| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
,From the Department of Anesthesiology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160-7415 USA.
Address correspondence to: Hiroshi Goto MD. Phone: 913-588-6670; Fax: 913-588-3365; E-mail:
 |
Abstract |
|---|
 TOP Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Methods: Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were measured and recorded after bolus injections of 1, 2 or 5 µg•kg–1 of remifentanil in neuraxis intact (n=6 for each dose) and baro-denervated rabbits (n=6 for each dose). Arterial baroreflex sensitivity was assessed by depressor tests. An additional six baro-denervated animals received remifentanil, 5 µg•kg–1 after pretreatment with naloxone, 40 µg•kg–1.
Results: All values were expressed in % change from baseline. In the neuraxis intact animals, MAP and HR were decreased briefly immediately after remifentanil injection. RSNA was increased dose-dependently: 137 ± 8% (mean ± SE), 170 ± 14% (P < 0.05) and 225 ± 29% (P < 0.05) after 1, 2 and 5 µg•kg–1 remifentanil, respectively. RSNA was increased even after MAP and HR had returned to baseline values. The depressor tests revealed that remifentanil did not attenuate arterial baroreflex sensitivity. In the baro-denervated animals, MAP and HR decreased gradually to 77 ± 3% (P < 0.05) and 94 ± 1% (P < 0.05), respectively 300 sec after 5 µg•kg–1 remifentanil. At that time, increased RSNA (159 ± 9%, P < 0.05) had returned to baseline. Pretreatment with naloxone in the baro-denervated animals abolished these changes.
Conclusion: Remifentanil decreases HR and MAP by its central vagotonic effect and by stimulating peripheral µ-opioid receptors. These effects appear to be counteracted and masked by its central sympathotonic effect and by maintaining arterial baroreflex integrity.
|
Introduction |
|---|
|
TOPAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The purpose of this study was, therefore, to evaluate the effects of remifentanil alone on hemodynamics, sympathetic outflow and arterial baroreflex sensitivity in order to elucidate the mechanisms by which remifentanil caused arterial hypotension and bradycardia. This is the first study to assess sympathetic outflow from the central nervous system and arterial baroreflex sensitivity after remifentanil injection. Both neuraxis intact and baroreceptor denervated rabbits were used as experimental models.
|
Methods |
|---|
|
TOPAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
New Zealand white rabbits (3.0-3.8 kg) were anesthetized with 1 g•kg–1 urethane iv, and anesthesia was maintained with supplemental administration of 100 mg•kg–1•hr–1 urethane throughout the experiment. The animals were tracheotomized and the lungs ventilated with an infant ventilator (model LS 104 150; Bourns Life Systems, Riverside, CA) using oxygen in nitrogen (FiO2 0.4). Polyethylene catheters were placed in a femoral vein for administration of drugs, and in the left femoral artery for measurement of arterial pressure and sampling of arterial blood. The animals were paralyzed with 0.1 mg•kg–1 vecuronium to avoid artifacts in the measurement of sympathetic nerve activity secondary to muscular movement. Acid-base balance was maintained within normal limits (PaCO2, 35-45 mmHg; pH 7.35-7.45) by adjusting the tidal volume and frequency. The PaO2 was maintained between 100 and 200 mmHg. Heart rate (HR) was calculated from lead II of the electrocardiogram using a cardiotachometer (Model 1321; San-ei, Tokyo, Japan). Body temperature was maintained 37.5°C by external warming. Arterial blood pressure was monitored with a pressure transducer (DTX Spectramed, Oxnard, CA) and recorded continuously. Mean arterial pressure (MAP) was derived by electronic integration of the pulsatile pressure signal. Measurement and recording of renal sympathetic nerve activity (RSNA) have been described elsewhere.6 Briefly, the left kidney was exposed and renal sympathetic nerves were isolated and placed on a bipolar silver electrode. Nerve impulses were amplified, rectified and integrated, and continuously recorded (Nihon Kohden AVB 10, bandwidth: 50-3000 Hz, Tokyo, Japan). The amplified nerve discharge was visualized on a dual-beam oscilloscope (Nihon Kohden VC11, Tokyo, Japan) and monitored by an audio speaker. A resistance and capacitance integrator circuit (2.0 sec for RSNA) integrated the neurogram.
