthetic concentration. On completion of the stimulus sequences, there was a 30- to 90-min period without halothane, and electrode sites were again stimulated. In the second set of experiments, dexmedetomidine (15 µg/kg PO) was administered to conscious cats, and the electrical stimuli were repeated over a time course similar to the above protocol. The third protocol involvedpretreatment with dexmedetomidine (15 µg/kg PO), followed immediately by the administration of halothane, as in Group 1 (MAC of halothane with 15 µg/kg PO dexmedetomidine 0.81 ± 0.05) (10).
Cats were killed with an overdose of pentobarbital, and stimulation sites were marked by passing a direct current between the tip of each electrode and an indifferent ground at the conclusion of all experiments. The brain was perfused in situ with saline, then with 10% formalin-saline solution (vol/vol). The brain was removed from the skull and placed in 10% formalin-saline solution with 0.5% sodium ferrocyanide to complete fixation and to develop Prussian blue marks at the electrode tip sites. After fixation for 48 h, the brains were cut into blocks, frozen, and sectioned for histological determination of electrode sites.
Pressor responses were calculated as the change in BP from baseline measurements taken immediately before stimulation of each CNS site. Pressor responses before and during halothane or dexmedetomidine administration were analyzed by using a repeated-measures analysis of variance. Statistical analyses were performed using SAS procedure GLM software (SAS Institute, Cary, NC). A Bonferroni multiple comparison procedure was used to make comparisons between treatment groups for a single site, dose, and stimulation current intensity, and for comparing halothane or dexmedetomidine with the control at a single site and voltage level. All changes were considered significant when the P value was <0.05. Data are expressed as mean ± SEM.
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Results |
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Animals weighed 2.0–3.4 kg, and there was no significant difference among groups. There were no differences among groups of animals in HR or BP at baseline control before the administration of halothane, dexmedetomidine, or both. The effects of dexmedetomidine on HR and systolic BP are demonstrated in Figure 1. Oral dexmedetomidine significantly but transiently decreased HR (from 216 ± 15 bpm at control to 165 ± 13 bpm 60 min after administration). There was a trend toward decreased BP after dexmedetomidine, although the changes did not reach statistical significance. The effects of halothane in the presence and absence of dexmedetomidine on systemic hemodynamics are shown in Table 1. Halothane dose-dependently decreased HR and BP. The addition of dexmedetomidine further enhanced the bradycardic actions of halothane with minimal effects on the halothane-mediated alterations in BP.
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Stimulation of both the hypothalamic and reticular formation vasomotor sites produced significant current-dependent pressor responses during baseline-control conditions (Figures 2 and 3). Reticular formation stimulation also produced a stereotypic "alerting response," characterized by bilateral pupillary dilation, mild tachypnea, head movement, and behavioral evidence of increased attentiveness. The administration of dexmedetomidine had no significant effects on the stimulation-induced increases in BP at any current level of stimulation in either the hypothalamus or the reticular formation (4x threshold stimulation of hypothalamus, control 64 ± 10 mm Hg; dexmedetomidine at 15 min 55 ± 12; dexmedetomidine at 60 min 66 ± 9 mm Hg). Hypothalamic stimulation increased HR (64 ± 10 mm Hg at 4x threshold current), whereas stimulation of the reticular formation caused variable and inconsistent alterations in HR. Although dexmedetomidine alone did not attenuate the stimulation-induced tachycardic responses (Table 2), the behavioral manifestations of the alerting response to stimulation seemed to be blunted.
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Halothane dose-dependently attenuated the pressor responses to hypothalamic and reticular formation stimulation (hypothalamus at 4x threshold: 71 ± 9 mm Hg at control, 25 ± 5 and 15 ± 3 mm Hg at 1.0% and 1.5% halothane, respectively) (Fig. 3). Although 0.7% halothane seemed to produce a degree of anesthesia, reticular formation stimulation produced behavioral attentiveness, as observed in the conscious state. These effects lasted approximately 20 s after stimulus presentation. Halothane 1.0% and 1.5% diminished these behavioral effects, in addition to the marked attenuation of the CNS-induced pressor responses. Halothane also blunted the stimulation-induced tachycardia (Table 2).
The combination of halothane and dexmedetomidine attenuated CNS-mediated pressor responses in a synergistic fashion, predominantly at the level of the hypothalamus (hypothalamus at 4x threshold: 67 ± 8 mm Hg at control, 2 ± 1 and 1 ± 0.4 mm Hg at 1.0% and 1.5% halothane, respectively) (Fig. 3). During 1.0 MAC halothane in the presence of dexmedetomidine (0.8% halothane) (10), the pressor response during hypothalamic stimulation was markedly attenuated (5 ± 2 mm Hg) compared with the response at 1.0 MAC halothane (1.2% halothane) in the absence of dexmedetomidine (18 ± 4 mm Hg). Pretreatment with dexmedetomidine also enhanced the effects of halothane on inhibiting the tachycardic response to CNS stimulation. Figures 4 and 5 show typical pressor responses to CNS stimulation during dexmedetomidine, halothane, or both.
