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Anesth Analg 2003;97:748-754
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Epidural Clonidine Suppresses the Baroreceptor-Sympathetic Response Depending on Isoflurane Concentrations in Cats

Yoshikazu Ikeda, MD*, Kiyonobu Nishikawa, MD*, Kenji Ohashi, MD{dagger}, Takashi Mori, MD*, and Akira Asada, MD*

*Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Osaka, Japan; and {dagger}Department of Anesthesia, Hoshigaoka Kosei-nenkin Hospital, Osaka, Japan

Address correspondence and reprint requests to Dr. Kiyonobu Nishikawa, Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545-8586, Japan. Address e-mail to kiyonishikawa{at}msic.med.osaka-cu.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Epidural administration of clonidine induces hypotension and bradycardia secondary to decreased sympathetic nerve activity. In this study, we sought to elucidate the change in baroreflex response caused by epidural clonidine. Thirty-six cats were allocated to six groups (n = 6 each) and were given either thoracic epidural clonidine 4 µg/kg or lidocaine 2 mg/kg during 0.5, 1.0, or 1.5 minimum alveolar anesthetic concentration (MAC) isoflurane anesthesia. Heart rate (HR), mean arterial blood pressure (MAP), and cardiac sympathetic nerve activity (CSNA) were measured. Depressor and pressor responses were induced by IV nitroprusside 10 µg/kg and phenylephrine 10 µg/kg, respectively. Baroreflex was evaluated by the change in both CSNA and HR relative to the peak change in MAP ({Delta}CSNA/{Delta}MAP and {Delta}HR/{Delta}MAP, respectively). These measurements were performed before and 30 min after epidural drug administration. Epidural clonidine and lidocaine decreased HR, MAP, and CSNA by similar extents. {Delta}CSNA/{Delta}MAP and {Delta}HR/{Delta}MAP for depressor response were suppressed with epidural lidocaine and clonidine in all groups but the clonidine 0.5 MAC isoflurane group (0.197 ± 0.053 to 0.063 ± 0.014 and 0.717 ± 0.156 to 0.177 ± 0.038, respectively, by epidural lidocaine [P < 0.05] but 0.221 ± 0.028 to 0.164 ± 0.041 and 0.721 ± 0.177 to 0.945 ± 0.239, respectively, by epidural clonidine during 0.5 MAC isoflurane). Those for pressor response were suppressed in all groups. We conclude that thoracic epidural clonidine suppresses baroreflex gain during isoflurane anesthesia >1.0 MAC but may offer certain advantages compared with epidural lidocaine during 0.5 MAC isoflurane by virtue of preserving baroreflex sensitivity when inadvertent hypotension occurs.

IMPLICATIONS: Epidural clonidine reduces blood pressure, heart rate, and sympathetic nerve activity but suppresses baroreflex gain, depending on background isoflurane anesthesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Epidural administration of clonidine reduces requirements for general anesthetics, provides postoperative analgesia (1–3) without respiratory suppression (4), and also yields hemodynamic stability, primarily by suppression of sympathetic nerve activity (5). In our previous animal studies, suppression of sympathetic nerve activity, hypotension, bradycardia, and attenuation of intracardiac conduction produced by epidural clonidine (6) were comparable to those with epidural lidocaine (7). Reduction of cardiac work by decreased arterial blood pressure and heart rate (HR) is especially beneficial for patients with ischemic heart disease (8,9). However, the baroreflex is an essential circulatory regulating reflex that compensates for hypotension and restores blood flow to the vital organs by increasing HR and by constricting peripheral (skin and muscle) resistance vessels. Baroreflex sensitivity has been reported to be suppressed by volatile anesthetics (10), cervicothoracic epidural anesthesia (11), and large doses of IV local anesthetics (12). Therefore, baroreflexes are significantly affected by combined general/epidural anesthesia with cardiac sympathectomy (13,14). Sudden bradycardia and severe hypotension secondary to decreased venous return or surgical bleeding can occur during combined general/thoracic epidural anesthesia because of decreased sympathetic response and increased vagal activation.

The effects of systemic administration of clonidine on baroreflex regulation differ from study to study, depending on species, background anesthesia, and presence or absence of hypertension (15–21). However, intrathecal administration of clonidine attenuates baroreflexes in awake sheep by sympatholysis at spinal sites (22).

