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Anesth Analg 1999;89:453
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

The Combined Effects of Sevoflurane and Remifentanil on Central Respiratory Activity and Nociceptive Cardiovascular Responses in Anesthetized Rabbits

Daqing Ma, MD, Mihir K. Chakrabarti, MPhil, and James G. Whitwam, PhD, FRCA

Department of Anaesthetics and Intensive Care, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom

Address correspondence and reprint requests to Dr. Daquing Ma, Department of Anaesthetics and Intensive Care, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, UK. Address e-mail to dma{at}rpms.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We studied the effects of sevoflurane and remifentanil, alone and in combination, on phrenic nerve activity (PNA), resting heart rate (HR), arterial pressure (MAP), and changes in HR ({Delta}HR) and MAP ({Delta}MAP) evoked by electrical stimulation of tibial nerves in anesthetized rabbits. The 50% effective dose (95% confidence intervals) for the depressant effects of sevoflurane on {Delta}HR, {Delta}MAP, and PNA were 2.3 (1.8%–2.6%), 2.7 (2.3%–2.9%), and 3.4 (3.1%–3.7%), respectively, and for remifentanil were 0.100 (0.050–0.132), 0.850 (0.720–1.450), and 0.090 (0.080–0.145) µg · kg-1 · min-1, which were reduced to 0.046 (0.021–0.065), 0.110 (0.080–0.200), and 0.030 (0.020–0.040) µg · kg-1 · min-1, respectively, by 1% sevoflurane. Depression of evoked cardiovascular responses relative to PNA was greater for sevoflurane and less for remifentanil both alone and in combination with sevoflurane. Sevoflurane acted synergistically with remifentanil on PNA and {Delta}MAP, but not {Delta}HR, for which their combined effect was additive. Coadministration of 1% sevoflurane with the highest infusion rate of remifentanil (1.6 µg · kg-1 · min-1) used during combined administration reduced resting HR and MAP by 25% (P < 0.05) and 41% (P < 0.05), respectively, which was greater than the predicted reductions of only 14% and 15% if their combined effects had been additive. We conclude that sevoflurane caused a relatively greater depression of nociceptive cardioaccelerator and pressor responses compared with PNA and vice versa for remifentanil. When coadministered, their combined effects on PNA, resting HR, MAP, and {Delta}MAP were synergistic, whereas they were merely additive for {Delta}HR.

Implications: Although sevoflurane caused relatively greater depression of nociceptive cardiovascular responses compared with phrenic nerve activity, remifentanil either alone or combined with sevoflurane caused a much greater depression of phrenic nerve activity than cardioaccelerator and pressor responses. This could imply that, during major surgery using anesthesia combining sevoflurane and remifentanil, spontaneous ventilation is not acceptable, and depression of the resting circulation may be much greater than anticipated.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Surgical trauma causes motor, somatosympathetic, and associated neurohumoral responses, often referred to as "stress," which may be associated with serious adverse cardiovascular complications (1,2). Obtunding these responses improves surgical outcome (3,4). For inhaled anesthetics, the minimum alveolar anesthetic concentration (MAC) is less than that which blocks the adrenergic response to surgery (MAC-BAR) (5). The MAC-BAR for inhaled anesthetics might cause clinically unacceptable reductions in blood pressure (6). However, the addition of opioids as anesthetic supplements greatly facilitates depression of neurohumoral and sympathetic responses (5,7).

Remifentanil is hydrolyzed rapidly by tissue esterases with a terminal half-life in humans of 10–20 min, regardless of hepatic and renal function, and has a rapid onset and offset of action (8,9). Although the effects of remifentanil and sevoflurane on cardiorespiratory systems have been observed during surgery (10), the nature of their combined effects, whether additive or interactive, has not been determined. Although the use of opioids for premedication and to supplement anesthesia reduces the inhaled anesthetic requirement, it is only recently that the synergistic nature of the interaction of sevoflurane and fentanyl, a µ opioid, has been reported (11,12).

