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Anesthesiology:
Laboratory Investigations

The Effects of Epidural Morphine on Cardiac and Renal Sympathetic Nerve Activity in α‐Chloralose‐anesthetized Cats

Mori, Takashi MD; Nishikawa, Kiyonobu MD; Terai, Takekazu MD; Yukioka, Hidekazu MD; Asada, Akira MD

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Abstract

Background: Epidural morphine yields postoperative pain relief and hemodynamic stability. However, the effects of epidural morphine on sympathetic tone are unclear. This study was designed to elucidate the effects of epidural morphine on cardiac (CSNA) and renal (RSNA) sympathetic nerve activity by direct measurement in anesthetized cats.
Methods: Thirty mongrel cats anesthetized with [Greek small letter alpha]‐chloralose were randomly assigned to one of the following five groups: control (0.2 ml/kg thoracic epidural normal saline; n = 5); thoracic epidural morphine (n = 9); lumbar epidural morphine (n = 6); vagotomized, sinoaortic denervated, thoracic epidural morphine (n = 5); or intravenous morphine (n = 5). Mean arterial pressure (MAP), heart rate (HR), CSNA, and RSNA were measured 0, 15, 30, 60, 90, and 120 min after saline or morphine (200 [micro sign]g/kg) administration and 15 min after reversal with 200 [micro sign]g naloxone given intravenously.
Results: In the control group, no changes in measured variables were found after either thoracic epidural saline or intravenous naloxone. Thoracic and lumbar epidural morphine both significantly reduced MAP, HR, CSNA, and RSNA 30 through 120 min after morphine administration (P < 0.05). These changes were reversed by intravenous naloxone. Changes after thoracic epidural morphine administration in vagotomized, baroreceptor‐denervated cats were similar to those in intact cats. Intravenous morphine produced no significant changes except for a decrease in MAP, which was reversed by intravenous naloxone.
Conclusion: In contrast to intravenous morphine, thoracic and lumbar epidural morphine both inhibited cardiac and renal sympathetic nerve activity and consequently reduced MAP and HR in [Greek small letter alpha]‐chloralose anesthetized cats.
INTRAVENOUS morphine decreases blood pressure (BP) as a result of multiple mechanisms, including a centrally mediated decrease in sympathetic outflow, an increase in vagal tone, histamine release, and direct and indirect venous and arterial vasodilation. [1,2] The cardiovascular effects of morphine depend on preexisting cardiovascular state, including that of the autonomic nervous system. [2] However, the direct effects of intravenous morphine on myocardial function and the cardiac conduction system have been shown to be small, [3,4] although morphine can produce bradycardia by increasing vagal tone. [1] Jurna and Rummel [5] showed that a large dose of intravenous morphine decreases cervical sympathetic nerve activity via opiate‐specific central sympathetic inhibition. Feldberg and Wei [6] examined the central cardiovascular effects of morphine in [Greek small letter alpha]‐chloralose anesthetized cats and suggested that a location near the obex at the dorsal surface of the medulla is the central site of action of morphine.
Epidural morphine binds at opioid receptors in spinal and supraspinal pain pathways and has a long‐lasting, potent antinociceptive effect. Epidural morphine is generally believed to have little effect on sympathetic nervous tone or the circulatory system. [7–9] However, there are several issues related to the circulatory effects of epidural morphine. Breslow et al. [10] reported that epidural morphine decreases postoperative hypertension by attenuating sympathetic hyperactivity. Several clinical reports have also described bradycardia, [11] mild hypotension, [12] and a reduced incidence of postoperative myocardial ischemia [13] after epidural morphine. Hotvedt et al. [14] found that thoracic epidural morphine decreases heart rate (HR) and prolongs intracardiac conduction time in pentobarbital‐anesthetized dogs by increasing vagal tone. These findings suggest that epidural morphine affects circulation via the autonomic nervous system. However, the effects of epidural morphine on sympathetic nerve activity have not been shown directly. The goal of this study was to elucidate the sympathetic contribution to hemodynamic changes induced by epidural morphine by means of direct measurements of cardiac and renal sympathetic nerve activities in anesthetized cats.