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Histologic examination showed that hypothalamic and reticular formations were located within 1.0–1.6 mm of the target coordinates in all three axes. Hypothalamic sites were located in the ventrolateral hypothalamus adjacent to the third ventricle, extending caudally to the mammillotegmental tract and rostrally toward the mammillothalamic tract. Reticular formation sites were located slightly lateral to the periaqueductal gray area and included the central tegmental field. Thus, electrode placement sites for electrical stimulation were within generally accepted boundaries of the target pressor regions and in locations similar to those reported previously (4,5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present investigation, we demonstrated that electrical stimulation of ventrolateral hypothalamic and mesencephalic reticular formation vasomotor sites in conscious, chronically instrumented cats produced dramatic, current-dependent increases in BP. Halothane administration significantly attenuated these CNS-mediated pressor responses. Although the
2-adrenergic agonist dexmedetomidine did not affect the stimulation-induced increases in BP, the attenuation of central pressor responses by halothane was significantly greater in the presence of dexmedetomidine. The mechanism(s) by which halothane attenuates CNS stimulation-induced pressor responses may involve actions along the sympathoexcitatory pathway, including alteration of the responsiveness of CNS cardiovascular/vasomotor centers. Previous findings suggest that this CNS modulation of cardiovascular homeostasis by halothane is important (3,4,11,12). Halothane, delivered to an isolated cephalic circulation, decreased BP, HR, and hemodynamic responses to carotid sinus occlusion (11). In vagotomized, decerebrate dogs, microinjections of halothane decreased medullary-stimulated pressor and depressor responses (12), which suggests a halothane-induced depression of CNS-mediated cardiovascular responses.
Halothane and isoflurane differentially alter CNS cardiovascular control centers (3–5). Previous studies from this laboratory demonstrated that isoflurane attenuated hemodynamic responses after CNS stimulation in chronically instrumented cats and dogs (3,5). The inhibitory effects of halothane on CNS-induced pressor responses are consistent with previous findings that halothane attenuated responses to hypothalamic, mesencephalic, or medullary stimulation (3,4). This attenuation and the stimulation current intensities required to elicit a threshold response are altered in the presence of baseline anesthetics (3); thus, in the present study, no baseline anesthetic was used. The depression of CNS neuronal activity by halothane is not specific to cardiovascular control centers, as the administration of halothane attenuates excitation of mesencephalic reticular formation neurons (13), thermosensitive neurons in the preoptic region of the anterior hypothalamus (14), and locus coeruleus neurons (15). In the present investigation, animals displayed an increase in behavioral attentiveness after stimulation, consistent with ascending reticular activation of rostral CNS sites. Low concentrations of halothane produced a light anesthesia, with preservation of such responses; higher levels of anesthesia, however, attenuated the behavioral responses.
The present results demonstrate an absence of effect of dexmedetomidine, when administered alone, on CNS-mediated pressor responses, which is somewhat surprising in light of previous findings with 2-adrenergic agonists. The 2-agonists, specifically dexmedetomidine, have many desirable actions, and their analgesia, sedative/hypnotic effects, and improved hemodynamic stability have made them useful anesthetic adjuvants (6–8,16,17). In addition, dexmedetomidine decreases anesthetic requirements and produces similar alterations in electroencephalographic activity in cats, as does halothane (18). Dexmedetomidine-induced alterations in hemodynamics occur via diminished sympathetic and/or augmented parasympathetic tone. Because 2-adrenoceptor agonists both reduce the amount of norepinephrine released from sympathetic nerve terminals and activate central receptors, any cardiovascular function that is modulated by sympathetic tone may be affected. This class of drugs has minimal direct effects on the heart but generally reduce myocardial contractility and HR by reducing sympathetic tone to the heart. Additionally, they may affect cardiovascular function by effects on coronary blood flow and, indirectly, by activation of the vagosympathetic trunk (8). Importantly, although the 2-adrenergic agonists result in a lowering of a set point for systemic BP and, thus, possibly increase in the gain of the baroreceptor system, dexmedetomidine preserves baroreceptor reflexes during halothane anesthesia (19). Baroreflexes may be maintained via an anesthetic-sparing action with a resultant lowered concentration of halothane, minimizing baroreceptor disruption (19). Such a preservation of the baroreceptor reflex may provide an important mechanism for maintenance of cardiovascular stability and a reason, in part, for the lack of effect on CNS pressor responses by dexmedetomidine. However, midazolam and etomidate, which both preserve baroreflexes to a great degree, significantly attenuate pressor responses to hypothalamic and reticular formation stimulation (5). In addition, although isoflurane preserves baroreflex control mechanisms and sympathetic efferent outflow more than halothane, the attenuation of central pressor responses by isoflurane (5) and halothane was similar. One difference between the central modulation of isoflurane and halothane is that during emergence from isoflurane, pressor responses are often converted to depressor responses (3,5). These paradoxical responses, which may be caused by a blunting of predominantly excitatory transmission at low residual levels of isoflurane, did not occur after the administration of halothane in the presence or absence of dexmedetomidine.