In the present study, directly recorded phrenic nerve activity (PNA), to indicate central respiratory neural output, and responses in heart rate (HR) and mean arterial pressure to electrical stimulation of peripheral nerves were used to determine the nature of the interactions between sevoflurane and remifentanil in anesthetized rabbits. The second purpose of this study was to examine their relative effects on PNA and nociceptive cardiovascular responses, which is important in relation to the potential adequacy of spontaneous ventilation during the management of anesthesia.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This research was approved by the UK Home Office. Experiments were performed on New Zealand White rabbits of both sexes, weighing 3.5–4.5 kg. Seventeen animals were anesthetized with methohexital 10–15 mg/kg IV and anesthesia was maintained with 1% {alpha}-chloralose in an initial bolus dose of 30 mg/kg IV, followed by a continuous infusion of 15–20 mg · kg-1 · h-1. Their lungs were mechanically ventilated with oxygen-enriched air through a tracheal tube inserted via a tracheostomy. Muscle paralysis was maintained with bolus doses of succinylcholine (2 mg/kg IV every 20–30 min). A femoral artery and vein were cannulated for recording arterial pressure, sampling blood, and the infusion of 1% {alpha}-chloralose and 0.9% saline, respectively. The marginal veins of both ears were cannulated for the infusion of drugs. Esophageal temperature was measured by using a thermistor (Yellow Springs Instruments, Yellow Springs, OH) and maintained between 37 and 38°C with a heating system in the operating table. pHa and arterial blood gas tensions were measured using a blood gas analyzer (ABL 3; Radiometer, Copenhagen, Denmark), and were maintained not only constant near to control levels in each preparation, but also within the ranges of pHa 7.30–7.40, PaCO2 36–40 mm Hg, and PaO2 170–210 mm Hg, by adjusting tidal volume without changing the frequency of ventilation, and occasionally by the administration of small doses of sodium bicarbonate. The resting HR and mean arterial pressure (MAP), and evoked changes in HR ({Delta}HR) and MAP ({Delta}MAP) were recorded and stored on disk for subsequent analysis (Maclab 8; ADInstruments, Castle Hill, Australia).

PNA
The right phrenic nerve in the neck was exposed by a ventral approach; a portion was dissected from adjacent tissues, a short section of which was desheathed and cut distally, immersed in a pool of mineral oil, and mounted on silver electrodes to record efferent activity. Signals from the phrenic nerve were preamplified and displayed on a dual-beam oscilloscope (Tektronix, Beaverton, OR). The amplified signals were rectified and integrated with a 100-ms time constant. Both amplified and integrated activities were also displayed on an oscilloscope and plotted with a thermal recorder. The total electrical activity of the rectified and integrated signals during 20-s periods was measured in arbitrary units. To eliminate the distortion of the PNA signals by the artifact from trains of electrical stimuli applied to the tibial nerve, at each stage of these experiments, recordings of PNA were processed before stimulation of the tibial nerve to evoke cardiovascular responses.

Evoked Changes in HR and MAP
The tibial nerve in the right hindleg was exposed in the upper to middle part of the thigh. A portion was dissected free from the surrounding tissues, and a short length (approximately 1.5 cm) was desheathed, cut distally, and mounted on silver electrodes in a mineral oil pool for electrical stimulation. Five-second trains of high-frequency supramaximal electrical stimuli (30 Hz, 30 V, duration 0.5 ms) were applied to the tibial nerve using a stimulator (S88; Grass, Quincy, MA). The stimulus frequency, intensity, and duration were determined from a pilot study, which demonstrated that the stimulus intensity was supramaximal for the evoked cardiovascular response and that a train duration of 5 s was sufficient to evoke maximal responses. The maximal increases in HR ({Delta}HR) and MAP ({Delta}MAP) in response to stimulation were recorded.

Seventeen animals were divided into three groups. Each preparation was allowed to stabilize for at least 30 min after the surgery. Control measurements were made and, to ensure stability, repeated 20–30 min later. Group I (n = 5): sevoflurane was administered to obtain end-expiratory concentrations of 1%–6%, each for 15 min. The expired concentrations were monitored with a Capnomac II (Datex, Helsinki, Finland) that was calibrated before each experiment with standard gas. Group II (n = 7): remifentanil (Glaxo Wellcome, Middlesex, UK) was administered with an initial bolus dose of 0.5 µg · kg-1 · min-1 IV before a continuous infusion at incremental rates from 0.0125 to 12.8 µg · kg-1 · min-1, each for 15 min, during which time the maximal effect of the drug reached a steady state (13). Group III (n = 5): after obtaining dose-response curves for the depressant effect of both sevoflurane and remifentanil and their 50% effective doses (ED50) in Groups I and II, in another five preparations, the two drugs were administered concurrently; sevoflurane was administered at an end-expiratory concentration of 1%, and its effects were allowed to stabilize for 15 min before remifentanil was infused at incremental infusion rates of 0.0125–1.6 µg · kg-1 · min-1, each for 15 min. The maximal concentration of sevoflurane and infusion rates of remifentanil in Groups I and II were chosen after pilot studies, showing that the evoked cardiovascular responses and PNA would be maximally depressed or abolished. The protocol required the measured values to return to control after termination of drug, which required <=30 min.