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Materials and Methods

This study was approved by our institution's Animal Research Committee. Thirty mongrel cats of either sex that weighed 2 ‐ 4 kg were anesthetized with isoflurane (5%) in oxygen in a polyethylene box. After intramuscular administration of 20 mg succinylcholine, cats were intubated orotracheally and mechanically ventilated (SN‐480–5, Shinano, Tokyo, Japan). During surgical preparations, anesthesia was maintained with isoflurane (1.5 to 2.5%) and 0.5 mg 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 every 40 min, and respiratory settings (tidal volume, frequency of respiration, and the inspiration:expiration ratio) were adjusted to keep the partial pressure of carbon dioxide between 35 ‐ 45 mmHg and the partial pressure of oxygen >300 mmHg. Metabolic acidosis was corrected with intravenous administration of sodium bicarbonate if the base excess was less than approximately 5 mEq/l, although this was required for only two cats. Rectal temperature was maintained between 36.5 and 37.5 [degree sign]C with an electric heater in the experimental table. A polyethylene catheter was inserted into the left femoral vein for intravenous administration of drugs and maintenance fluid (lactated Ringer's solution at 5 ml [middle dot] kg‐1 [middle dot] h‐1). Another polyethylene catheter was inserted into the left femoral artery and used for continuous monitoring of arterial BP. The surface electrocardiogram (lead II) was recorded using skin needle electrodes.
A median incision was made in the back at either T7–8 or L7‐S. The muscles were dissected and a small hole approximately 3 mm in diameter was made through the T8 or L7 lamina with an electric microengine drill (BL‐F[N]; Osada Electric Co., Tokyo, Japan). After identification of the dura mater and the epidural space, an 18‐gauge epidural catheter (Hakko Medical, Tokyo, Japan) was inserted into the epidural space under direct observation and then advanced 3 cm cephalad. The laminectomy window was carefully packed with bone wax for hemostasis and to prevent leakage of epidurally administered solutions, and then the skin incision was closed.
The cats were placed in the right lateral position with their forelimbs extended. A left thoracotomy was performed at the second intercostal space. The second and third ribs were removed, and the left lung was retracted caudally. Details of measurements and recording of cardiac sympathetic nerve activity (CSNA) have been described elsewhere. [15] 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 high‐cut filter of 1 KHz. Nerve activity was quantified by feeding the amplified output to an integrator (EI‐601G; Nihon Kohden). The full‐wave rectified signal was integrated at 5‐s intervals. Recorded activity was confirmed as cardiac sympathetic efferent activity by the finding that nerve activity nearly disappeared and increased arterial pressure immediately after intravenous injection of 3 [micro sign]g/kg norepinephrine. The integration system was not calibrated with reference to a known input because we were interested only in relative changes in nerve activity. Actual CSNA was calculated by subtracting the height of the integrated wave of baseline noise without nerve activity from the height of the integrated responses.
After surgical preparation, inhalation of isoflurane was discontinued and anesthesia was maintained with a bolus injection of 30 mg/kg [Greek small letter alpha]‐chloralose followed by a continuous intravenous infusion at a dose of 30 mg [middle dot] kg‐1 [middle dot] h‐1. After an equilibration period of 30 ‐ 40 min following bolus injection of [Greek small letter alpha]‐chloralose, cats were randomly assigned to five experimental groups. Five cats were given 0.2 ml/kg normal saline into a thoracic epidural space (control group). Nine cats were given 200 [micro sign]g/kg morphine sulfate into a thoracic epidural space (thoracic epidural morphine group). Six cats were administered 200 [micro sign]g/kg morphine sulfate into a lumbar epidural space (lumbar epidural morphine group). Five cats were administered 200 [micro sign]g/kg morphine intravenously (intravenous morphine group). To determine the direct effect of thoracic epidural morphine on sympathetic nerve activity, five additional cats underwent bilateral vagotomy and sinoaortic nerve resection in the cervical region to eliminate the baroreceptor reflex and vagal effects of thoracic epidural morphine, and then underwent epidural administration of 200 [micro sign]g/kg morphine (thoracic epidural morphine, denervated group). Successful baroreceptor denervation was confirmed by observing a lack of decrease or increase in CSNA in response to a mean arterial BP (MAP) change induced by 3 [micro sign]g/kg norepinephrine given intravenously or 2 [micro sign]g/kg prostaglandin E1 given intravenously. The morphine solution was prepared by dissolving crystals of morphine sulfate in normal saline to 0.1 a weight/volume percentage.