No information is available on the effects of epidurally administered clonidine during general anesthesia on baroreflex-sympathetic responses. We hypothesized that epidural clonidine might preserve baroreflex-sympathetic responses during isoflurane anesthesia and tried to elucidate this hypothesis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by our institution’s Animal Research Committee. Thirty-six mongrel cats of either sex that weighed 2.5–4.0 kg were anesthetized with isoflurane (5%) in oxygen in a polyethylene box. After IM administration of 20 mg of succinylcholine, cats were intubated orotracheally and mechanically ventilated (SN-480-5; Shinano, Tokyo, Japan). During surgical preparations, anesthesia was maintained with isoflurane (2.0%–2.5%) and 0.5 mg of vecuronium bromide every hour. End-expiratory concentrations of isoflurane and carbon dioxide were monitored continuously (Capnomac Ultima; Datex, Copenhagen, Denmark). Arterial blood gas analyses were performed with an ABL-4 (Radiometer, Copenhagen, Denmark) every 40 min. The partial pressures of carbon dioxide and oxygen were maintained between 35 and 45 mm Hg and >300 mm Hg, respectively, by adjusting the ventilator variables (tidal volume, frequency of respiration, and the inspiration/expiration ratio).

Metabolic acidosis was corrected with IV administration of 8.4% (wt/vol) sodium bicarbonate at (body weight x 0.2 x base excess) milliliters if base excess was less than -5 mEq/L; this was required in two cats in all experiments. Rectal temperature was maintained between 36.5°C and 37.5°C with an electric heater on the experimental table. Maintenance crystalloid fluids (lactated Ringer’s solution at 5 mL · kg-1 · h-1) and drugs were administered via a femoral vein polyethylene cannula. The intracardiac electrocardiogram was monitored by inserting multipolar catheter electrodes via the right femoral vein. Arterial blood pressure was continuously monitored with a femoral cannula. An 18-gauge epidural catheter (Hakko Medical, Tokyo, Japan) was inserted into the epidural space under direct observation and advanced 3 cm cephalad via a small window made at the T8 lamina.

The cats were placed in the right lateral position. A left thoracotomy was performed at the second intercostal space. Details of measurements and recording of cardiac sympathetic nerve activity (CSNA) have been described elsewhere (6,7). Briefly, after identification of the left stellate ganglion, the ventral medial or the ventral lateral nerve was followed approximately 2 cm distally. The nerve was cut distally, and the proximal end of the nerve was placed on a bipolar hook-shaped silver wire electrode (0.4 mm in diameter) and immersed in liquid paraffin. The nerve signal was magnified with a high-gain biophysical amplifier (AB-601G; Nihon Kohden, Tokyo, Japan) that had a time constant of 0.003 s and a high-cut filter of 1 kHz. Nerve activity was quantified by feeding the amplified output to an integrator (EI-601G; Nihon Kohden). CSNA was quantified by integrating the full-wave rectification of amplified nerve signals at 5-s intervals. Recorded activity was confirmed as cardiac sympathetic efferent activity by the finding that nerve activity was synchronous with spontaneous HR fluctuation and nearly disappeared in response to increased arterial blood pressure immediately after IV injection of norepinephrine 3 µg/kg (6,7). The actual CSNA was calculated by subtracting the height of the integrated wave of baseline noise from the heights of integrated responses. Baseline noise without nerve activity was determined at the death of the animal. The CSNA was not calibrated with a known input signal, but the amplifier setting was unchanged in all experiments, and the preparation of the nerve bundle was performed carefully so that the integrated signal would be a linear function of the raw CSNA signals.

Cats were randomly assigned to one of six groups, depending on the epidurally administered drug (clonidine or lidocaine) and on the concentration of isoflurane for background anesthesia (0.8% [0.5 minimum alveolar anesthetic concentration; MAC], 1.6% [1.0 MAC], or 2.4% [1.5 MAC] end-tidal concentration). Each group included six cats. The 4 µg/kg dose of epidural clonidine was chosen because it had the most potent hypotensive effect derived from profound suppression of the CSNA, accompanied by a less direct peripheral vasoconstrictive effect than a larger dose of clonidine in the cat (6). Clonidine solution was prepared by dissolving crystals of clonidine hydrochloride (Sigma, St. Louis, MO) in normal saline so that the volume of drug solution relative to body weight was 0.2 mL/kg in all experiments. The dose of epidural lidocaine was 2 mg/kg. Commercial 1% lidocaine was used to match the volume of its solution to that of the clonidine solution.