The effects of the drugs on the resting circulation are reported as HR and MAP. For PNA, the average of three measurements was used for each data set, i.e., 3 x 20-s periods of a continuous multifiber recording, expressed in arbitrary units as a percentage of control values, but the statistical analysis used the original data and is expressed as mean ± SD and ED50 (95% CI). Statistical analysis was performed by using analysis of variance, followed, where indicated, by paired t-tests with Bonferroni’s correction. P < 0.05 was considered to be statistically significant. The ED50 values for depressant effects on PNA, {Delta}HR, and {Delta}MAP were calculated from the dose-response curves, together with 95% CI. The predicted ED50 values, assuming simple additivity, were calculated according to the equation of Berenbaum (14). Isobolograms plotting the ED50 values of both drugs were used to determine the nature of their combined antinociceptive effects. The additive data for MAP and HR were the sum of the mean effects of 1% sevoflurane and remifentanil at an infusion rate of 1.6 µg · kg-1 · min-1.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Examples of recordings from single preparations showing the effects of sevoflurane on PNA and evoked circulatory responses to tibial nerve stimulation are shown in Figure 1 . In one preparation in Group II, PNA did not return to control values at the end of the experiment, and all the data were rejected.



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  		Figure 1. A, Effects of sevoflurane on phrenic nerve activity (PNA) in one preparation. Upper traces, rectified integral of the recorded activity; lower traces, directly recorded PNA. B, Effects of sevoflurane in the same preparation on the resting circulation and evoked cardiovascular responses. Upper traces, evoked changes in HR; lower traces, evoked changes in arterial pressure (AP). Start of 5-s trains of electrical stimuli (30 Hz, 30 V, duration 0.5 ms) applied to a tibial nerve (arrows).

 
Resting HR and MAP
Sevoflurane caused a significant decrease in mean HR, from the control value of 245 bpm to 229 bpm (P < 0.05) and 210 bpm (P < 0.05) at 5% and 6% concentrations, respectively. It caused a concentration-dependent reduction in mean MAP from the control value of 100 mm Hg to 45 mm Hg (P < 0.01) at 6% in Group I (Fig. 2 A).



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  		Figure 2. Effects of sevoflurane (A), remifentanil (B), and their combination (C) on resting mean heart rate (HR) and mean arterial pressure (MAP). Mean ± SD, n = 5 in the sevoflurane and combination groups, and n = 6 in the remifentanil group. *P < 0.05; **P < 0.01 versus control.

 
In Group II, remifentanil caused no significant changes in mean HR from the control value of 250 bpm up to an infusion rate of 6.4 µg · kg-1 · min-1; the reduction to 215 bpm at 12.8 µg · kg-1 · min-1 was significant (P < 0.05). Mean MAP decreased significantly to 80 mm Hg and 75 mm Hg (P < 0.05) from the control value of 95 mm Hg at infusion rates of 6.4 and 12.8 µg · kg-1 · min-1, respectively (Fig. 2B).

In Group III, 1% sevoflurane caused no significant changes in mean HR and MAP. Remifentanil, administered concurrently, caused significant reductions in mean HR, from 245 to 183 bpm (P < 0.05), and in mean MAP, from the control value of 97 mm Hg to 57 mm Hg (P < 0.01) at 1.6 µg · kg-1 · min-1 (Fig. 2C). The drugs’ combined effects on mean HR and MAP were synergistic (Table 1 ).


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  		Table 1. Reduction in Resting HR and MAP
 
PNA
Sevoflurane caused an almost linear depression of mean PNA from 83% to 9% of the control value at concentrations from 1% to 6%. It was completely abolished in one preparation by 5% sevoflurane, but in the other four, residual activity persisted up to 6% in Group I (Fig. 3 A). Remifentanil caused a dose-related depression of PNA, which was completely abolished at infusion rates of 0.8 µg · kg-1 · min-1 Group II (Fig. 3B, closed squares).



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  		Figure 3. Effects of sevoflurane, remifentanil, and their combination on phrenic nerve activity (PNA), evoked changes in HR ({Delta}HR), and mean arterial pressure ({Delta}MAP). Mean ± SD, n = 5 in the sevoflurane and combination groups, and n = 6 in the remifentanil group. *P < 0.05; **P < 0.01 versus control.

 
In Group III, the mean PNA was depressed to approximately 82% of control by 1% sevoflurane. The additional infusion of remifentanil at increasing rates produced a progressive further depression of mean PNA, which was abolished at a rate of 0.4 µg · kg-1 · min-1 (Fig. 3B, closed triangles).