After baseline measurements were taken, MAP, HR, and CSNA were measured 15, 30, 60, 90, and 120 min after administration of saline or morphine in all groups. One hundred twenty minutes after administration, 200 [micro sign]g naloxone was administered intravenously and measurements were repeated 15 min later.
To determine the spread of the sympathetic effects of epidural morphine, CSNA and renal sympathetic nerve activity (RSNA) were measured simultaneously in five cats in the thoracic epidural morphine group, all cats of the lumbar epidural morphine group, and in all cats in the control group. As described in detail elsewhere, [16] the RSNA was directly recorded from the left renal nerve. The RSNA was measured according to the same method used for CSNA.
After all measurements were complete, 0.2 ml/kg 1% lidocaine with 0.2% methylene blue was administered through an epidural catheter in all cats. Reductions of CSNA, RSNA, HR, and MAP after injection of the solution were confirmed in all cats. Laminectomy was performed from C‐3 to s in three cats in the thoracic epidural morphine group, in three cats in the lumbar epidural morphine group, and in two cats in the baroreceptor denervated group, and the positions of the catheter tips and the extent of dye staining were determined.
All values are expressed as means +/‐ SD. The upper and lower levels of spread of methylene blue in the epidural space are presented as medians. Comparisons among the baseline values of the five groups were examined by one‐way analysis of variance, followed by Scheffe tests. Significant differences among the groups for each measured parameter were examined by repeated‐measures analysis of variance. If a significant difference was observed, overall differences among the values of the five groups in each parameter were examined by Scheffe tests. In addition, comparisons among the values just before (0) and 15, 30, 60, 90, and 120 min after administration of morphine or saline and 15 min after intravenous injection of naloxone within each group were made using one‐way analysis of variance for repeated measures followed by Scheffe tests to determine which time point had values significantly different from those of baseline. Super ANOVA (Abacus, Berkeley, CA) was used for between‐group comparisons, and Stat View II (Abacus, Berkeley, CA) was used for within‐group comparisons. Probability values <0.05 were considered significant.
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Results

Table 1
Table 1
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(Table 1) lists the baseline values of measured variables in each group. There was no significant difference among the groups in any measured variable except MAP. The baseline value of MAP in the denervated group was significantly higher than that in the thoracic epidural morphine group (P < 0.05).
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Mean Arterial Pressure
Figure 1
Figure 1
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(Figure 1A) shows the changes in MAP after morphine or saline administration. In the control group, during the period of measurement, MAP did not significantly change after either epidural administration of normal saline or after intravenous naloxone. Thoracic and lumbar epidural morphine each significantly reduced MAP from 30 through 120 min after administration (P < 0.01), and intravenous naloxone restored MAP to the baseline level. In denervated cats, thoracic epidural morphine significantly reduced MAP from 60 through 120 min after administration, and this change was reversed by intravenous naloxone. Intravenous morphine also reduced MAP significantly from 30 through 120 min, an effect that was also reversed by intravenous naloxone. The decrease in MAP induced by thoracic epidural morphine tended to be larger than that induced by intravenous morphine.
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Heart Rate
(Figure 1B) shows the changes in HR after morphine or saline administration. In the control group, no change was found in HR. Thoracic epidural morphine significantly reduced HR from 30 through 120 min after administration. Lumbar epidural morphine significantly reduced HR from 60 min through 120 min after administration. Intravenous naloxone reversed the decreases in HR in both the thoracic and lumbar epidural morphine groups. In denervated cats, thoracic epidural morphine also significantly reduced HR. This change was reversed by intravenous naloxone. The degree of reduction in HR after thoracic epidural morphine in denervated cats tended to be less than that in intact cats. Intravenous morphine produced no significant change in HR.