After surgical preparations, the concentration of isoflurane was changed so that the end-expiratory isoflurane concentration became the predetermined MAC value for measurement. After stabilization of mean arterial blood pressure (MAP), HR, and CSNA, baseline measurements were performed. Baroreflexes were tested both for depressor and pressor responses. MAP was artificially decreased by bolus IV administration of sodium nitroprusside 10 µg/kg. After MAP, HR, and CSNA recovered to baseline levels, MAP was artificially increased by bolus IV administration of phenylephrine 10 µg/kg. Thirty minutes after the epidural drug administration of clonidine or lidocaine, these measurements were repeated. In the clonidine-administered groups, an {alpha}2-adrenergic antagonist, yohimbine 200 µg/kg, was administered IV to confirm reversal of hemodynamic changes and baroreflex sensitivity. In the lidocaine groups, recovery of hemodynamic change and baroreflex was confirmed approximately 2 h after epidural drug administration.

Baroreflex gain was evaluated by the changes in both CSNA and HR relative to the change in MAP. {Delta}CSNA/{Delta}MAP (ratio of the peak change in CSNA to the peak change in MAP) and {Delta}HR/{Delta}MAP (ratio of the peak change in HR to the peak change in MAP), which represent the slopes of the baroreflex curves, were examined. MAP, HR, CSNA, and baroreflex gain were compared between baseline and 30 min after epidural drug administration and also among isoflurane concentrations.

All values are expressed as means ± SE. Data were analyzed by repeated-measures analysis of variance and contrast. Findings of P value <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Figure 1 shows an original tracing of MAP, HR, CSNA, and integrated CSNA after the administration of sodium nitroprusside and phenylephrine at control measurements under 0.5 MAC isoflurane anesthesia. CSNA and HR increased and MAP decreased with nitroprusside. However, CSNA almost disappeared and HR decreased, whereas MAP increased, with phenylephrine.



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  		Figure 1. A tracing presenting changes of heart rate (HR), mean arterial blood pressure (MAP), and cardiac sympathetic nerve activity (CSNA) induced by IV nitroprusside 10 µg/kg and phenylephrine 10 µg/kg during 0.5 minimum alveolar anesthetic concentration of isoflurane anesthesia in the absence of epidural drug administration. HR and CSNA were increased by baroreflexes, whereas MAP was decreased with nitroprusside and HR was decreased, CSNA was almost abolished, and MAP was increased with phenylephrine.

 
There were no significant differences between the clonidine group and the lidocaine group at the same concentration of isoflurane in baseline values of MAP, HR, or CSNA. The baseline values of MAP and CSNA decreased as the concentration of isoflurane was increased, but the baseline value of HR was not significantly changed (Table 1).


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  		Table 1. The Baseline Values of Mean Arterial Blood Pressure, Heart Rate, and Cardiac Sympathetic Nerve Activity
 
Baseline values of baroreflex-CSNA gain ({Delta}CSNA/{Delta}MAP) for the depressor test tended to decrease as the concentration of isoflurane was increased, although this change did not reach significance. Baroreflex-HR gain ({Delta}HR/{Delta}MAP) for the depressor test significantly decreased with an increase in isoflurane concentration. Both {Delta}CSNA/{Delta}MAP and {Delta}HR/{Delta}MAP for the pressor test were decreased as isoflurane concentration was increased (Table 2).


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  		Table 2. The Change in Baroreflex Sensitivity During the Depresser Test and Pressor Test
 
Epidural clonidine 4 µg/kg and epidural lidocaine 2 mg/kg reduced MAP, HR, and CSNA to similar extents when the concentration of isoflurane was the same (Fig. 2). Baroreflex-CSNA gain for the depressor response after clonidine administration was not significantly different from the control value during 0.5 MAC isoflurane. However, those during 1.0 and 1.5 MAC isoflurane were decreased significantly compared with the corresponding control values. Baroreflex-CSNA gains for pressor response were significantly decreased with epidural clonidine from the corresponding control values for all three concentrations of isoflurane. Baroreflex-CSNA gains for both depressor and pressor responses were significantly reduced from the corresponding control values after lidocaine administration for all three concentrations of isoflurane (Table 2).



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  		Figure 2. The magnitudes of suppression of mean arterial blood pressure (MAP), cardiac sympathetic nerve activity (CSNA), and heart rate (HR) by epidural clonidine and lidocaine were compared. Data are values relative to the baseline values before epidural drug administration at each isoflurane concentration. MAC = minimum alveolar anesthetic concentration.