To quantify nerve activities, the resting spontaneous nerve discharge before drug administration was defined as 100% control value. All variables were measured continuously and recorded on DAT tape PCM recorder (RD-100T TEAC, Montebello, CA) and played back on a multichannel chart recorder (Omnicorder 8M14, San-ei, Japan).
Study 1: Neuraxis Intact Group
The effects of remifentanil on hemodynamics, RSNA and arterial baroreflex control of RSNA were evaluated. Eighteen neuraxis intact rabbits were divided into three groups (n=6 each group): 1, 2 or 5 µg•kg–1 remifentanil were administered iv as a bolus over five seconds. Sodium nitroprusside (SNP: 15 µg•kg–1 iv) was used as a control arterial baroreflex sensitivity test, which was performed before and five minutes after remifentanil administration in all groups. Arterial baroreflex sensitivity in response to SNP- and remifentanil-induced hypotension was assessed by calculating the ratio of maximum increase in RSNA (
RSNA) to maximum reduction of MAP (MAP) (RNSA/MAP).
Study 2: Baro-denervated Group
The effect of remifentanil on hemodynamics and RSNA in baroreflex-denervated rabbits was determined. Twenty-four rabbits underwent combined bilateral denervation of the carotid sinus and aortic nerves, and vagal nerves to eliminate arterial and cardiopulmonary baroreflex, respectively. Complete denervation was verified by the lack of reflex changes in RSNA in response to 15 µg•kg–1 SNP-induced hypotension. After a steady state was established, 1, 2 or 5 µg•kg–1 remifentanil alone or 5 µg•kg–1 remifentanil after pretreatment with 40 µg naloxone were administered as a bolus over five seconds (n=6 each group). The HR, MAP, RSNA were continuously monitored and recorded.
All data were expressed as mean ± SE. Repeated measure ANOVA followed by Newman-Keul's procedure was used for statistical analysis. Differences with a P < 0.05 were considered significant.
|
Results |
|---|
|
TOPAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
, upper panel).
|
, lower panel).
There were no differences in (RSNA/(MAP before, during or after three different doses of remifentanil (Figure 2).
|
).
|
|
Discussion |
|---|
|
TOPAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Brief but abrupt reductions of HR and MAP soon after remifentanil injection were observed in the neuraxis intact animals (vagus intact) but not in the baro-denervated bilaterally vagotomized animals (Figure 1). This means that remifentanil exerts central vagotonic action, leading to bradycardia and hypotension. The central vagotonic effect of fentanyl, another µ-opioid receptor agonist, is well documented8 and, clinically, patients' heart rates slow down after a bolus injection of fentanyl during anesthesia. The central vagotonic effect of remifentanil is short-lived or soon after its onset, it is opposed by increased sympatehtic activity.
Dose-dependent increased RSNA in the neuraxis intact animals is likely mediated by arterial baroreflex in response to reduced arterial pressure. However, RSNA was still increased, even after MAP had returned to baseline (Figure 1, upper panel). This suggests that the sympathetic outflow from the central nervous system may by augmented by remifentanil. Overshoot of the arterial baroreflex might have been another reason for the persistence of increased RSNA. It has been shown that direct stimulation of µ-opioid receptors in the central nervous system, including nucleus tractus solitarius can elicit an increase in sympathetic outflow.9,10 Other µ-receptor opioid agonists, fentanyl and morphine, when injected iv, have been shown to increase sympathetic nerve activity in rabbits11 and rats,12 respectively. The increased RNSA with 5 µg•kg–1 remifentanil was abolished by pretreatment with naloxone; a µ-receptor antagonist in the baro-denervated animals (Figure 3). This means that remifentanil stimulates µ-receptors in the central nervous system, leading to an increase in RSNA.
It has not been clearly demonstrated as to whether µ-receptor agonists increase sympathetic outflow in humans. However, increased arterial blood pressure and heart rate after iv injection of remifentanil alone in healthy non-premedicated volunteers5 could have been due, at least in part. to the central sympathetic stimulating effect of remifentanil.