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Cardiac and Renal Sympathetic Nerve Activity
Figure 2
Figure 2
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Figure 3
Figure 3
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(Figure 2) shows an original tracing of arterial BP, HR, CSNA, RSNA, and integrated CSNA after administration of morphine into the thoracic epidural space and administration of intravenous naloxone. Figure 3 A and B show the changes in CSNA and RSNA after morphine or saline administration. In the control group, no changes were found in CSNA or RSNA. Thoracic epidural morphine significantly reduced both CSNA and RSNA from 30 through 120 min after administration. Lumbar epidural morphine also reduced both CSNA and RSNA significantly from 30 through 120 min. Intravenous naloxone reversed the decreases in CSNA and RSNA in both the thoracic and lumbar epidural morphine groups. In denervated cats, thoracic epidural morphine significantly reduced CSNA from 15 through 120 min after administration, and intravenous naloxone reversed this change. Intravenous morphine produced no significant changes in CSNA during the 120 min period after administration. These overall changes in CSNA and RSNA in the epidural morphine groups were significantly different from those in the control and intravenous morphine groups.
On dural staining with methylene blue, the thoracically administered solution spread from a median level of C5 to a median of T8, and lumbar administered solution spread from a median level of T7 to S.
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Discussion

In the current study, both thoracic and lumbar epidural administrations of morphine decreased cardiac and renal sympathetic nerve activities and simultaneously decreased BP and HR. These depressant effects of epidural morphine were reversed by intravenous naloxone. In contrast, the same dose of intravenous morphine had no effect on any parameter except mildly decreasing BP. These findings indicate that epidural morphine inhibits sympathetic nerve activity and cardiovascular function more strongly than does intravenous morphine. Breslow et al. [10] suggested two potential mechanisms by which epidural morphine reduces sympathetic outflow. One is indirect, via attenuation of pain perception resulting from superior analgesia through inhibition of spinal pain pathways, and the other is direct inhibition of the sympathetic nervous system at the level of the brain stem and spinal cord by morphine. Incomplete inhibition by basal anesthesia of sympathetic responses to stimulation of nociceptive efferents from surgical wounds may indirectly cause sympathetic inhibition, via pain attenuation by epidural morphine. However, because the cats in the current study were anesthetized continuously with [Greek small letter alpha]‐chloralose during the measurement period and were to some degree relieved from pain, [17] we speculate that sympathetic inhibition by epidural morphine was mainly the result of direct inhibition at the level of the brain stem and spinal cord during [Greek small letter alpha]‐chloralose anesthesia.
Opioid receptors are located in the central cardiovascular control center (several brain stem nuclei) and in the respiratory center. [18] Opioids binding to these sites produce cardiovascular inhibition via autonomic effects, including both decreases in sympathetic nerve activity and increases in vagal nerve tone. [19,20] Furthermore, opioid receptors have been shown to exist in close proximity to preganglionic sympathetic neurons in the intermediolateral cell column in the spinal cord, [21,22] and a functional relation between opioid receptors and preganglionic sympathetic neurons at the spinal level has been suggested. Opiate receptors may modulate sympathetic nerve activity at the level of the spinal cord and the brain stem. However, the relation between opioids and the spinal sympathetic pathway is not well understood and requires further study.
In the current study, dural staining with methylene blue proved that a solvent volume of 0.2 ml/kg spread extensively cephalad in epidural space C5‐T8 with thoracic epidural administration and in T7‐S with lumbar epidural administration. Lumbar epidural morphine induced changes in the measured variables similar to those induced by thoracic epidural morphine. Because morphine is hydrophilic, it may spread to the brain stem in cerebrospinal fluid independent of solvent volume and its extent of spread in the epidural space. [23,24] Morphine administered into the epidural space is known to penetrate slowly into dura, to spread extensively in cerebrospinal fluid, and to slowly penetrate into the neuraxis; from the neuraxis it is slowly eliminated. [23–25] Therefore, the depressive effect of epidural morphine on sympathetic nerve activity may be due to the effects at both the circulatory control center in the brain stem and preganglionic neurons in the spinal cord. In addition, our findings show that thoracic epidural morphine tends to have a slightly more rapid and profound onset than lumbar epidural morphine to some degree early (15 min) after administration (Figure 1 and Figure 3). This may indicate that morphine administered into the thoracic epidural space can reach the brain stem and spinal sympathetic pathway faster than that administered into the lumbar epidural space.