 
Baroreflex-HR gain for depressor response after clonidine administration was not significantly different from the control value during 0.5 MAC isoflurane. However, those during 1.0 and 1.5 MAC isoflurane were decreased significantly compared with the corresponding control values. Baroreflex-HR gains for the pressor response with epidural clonidine were significantly decreased from the corresponding control values with all three concentrations of isoflurane. Baroreflex-HR gains for both the depressor and pressor responses were significantly reduced after lidocaine administration from the corresponding control value with all three concentrations of isoflurane (Table 2).

Notably, the magnitude of MAP increase with phenylephrine tended to increase after epidural clonidine administration and reached significance for 1.0 MAC isoflurane, whereas the magnitude of MAP decrease with nitroprusside was unchanged. In addition, MAP increase with phenylephrine was larger during 1.5 MAC isoflurane than during 0.5 and 1.0 MAC isoflurane. The MAP increase with phenylephrine and MAP decrease with nitroprusside were unchanged after epidural lidocaine. The MAP increase with phenylephrine was larger after epidural lidocaine during 1.5 MAC isoflurane than during 1.0 MAC isoflurane (Fig. 3).



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  		Figure 3. Peak decrease and increase in mean arterial blood pressure (MAP) by sodium nitroprusside and phenylephrine, respectively, were compared between control and after epidural clonidine, between control and after epidural lidocaine, and among the concentrations of isoflurane tested. Epidural clonidine augmented the peak increase in MAP during 1.0 minimum alveolar anesthetic concentration (MAC) isoflurane. The peak increase in MAP during 1.5 MAC isoflurane was larger than those during 0.5 and 1.0 MAC isoflurane. However, peak increase was unaffected by epidural lidocaine, and peak decrease was unaffected by either epidural clonidine or lidocaine. {Delta}MAP = peak change in MAP. *P < 0.05 compared with control; {dagger}P < 0.05 compared with 0.5 MAC; {ddagger}P < 0.05 compared with 1 MAC.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of our study are the following: 1) epidural clonidine and lidocaine decreased HR, MAP, and CSNA to similar extents and 2) {Delta}CSNA/{Delta}MAP and {Delta}HR/{Delta}MAP for the depressor response were suppressed by epidural clonidine 4 µg/kg, depending on isoflurane concentration, but were suppressed by epidural lidocaine 2 mg/kg independently of isoflurane concentration. Those for pressor response were suppressed in all groups.

Epidural clonidine at 4 µg/kg during 0.5 MAC isoflurane decreased baseline MAP, HR, and CSNA and thereby shifted the baroreflex response curve toward smaller values. Baroreflex-sympathetic and baroreflex-HR responses, which account for the ability of the cardiovascular system to compensate for sudden hypotension, were preserved. However, net cardiac work likely decreased after epidural clonidine, perhaps yielding cardioprotective effects.

Cervicothoracic epidural lidocaine has been reported to attenuate pressor baroreflexes but to maintain depressor baroreflexes (11). Lumbar epidural bupivacaine has been reported to enhance both depressor and pressor baroreflex due to increased cardiac sympathetic activity at unanesthetized segments and increased vagal activity by reduced venous return (23). In our study, thoracic epidural lidocaine during isoflurane anesthesia suppressed both depressor and pressor responses, partly consistent with previous reports (13,14). Our study also showed that the effects of epidural clonidine and epidural lidocaine on baroreflexes differed. The interaction between the effects of isoflurane and epidural clonidine on baroreflex depressor responses was minimal at 0.5 MAC isoflurane but appeared to be cooperative at a larger concentration of isoflurane. However, baroreflex sensitivity was consistently suppressed by epidural lidocaine at all concentrations of isoflurane. This difference may be due to the fact that the sites act differently between epidural clonidine and epidural lidocaine, although there is a potential for a Type II statistical error due to the small sample size in this study, and species effects are likely (15–22). The sites of epidural clonidine to act are still controversial. Epidural clonidine acts not only at the spinal cord (24), but also at supraspinal sites by systemic absorption (25) and rostral diffusion in the cerebrospinal fluid (26). Epidural lidocaine at a clinically relevant dose during general anesthesia suppresses sympathetic activity both by axonal conduction block at the spinal cord and from central nervous system (CNS) effects by systemic absorption, but the former is more dominant (7,27). Isoflurane suppresses synaptic transmission both at the CNS and spinal cord (28). Clonidine seems to share many more action sites with isoflurane than lidocaine. Because we tested a single dose of lidocaine and clonidine, a further dose-response study will be needed to clarify the mechanism of the pharmacological interaction.