Unlike the neuraxis intact animals, HR and MAP decreased gradually for several minutes with 5 µg•kg–1 remifentanil in the baro-denervated animals. The decreased HR and MAP were unlikely to have been due to the central effects of remifentanil since the animals were vagotomized, which precludes bradycardia induced by increased central vagal tone, and sympathetic outflow was not reduced to cause arterial hypotension. It is interesting that HR and MAP started to decrease at about the time when increased RSNA returned toward baseline values (Figure 1, lower panel). Thus, the bradycardic and hypotensive effects of remifentanil were offset by increased sympathetic outflow for several minutes after bolus injections of remifentanil.
Thus, decreased HR and MAP in baro-denervated animals without decreased sympathetic outflow suggest that remifentanil exerts a peripheral action to depress the cardiovascular system. It has been suggested that approximately 10% of the bradycardic effect of fentanyl in dogs is attributable to its peripheral action rather than to its central vagotonic action.8 Electrophysiological study demonstrated that fentanyl exerts a direct negative chronotropic action by stimulating µ-receptors in the rabbit sino-atrial node.13 Thus, remifentanil might have exerted a negative chronotropic action similar to that of fentanyl. This is probably true because pretreatment with naloxone abolished the bradycardic effects of remifentanil in the baro-denervated and vagotomized animals (Figure 3).
Since remifentanil has been shown not to release histamine,14 decreased MAP without reduced sympathetic outflow in the baro-denervated animals suggests that remifentanil may exert a direct negative inotropic action or other mechanism to decrease arterial blood pressure. Pretreatment with naloxone abolished the hypotensive action of remifentanil, suggesting that µ-receptors in the peripheral nervous system and the cardiovascular system may be involved in this remifentanil-induced arterial hypotension. Further study is necessary to clarify the direct effect of remifentanil on these systems.
Maintaining arterial baroreflex integrity is important in maintaining stable hemodynamics during anesthesia and surgery. Nitroprusside was used as a control baro-sensitivity study since it does not impair arterial baroreflex integrity.15 It was found that remifentanil did not attenuate arterial baroreflex (Figure 2). Similarly, it has been demonstrated that arterial baroreflex integrity is well preserved with fentanyl in dogs.16
In summary, fast bolus injections of remifentanil in our experimental model were used to explore the mechanisms of the hemodynamic changes associated with remifentanil. Remifentanil produces arterial hypotension and bradycardia by its central vagotonic effect and by stimulating µ-receptors presumably in the peripheral nervous system and the cardiovascular system. These hypotensive and bradycardic effects can be counteracted by its sympathetic stimulating effect mediated through µ-opioid receptors in the central nervous system. In addition, preserved arterial baroreflex integrity contributes rather stable hemodynamics during remifentanil anesthesia.
|
Footnotes |
|---|
Current address: Kochi Municipal Central Hospital, 2-7-33 Sakurai-cho, Kochi, Japan.
Accepted for publication January 16, 2000.
|
References |
|---|
|
TOPAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
2 Hogue CW Jr, Bowdle TA, O'Leary C, et al. A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg 1996; 83: 279–85.[Abstract]
3 Warner DS, Hindman BJ, Todd MM, et al. Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy. Anesth Analg 1996; 83: 348–53.[Abstract]
4 Schüttler J, Albrecht S, Breivik H, et al. A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery. Anaesthesia 1997; 52: 307–17.[Medline]
5
Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993; 77: 1031–40.
6 Taneyama C, Goto H, Goto K, Benson KT, Unruh GK, Arakawa K. Attenuation of arterial baroreceptor reflex response to acute hypovolemia during induced hypotension. Anesthesioology 1990; 73: 433–40.
7
Ishikawa N, Kallman CH, Sagawa K. Rabbit carotid sinus reflex under pentobarbital, urethane, and chloralose anesthesia. Am J Physiol 1984; 246: H696–701.
8
Reitan JA, Stengert KB, Wymore ML, Martucci RW. Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg 1978; 57: 31–6.