In the current study, thoracic and lumbar epidural morphine each significantly decreased HR and decreased CSNA in both intact and denervated cats. In our previous study, cardiac sympathetic block by thoracic epidural administration of local anesthetics induced changes in HR similar to those found in the present study. [26] Hotvedt and Refsum [14] found that the increased vagal nerve activity caused by thoracic epidural morphine (120 [micro sign]g/kg, 1 mg/ml in normal saline = 0.12 ml/kg) reduced spontaneous HR and lengthened atrioventricular nodal conduction and refractoriness in pentobarbital‐anesthetized dogs. Our findings showed that the degree of decrease in HR by thoracic epidural morphine in denervated cats tended to be less than that in intact cats, suggesting that the bradycardic effect of epidural morphine in intact cats may be due in part to increased vagal nerve tone. In addition, absence of an increase in CSNA and HR in response to the MAP decrease induced by intravenous morphine suggests that the baroreflex system may be inhibited by systemic morphine. The finding of no significant difference between nerve‐intact and denervated cats in changes of CSNA and MAP by epidural morphine suggests primary sympathetic inhibition by epidural morphine. However, further investigation is needed to elucidate the effects of epidural morphine on the baroreflex system.
Extensive clinical experience has proved that epidural morphine has potent analgesic effects and can be safely used in hospitals. [7,8] Most studies attribute epidural morphine's circulatory properties to a lack of sympathetic blockade. The findings of our study suggest that a large dose of epidural morphine sometimes may induce cardiovascular depression with central inhibition of sympathetic nerve activity, but it often yields hemodynamic stability.
Because background anesthesia modulates the hemodynamic and sympathetic effects of morphine, [2] its selection is important when the sympathetic and circulatory effects of morphine are examined. Alpha‐chloralose, which we used in our study, is believed to preserve myocardial function [17] and to have little suppressive effect on sympathetic activity [27,28] and intracardiac conduction. [29] Matsukawa et al. [28] found that [Greek small letter alpha]‐chloralose (bolus dose of 40 ‐ 50 mg/kg) decreased CSNA and increased RSNA in awake cats, but that the decrease in CSNA by [Greek small letter alpha]‐chloralose was less than that by pentobarbital. These authors' study also showed that [Greek small letter alpha]‐chloralose maintains hemodynamic and sympathetic stability for 3 h after administration. The stable cardiovascular state during [Greek small letter alpha]‐chloralose anesthesia permitted comparison of the effects on sympathetic nerve activity of epidural and intravenous morphine.
In this study, we tested a dose of 200 [micro sign]g/kg of morphine, because it is thought to be the maximal dose for bolus epidural administration during the perioperative period in humans [24] but has proved to have little circulatory effect when administered intravenously in animals. [5]
Intravenous naloxone at a dose of 200 [micro sign]g restored the sympathetic and circulatory effects of epidural morphine, but without a preceding administration of morphine, naloxone had no effect on these variables. These findings suggest that the sympathetic depressant effects of epidural morphine are mediated via opioid receptors and are not nonspecific effects of morphine.
In conclusion, we found that epidural morphine inhibits both cardiac and renal sympathetic nerve activity and simultaneously reduces BP and HR in [Greek small letter alpha]‐chloralose anesthetized cats, and that these effects can be reversed by naloxone.
The authors thank Professor Emeritus Mitsugu Fujimori of the Osaka City University Medical School for his suggestions and helpful advice.
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Keywords:
Blood pressure; heart; heart rate; kidney

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