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Department of Anesthesia, Akita University School of Medicine, Akita-city, Japan
Address correspondence and reprint requests to Makoto Tanaka, MD, Department of Anesthesia, Akita University School of Medicine, Hondo 1-1-1, Akita-city 010-8543, Japan. Address e-mail to mtanaka{at}med.akita-u.ac.jp.
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Abstract |
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Introduction |
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Volatile anesthetics typically depress baroreflex control of heart rate in a concentration-dependent manner and continue to exert depressive effects after emergence from general anesthesia in humans (8–10). Although many baroreflex studies have been performed under general anesthesia in humans, most previous results have been limited to determinations of baroreflex gains (9–12), reflecting only a part of the sigmoid-shaped baroreceptor-cardiac reflex relation. Determination of the entire baroreflex curve defines the range of the reflex (maximum buffering capacity of vagally mediated hemodynamic control), and its depression, if any, may explain perioperative hemodynamic vulnerability by general anesthetics.
In addition to depression of vagal reflex activity by anesthetics, hypotension, per se, may have two possible independent consequences on cardio-vagal baroreflex function. First, sustained hypotension by nitroprusside infusion shifts the operational point (relative position of the resting set point within the entire baroreflex response curve) towards the more flattened, nonlinear region (threshold) in conscious humans (13,14). Therefore, general anesthesia-induced hypotension alone may reduce the tangential slope at the operational point without altering the maximum slope of the linear portion. Second, hypotension-induced vagal withdrawal may further attenuate dynamic, beat-to-beat modulation of the cardiac cycle.
Accordingly, this study was designed to test the hypothesis that gain, as well as range, of the baroreflex relation is depressed by sevoflurane anesthesia. In addition, we hypothesize that the depressed gain is partly caused by repositioned operational point and hypotension-induced vagal withdrawal. To eliminate effects of anesthesia-induced hypotension, per se, baroreflex variables were determined during phenylephrine infusion to maintain conscious baseline arterial blood pressure (BP). Furthermore, heart rate variability indices were calculated to elucidate possible relations between vagal nerve activities and baroreflex variables.
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Methods |
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All volunteers were familiarized with the laboratory and interventions before the study. They arrived at the laboratory at 7:00 am after an 8-h fast, and the study commenced at 8:00 am. They were placed in the supine position, and a 22-gauge IV catheter was inserted into a peripheral vein for administration of balanced salt solution containing 5% dextrose at 2 mL · kg–1 · h–1 throughout the study. Fluid temperature was maintained at approximately 30°C. Determinations of BP and R-R interval were made from a radial arterial catheter and an electrocardiogram (Viridia CMS 2000 TM; Hewlett Packard, Boeblingen, Germany), respectively. All subjects received whole-body forced-air warming to maintain baseline temperature while tympanic temperature was monitored. The ambient temperature was set to 25°C–30°C to avoid postanesthesia shivering.
General anesthesia was induced using 5% sevoflurane (inspiratory) in air and oxygen, and a laryngeal mask airway was inserted without any other adjuvant. Their lungs were mechanically ventilated (tidal volume, 7–10 mL/kg at a respiratory rate of 12 breaths/min). Anesthesia was maintained with 2% end-tidal sevoflurane in air and oxygen (fraction of inspired oxygen [Fio2] = 0.34), whereas end-tidal carbon dioxide tension was maintained at 35 mm Hg throughout the anesthesia period. Breath-by-breath end-tidal sevoflurane concentration and carbon dioxide tension were measured by a gas analyzer (Capnomac Ultima SV; Datex, Helsinki, Finland). The end-tidal sevoflurane concentration was maintained at 2% for 30 min by frequently adjusting inspiratory sevoflurane concentrations before measurements. When the protocol for the anesthesia period was completed, sevoflurane was discontinued, and the return of adequate spontaneous respiration and responses to verbal commands were confirmed. Then, the laryngeal mask airway was removed after approximately 3 h of general anesthesia. The subjects breathed supplemental oxygen 2 L/min via a face mask to ensure oxygen saturation 
98%.
Determination of carotid-cardiac baroreflex response and heart rate variability measurements were made at the following time points: baseline awake, during sevoflurane anesthesia (3 h long), and at 30, 60, 120, and 180 min after recovery from anesthesia. Measurements during anesthesia were repeated after infusion of phenylephrine titrated to achieve baseline arterial BP. The order of testing with and without phenylephrine was randomized. When baroreflex and heart rate variability determinations with phenylephrine infusion were to be made first, phenylephrine was started immediately after the induction of general anesthesia. During the recovery phase, the end-tidal sevoflurane concentrations were measured during deep exhalation through a cannula advanced 2–3 cm into a naris.
The neck chamber device used to measure the carotid-cardiac baroreflex response was described previously (15,16). A tightly sealing, paired neck chamber, rimmed with silicone rubber, was strapped to the anterior neck. A custom-made paired chamber was used for each subject. The chamber was attached to a pressure system containing a stepping motor-driven bellows that delivered rapid (
300 mm Hg/s) changes of chamber pressure triggered by the R-wave. Software was developed for system operation and data acquisition. Carotid-cardiac reflex responses were elicited by a complex sequence of chamber pressure, as previously described (13). During held expiration, chamber pressure was increased from ambient level to 40 mm Hg and was sustained for 5 heartbeats. Then, the chamber pressure was decreased by successive R-wave triggered 15-mm Hg decrements to –65 mm Hg.