9 Appel NM, Kiritsy-Roy JA, Van Loon GR. Mu receptors at discrete hypothalamic and brainstem sites mediate opioid peptide-induced increases in central sympathetic outflow. Brain Res 1986; 378: 8–20.[Medline]
10
Hassen AH, Feuerstein G. µ-opioid receptors in NTS elicit pressor responses via sympathetic pathways. Am J Physiol 1987; 252: H156–62.
11 Honda K, Aibiki M, Ogura S, Umegaki O. Effects of fentanyl on renal sympathetic nerve activity, heart rate and systemic blood presure in anesthetized rabbits—an evaluation in both rabbits and humans. (Japanese) Masui 1994; 43: 830–9.
12
Delle M, Thorén P, Skarphedinsson JO, Hoffman P, Carlsson S, Ricksten S. Differentiated responses of renal and adrenal sympathetic nerve activity to intravenus administration in anesthetized rats. J Pharmacol Exp Ther 1990; 253: 655–60.
13 Saeki T, Nishimura M, Sato N, Fujinami T, Watanabe Y. Electrophysiological demonstration and activation of µ-opioid receptors in the rabbit sinoatrial node. J Cardiovasc Phamacol 1995; 26: 160–8.[Medline]
14 Sebel PS, Hoke JF, Westmoreland C, Hug CC Jr, Muir KT, Szlam F. Histamine concentrations and hemodynamic responses after remifentanyl. Anesth Analg 1995; 80: 990–3.[Abstract]
15
Taneyama C, Goto H, Benson KT, Unruh GK, Arakawa K. Vagal involvement in the action of exogenous adenosine triphosphate on reflex renal sympathetic nerve activity. Anesth Analg 1991; 72: 351–8.
16
Taneyama C, Goto H, Kohno N, Benson KT, Sasao J, Arakawa K. Effects of fentanyl, diazepam and the combination of both on arterial baroreflex and sympathetic nerve activity in intact and baro-denervated dogs. Anesth Analg 1993; 77: 44–8.
This article has been cited by other articles:
 |
|
 |
|
  Z.-Y. Hu, P.-T. Lin, J. Liu, and D.-Q. Liao Remifentanil induces L-type Ca2+ channel inhibition in human mesenteric arterial smooth muscle cells: [Le remifentanil provoque l'inhibition des canaux calciques de type L dans les cellules musculaires lisses des arteres mesenteriques chez l'humain] Can J Anesth, April 1, 2008; 55(4): 238 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Baumert, M. Hein, K. E. Hecker, S. Satlow, J. Schnoor, and R. Rossaint Autonomic cardiac control with xenon anaesthesia in patients at cardiovascular risk Br. J. Anaesth., June 1, 2007; 98(6): 722 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Baumert, K. E. Hecker, M. Hein, M. Reyle-Hahn, N. A. Horn, and R. Rossaint Effects of xenon anaesthesia on the circulatory response to hypoventilation Br. J. Anaesth., August 1, 2005; 95(2): 166 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Baumert, K. E. Hecker, M. Hein, S. M. Reyle-Hahn, N. A. Horn, and R. Rossaint Haemodynamic effects of haemorrhage during xenon anaesthesia in pigs Br. J. Anaesth., June 1, 2005; 94(6): 727 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Leone, J. Albanese, X. Viviand, F. Garnier, A. Bourgoin, K. Barrau, and C. Martin The Effects of Remifentanil on Endotracheal Suctioning-Induced Increases in Intracranial Pressure in Head-Injured Patients Anesth. Analg., October 1, 2004; 99(4): 1193 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Noseir, D. J. Ficke, A. Kundu, S. R. Arain, and T. J. Ebert Sympathetic and Vascular Consequences from Remifentanil in Humans Anesth. Analg., June 1, 2003; 96(6): 1645 - 1650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sasao, S. D. Tarver, J. D. Kindscher, C. Taneyama, K. T. Benson, and H. Goto In rabbits, landiolol, a new ultra-short-acting {beta}-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol : [Le landiolol, un nouveau {beta}-bloquant a action tres breve, a un effet chronotropic negatif plus puissant et agit moins sur la tension arterielle que l'esmolol chez le lapin] Can J Anesth, November 1, 2001; 48(10): 985 - 989. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