The reduction of the MAC of volatile anesthetics after pretreatment with dexmedetomidine is a well recognized phenomenon (10, 19, 20). In the present study, despite the reduction in MAC, lower concentrations of halothane, when combined with dexmedetomidine to provide equi-MAC levels, produce significantly greater attenuation of CNS-mediated pressor responses than those observed with halothane alone. Thus, the enhancement of halothane effects by dexmedetomidine is not due to an anesthetic-sparing action. Indeed, the results of this study suggest that dexmedetomidine has an anesthetic-sparing effect on the CNS modulation of cardiovascular control by halothane. Although this modulation seems to be synergistic, true isobolographic analysis to aid in this confirmation was not performed in the present investigation. Thus, it is also possible that the dexmedetomidine dose used was subthreshold and that an additive effect occurred only when given with a suprathreshold dose of halothane.
Control of cardiovascular responses involves neuronal integration at many neuraxial levels. Vasomotor centers include sites within the hypothalamus, reticular formation, medulla, and cerebellum (3,21,22). The hypothalamus, reticular formation, and major primary afferent terminations of the baroreceptors, including the nucleus tractus solitarius, have extensive interconnections that modulate cardiovascular homeostasis. Cardiovascular control centers in the hypothalamus and reticular formation modulate sympathetic outflow partially through diffuse polysynaptic neuronal pathways. The nucleus tractus solitarius and paramedian reticular nucleus receive the primary afferent fibers of the baroreceptors (23). Secondary neurons project to the intermediolateral cell column of the spinal cord and to brainstem areas, the hypothalamus, and the rostral and ventral lateral medulla. Halothane may modulate CNS-induced pressor responses by specific actions predominantly at any of these sites or at secondary projections at this level, including those to the medulla or the mesencephalic reticular formation (3,4). The CNS modulation of cardiovascular function by halothane is dependent on an intact suprabulbar system and may be partially independent of forebrain structures (4). 2-Adrenergic agonist-induced alterations in cardiovascular regulation may also be mediated at brainstem nuclei. The ventrolateral medulla, which is involved in the tonic maintenance of systemic arterial pressure, is under tonic modulation from the nucleus tractus solitarius and has neuronal projections directly to the sympathetic preganglionic cell bodies in the intermediolateral cell column (24). It is also a candidate for a loci of action for dexmedetomidine. The locus coeruleus, a site of action for the hypnotic effect of dexmedetomidine (25) with diffuse CNS projections, may also be involved in the CNS modulation of cardiovascular responses by halothane. Studies with in vitro brain slices suggest a strong interaction of halothane with dexmedetomidine at this brainstem level (15).
Methodological limitations of the present study include the possibility of current spread and electrolytic lesions. The importance of these factors have been lessened by minimizing electrode manipulation and by using threshold current levels. In addition, stimulation of areas adjacent to the target regions do not produce similar hemodynamic responses (unpublished observations). Carotid artery cannulation may compromise cerebral blood flow; however, there is no evidence of cerebral ischemia in behavior, hemodynamics, or regional electroencephalogram. Finally, although the use of a single dose of dexmedetomidine does not exclude the possibility that this anesthetic affects CNS pressor responses at larger doses, the observation that there were significant systemic hemodynamic alterations and modulation of the halothane-mediated response at the dose studied is of primary importance.
In summary, the present results suggest that although halothane alters cardiovascular homeostasis via multiple peripheral mechanisms, modulation of central neuronal pools responsible for cardiovascular control may contribute to the alterations in hemodynamic regulation produced by halothane. In contrast, although dexmedetomidine itself does not exhibit significant effects on central vasomotor responses, it significantly modulates the effects of halothane on these responses.
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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, Society for Pediatric Anesthesia and Ohmeda (NEF) and by National Institutes of Health Grant RO1 GM 56398–01 (NEF) and Medical Research Funds from the Department of Veteran Affairs.
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