We were unable to assess the effect of 0.5 MAC isoflurane alone on baroreflex control because of the lack of an awake control. However, in a human study, 0.5 MAC isoflurane decreased the cardiac baroslope but preserved the sympathetic baroslope (29). Epidural clonidine suppressed the baroreflex for depressor response depending on isoflurane concentration. This suggests that isoflurane and epidural clonidine may act at the same sites of the baroreflex arc, in part, cooperatively. Epidural clonidine markedly reduces the intraoperative isoflurane supplementations (3) and depresses the electroencephalogram during enflurane/nitrous oxide anesthesia (30). Taking into account these facts, our result that epidural clonidine preserves baroreflexes for the depressor response during 0.5 MAC isoflurane anesthesia is clinically relevant.

Baroreflex-HR gain for pressor responses was suppressed by both epidural clonidine and lidocaine. This appeared to be due to the preexisting cardiac sympathectomy induced by epidural clonidine or lidocaine, which does not allow further sympathetic suppression and minimizes the additional effect of vagal activation on HR decrease. Prevention of HR reduction on increases in MAP may result in circulatory stability (20). Isoflurane and epidural clonidine enhanced the peak MAP increase by phenylephrine but did not affect the peak MAP decrease induced by nitroprusside. An augmented pressor response to phenylephrine and a tachycardic response to isoproterenol by oral clonidine, presumably caused by increased responses at postjunctional adrenoreceptors, have been reported (21,31). This enhancement of MAP increase might also have contributed to the apparent decrease in baroreflex gain for pressor responses, because CSNA is fully suppressed at more than a certain MAP.

This study aimed to elucidate the effects of epidural clonidine on baroreflex control and therefore was not designed to assess the analgesic effect itself. However, an initial dose of 4 µg/kg of epidural clonidine used as a sole analgesic has been reported to possess a modest analgesic effect in major abdominal surgery (2). Thoracic epidural clonidine of doses larger than 2 µg/kg causes suppression of CSNA, hypotension, bradycardia, and attenuation of intracardiac conduction in cats anesthetized with {alpha}-chloralose (6). Thoracic epidural lidocaine 2 mg/kg induces similar hemodynamic changes in cats anesthetized with halothane (7). The doses of epidural clonidine and lidocaine used in this study were clinically relevant and similarly suppressed MAP, HR, and CSNA during isoflurane anesthesia.

Isoflurane has been reported to reduce sympathetic nerve activity, MAP, and baroreflex sensitivity in rabbits (10) and humans (29). In our study, CSNA and MAP were significantly reduced but HR was not decreased as the concentration of isoflurane increased, possibly because of vagal withdrawal by isoflurane (32,33). Baroreflex-CSNA gain for depressor response tended to be suppressed as the concentration of isoflurane was increased, but this change was not statistically significant. Baroreflex-CSNA gain for pressor response and baroreflex-HR gains for both depressor and pressor responses were suppressed as the concentration of isoflurane was increased. Isoflurane concentration did not significantly affect the peak MAP changes induced by nitroprusside (Fig. 3).

Synthetic nerve activity of unanesthetized segments increases and that of anesthetized segments decreases with epidural lidocaine 1 mg/kg (34). Epidural administration of lipophilic drugs such as clonidine (6) induces segmental sympatholysis (35), whereas hydrophilic drugs such as morphine cause extensive sympatholysis (36). Simultaneous measurement of renal nerve activity in addition to CSNA is necessary to clarify the changes in the baroreflex-sympathetic response of unaffected segments induced by epidural clonidine.

In summary, thoracic epidural clonidine shifted baseline MAP, HR, and CSNA to smaller values and suppressed baroreflex-sympathetic responses depending on the isoflurane concentration in cats. Baroreflex sensitivity was unchanged with thoracic epidural clonidine during 0.5 MAC isoflurane anesthesia. Thoracic epidural clonidine may not only yield cardioprotective effects, but may also be more beneficial than thoracic epidural lidocaine during light isoflurane anesthesia by virtue of preserving baroreflex sensitivity when inadvertent hypotension occurs.


   Acknowledgments
 
Supported in part by Grant-in-Aid 07671679 for Research from the Ministry of Education, Science and Culture of Japan.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 23, 2003.




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Comparison of three different epidural solutions in off-pump cardiac surgery: pilot study
Br. J. Anaesth., November 1, 2005; 95(5): 685 - 691.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press