Evoked Changes in HR and MAP
Sevoflurane caused depression of mean {Delta}HR to 77% (P = not significant) and 8% (P < 0.01) of control values at concentrations of 1% and 5%, respectively, and abolished this response at 6%. It also caused a progressive depression with ultimate abolition of mean {Delta}MAP between 1% and 6% in Group I (Fig. 3, C and E). {Delta}HR and {Delta}MAP were depressed to 19% and 24% of control values, respectively, at the highest infusion rate of remifentanil, i.e., 12.8 µg · kg-1 · min-1 in Group II (Fig. 3, D and F, closed squares).

In Group III, during the administration of 1% sevoflurane, superimposed infusions of remifentanil to a maximum of 1.6 µg · kg-1 · min-1 caused a greater depression of {Delta}HR and {Delta}MAP compared with remifentanil alone (Fig. 3, D and F, closed triangles).

Analysis of the Nature of the Interaction Between Sevoflurane and Remifentanil on PNA and Evoked Circulatory Responses
As measured by the expected and observed effects of sevoflurane alone and in combination with remifentanil on PNA, {Delta}HR, and {Delta}MAP (Table 2 ) and the isobolograms for their effects on PNA, {Delta}HR, and {Delta}MAP (Fig. 4 ), the drugs’ interactions were synergistic for PNA and {Delta}MAP but only additive for {Delta}HR.


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  		Table 2. ED50 (95% CI) Values for Sevoflurane and Remifentanil Alone on PNA and {Delta}HR and {Delta}MAP Evoked by Electrical Stimulation (30 Hz, 30 V, duration 0.5 ms) of a Tibial Nerve, and the Ratios of ED50 for {Delta}HR and {Delta}MAP to PNA
 


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  		Figure 4. Isobolograms for the combination of sevoflurane and remifentanil on phrenic nerve activity (PNA), evoked changes in mean heart rate ({Delta}HR), and mean arterial pressure ({Delta}MAP). The solid diagonal lines are the additive lines constructed by joining the 50% effective dose (ED50) (95% CI indicated on the axes) for each drug. The open symbols on the lines are the ED50 values of the predicted infusion rates of remifentanil causing depression of mean PNA, {Delta}HR, and {Delta}MAP if its interactions with sevoflurane are additive. The closed symbols are the observed ED50 values (95% CI) for the effects of remifentanil when combined with sevoflurane. The observed ED50 values for PNA and {Delta}MAP are below and to the left of the additive line, whereas, for mean {Delta}HR, it is on the additive line, which indicates that their interactions on PNA and {Delta}MAP are synergistic, whereas they are additive for {Delta}HR.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The aims of this study were to examine the relative effects of sevoflurane and remifentanil on PNA and nociceptive cardiovascular responses and the nature of their interactions. We sought to determine the possibility of retaining sufficient central respiratory activity to support spontaneous ventilation when nociceptive cardiovascular responses are abolished during anesthesia with sevoflurane and remifentanil. In anesthetized rabbits, increasing concentrations of sevoflurane caused virtually linear depression of {Delta}HR and {Delta}MAP that were greater than sevoflurane’s effect on PNA. In contrast, remifentanil caused equal depression of PNA and {Delta}HR, which was 9 times greater than its effect on {Delta}MAP. The combined effects of sevoflurane and remifentanil on PNA, {Delta}MAP, resting HR, and MAP were synergistic, whereas they were additive for {Delta}HR.

Efferent PNA is a final common pathway from spinal motor neurons that respond to corticospinal pathways and respiratory neurons in the medulla that, in turn, are modulated by supramedullary centers, central chemoreceptors, and inframedullary reflexes. It provides evidence of changes in the output of the central respiratory control system (15) and has been used to study the effect of drugs on respiration (16). Previous studies have shown that halothane and isoflurane cause a concentration-dependent depression of PNA and responses to hypoxia and hypercapnia (17–19). However, the relative depressant effects of sevoflurane and other inhaled anesthetics on PNA are difficult to evaluate because of differences in the species studied and the experimental protocols. Studies in both humans and animals show that sevoflurane depresses respiratory function more than halothane (20). Inhaled anesthetics cause greater depression of PNA than that of medullary respiratory neurons, which could be caused by additional direct effects on the efferent motor neurons in the spinal cord (17,18). However, the relative contributions of the effects of these drugs on the various components of the respiratory control system to the final common pathway represented by PNA have yet to be determined. In contrast, opioid-induced respiratory depression is caused by a reduction in the responsiveness of the brainstem respiratory centers to carbon dioxide (21), which is relevant to the effects of remifentanil on PNA reported in this article.

{Delta}HR and {Delta}MAP in response to nociceptive stimulation are due to reflex activation of the autonomic nervous system (22) and are important in surgical outcome (3,4), monitoring the adequacy of anesthesia, and for evaluating the antinociceptive effect of drugs (23,24). Halothane and desflurane cause a concentration-related depression of nociceptive responses in HR and MAP in rats (23,24) similar to the findings for sevoflurane in rabbits in the present study. It is unlikely that the depressant effects of sevoflurane on {Delta}MAP are mediated simply by a decrease in blood pressure because a previous study showed that a decrease in arterial pressure, induced with sodium nitroprusside, had no significant effect on nociceptive cardiovascular responses (23). Inhaled anesthetics have effects throughout the cardiovascular control system, including the spinal cord, supraspinal centers, and the efferent sympathetic pathway. In recent years, the importance of the spinal cord as one of the principal sites of action of inhaled anesthetics has been established (25,26). In addition, halothane attenuates pressor responses evoked by electrical stimulation of the hypothalamus, reticular formation, and medulla (27), and halothane, isoflurane, and desflurane inhibit transmission in sympathetic ganglia (28,29), which has not yet been reported for sevoflurane. The changes in both adrenal nerve activity and adrenaline secretion caused by noxious stimulation of a hindpaw in rats are attenuated progressively by sevoflurane in a concentration-dependent manner (30). In dogs, sevoflurane depresses somatosympathetic reflexes progressively at increasing concentrations (31), and it interacts synergistically with the effects of intrathecal fentanyl on the spinal cord (12).

Previous studies have reported MAC-BAR values are usually higher than the MAC (5–7) and that fentanyl, when administered alone, even at very large doses, does not abolish such responses (32). Although these responses are readily abolished by combinations of inhaled anesthetics and opioids (5,7), there are no data on the nature of such interactions. We clearly demonstrated that the interactions between sevoflurane and remifentanil are synergistic, not only for nociceptive pressor responses, but also for PNA. The clearance of remifentanil is not altered by isoflurane (33), and there is no report of any pharmacokinetic interactions between sevoflurane and remifentanil. The synergistic interactions we report between sevoflurane and remifentanil are probably due to effects at the cellular level and within neuronal networks.

It has been reported that, whereas sevoflurane causes a concentration-related reduction in arterial pressure baroreflex compensation is retained for HR up to concentrations of 4% (34). We confirmed this by demonstrating that an increase in depression of such compensation occurred at concentrations of 5% and 6% (Fig. 3A). The complexity of the effects of µ opioids and inhaled anesthetics on baroreflexes could provide an explanation for the additive nature of the effects of sevoflurane and remifentanil on {Delta}HR in the current study.

The combined depressant effects of sevoflurane and remifentanil on resting HR and MAP are also synergistic. Because remifentanil has a very short, constant context-sensitive half-time (approximately three minutes) (35) and does not compromise recovery, unnecessarily large doses may be administered and may cause serious circulatory depression. Further clinical studies and the collective experience of anesthesiologists are required to determine the optimal dose of remifentanil, both alone and in combination with other drugs, for maintaining controlled depression of MAP with hemodynamic stability while providing adequate reflex depression.

Ethical considerations for this type of experiment require using a background anesthetic, which could cause overestimation of the extent of the interaction between drugs. However, {alpha}-chloralose is used as a basal anesthetic drug in cardiovascular and neurosciences because it provides satisfactory anesthesia while preserving neural and cardiovascular reflexes (36). Moreover, when used as a basal anesthetic in animals, {alpha}-chloralose has no significant effect on PNA (37); in cats, chemoreflexes remain the same as in the conscious state (38). Baseline data during {alpha}-chloralose anesthesia also remained constant and returned to control values after withdrawal of the study drugs. Basal {alpha}-chloralose anesthesia was therefore an acceptable starting point for our studies.

A previous study showed that a decrease in MAP, acting through the baroreflexes, causes an increase in PNA and vice versa (39). Therefore, the combined effect of sevoflurane and remifentanil on PNA, which should normally increase during hypotension, may have been underestimated.

In conclusion, the depressant effect of sevoflurane on PNA was less than for {Delta}HR and {Delta}MAP. In contrast, for remifentanil, PNA and {Delta}HR were each approximately 9 times more sensitive to its depressant effects than {Delta}MAP. The interactions between sevoflurane and remifentanil on PNA, resting HR and MAP, and evoked changes in MAP, were synergistic, whereas their combined effect on evoked nociceptive responses in HR was additive. The data suggest that, during major surgery, when cardiovascular responses are virtually abolished by a combination of sevoflurane and remifentanil, spontaneous ventilation may not be feasible.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 16, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press