For heart rate variability analyses, 10 min or 512 beats recordings of R-R intervals free of artifacts were made during awake and the anesthesia periods. Recordings of awake electrocardiography signals were made while subjects breathed in synchrony with an auditory signal at 12 breaths/min using a metronome. During sevoflurane anesthesia, respiratory rate was fixed at 12 breaths/min (17).
Arterial BP and R-R intervals were digitized and stored at a sampling rate of 200 Hz in a computer and subsequently analyzed offline. A custom program was developed to process the digitized data using a 16-bit analog-digital converter (AD7120; ATM Communications, Tokyo, Japan), which detected R-waves from the electrocardiogram. The recordings were also observed on an oscilloscope during transfer for elimination of nonsinus or artifactual signals. Trials were repeated if the neck chamber failed to seal properly or if the subject was unable to hold their breath during the sequence. Each test session comprised seven successful applications of neck pressure-suction sequences, and the results were averaged to provide a single data set for each subject during each session. Mean SBP during the application of the pressure-suction sequence was compared with the mean of three systolic BP values obtained immediately before the sequence. Similarly, the mean of three R-R intervals before each pressure-suction sequence was regarded as the pretest R-R interval at the operational point.
For each pressure-suction sequence, R-R intervals were plotted as a function of the preceding carotid distending pressure (systolic BP – neck chamber pressure). The following discrete variables were obtained from each stimulus-response relation: maximum R-R interval at saturation, where no further increase in R-R interval was obtained with a greater carotid distending pressure; minimum R-R interval at threshold, where no further decrease in R-R interval was obtained with a smaller carotid distending pressure; range determined by [R-R interval at saturation] – [R-R interval at threshold]; maximum gain determined by application of least-square regression analysis to every set of 3 consecutive points (every 2 consecutive segments), and operational point ([baseline R-R interval – R-R interval at threshold]/range x 100%) on the baroreflex relation. If saturation or threshold could not be attained within a range of carotid distending pressure, the sigmoid-shaped curves were reduced to the following 4 parameter exponential model as described previously (16,18):
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where x = carotid distending pressure, y = calculated R-R interval, A1 = R-R interval range, A2 = slope of the exponential curve or parameter multiplier, A3 = centering point for equal pressor and depressor responses, and A4 = R-R interval at threshold.
Time-domain analysis of heart rate variability was made from the square root of the mean squared difference of successive R-R intervals (RMSSD) and the proportion of successive R-R intervals that exceeds 50 ms in relation to the total cardiac cycles (pNN50) (19). The method for frequency-domain analysis of heart rate has been explained in detail (20,21). For each tachogram of 512 artifact-free consecutive R-R intervals, a fast Fourier transformation was applied to calculate amplitude of variations of R-R intervals as a function of frequency (power spectral density: R-R interval powers [units of milliseconds (2)] as a function of frequency [hertz]). The R-R interval powers were the integrated area under the power spectral density plots as an index of the frequency-specific degree of R-R interval variability. Spectral power was determined over the high-frequency (HF; 0.15–0.4 Hz) spectrum (19).
Power analysis based on previous similar studies revealed that at least nine subjects would provide a power (ß) more than 0.8 with significance (
) 0.05 to detect a 40% change in baroreflex gains (11,22). All data were first analyzed by two-way analysis of variance for repeated measurements. Log transformation was used before performing analysis of variance if the data were not normally distributed. If a significant difference was detected with respect to time, it was followed by paired t-test with Bonferroni correction. Correlations between heart rate variability and baroreflex variables were analyzed by Pearson correlation coefficient. Data are presented as mean ± sd, and a P value < 0.05 was considered to be statistically significant.
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Results |
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Compared with conscious baseline values, systolic BP decreased significantly, but heart rate and R-R intervals were unchanged during sevoflurane anesthesia without phenylephrine (Table 1). Phenylephrine infusion during anesthesia restored systolic BP similar to that of the baseline value, whereas heart rate significantly decreased compared with the baseline value. After emergence, no significant difference in systolic BP was observed, whereas heart rate values were significantly greater at 30 min and 60 min after recovery than baseline values. Tympanic temperature remained unchanged throughout the study.
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Mean systolic BP during the neck pressure-suction sequence was comparable to that immediately before the sequence at each study interval (data not shown). Sevoflurane anesthesia without phenylephrine resulted in a significant decrease in maximum gain and range compared with awake values as a result of a significant reduction of R-R interval at saturation (Table 1; Fig. 1). Phenylephrine infusion only partially restored gain and range, which were still significantly less than the conscious baseline values (Table 1; Fig. 1). Likewise, RMSSD, pNN50, and log HF power all significantly decreased during sevoflurane anesthesia compared with awake values and partially recovered by phenylephrine infusion (Fig. 2). Significant correlations were noted between RMSSD, pNN50, and log HF power versus baroreflex gain and range before and during sevoflurane anesthesia with or without phenylephrine (0.69 < R < 0.84; P < 0.0001).
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After emergence from anesthesia, significant decreases in maximum gain and range were noted for 60 min compared with the baseline values (Table 1; Fig. 3). These baroreflex variables returned to the baseline values at 120 min after recovery and thereafter. Operational points remained unchanged throughout the study (Table 1).
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Discussion |
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A number of studies using pharmacological methods revealed profound depression of cardio-vagal baroreflex gain by volatile anesthetics in humans, but anesthetic effects on other baroreflex variables, including the range, were not examined (9,11,22,24). By applying graded, ramped neck suctions to humans, depression of baroreflex gain by volatile and IV anesthetics have been observed (9,25–27). Application of neck suction alone without pressure may identify linear and saturation portion but neither define the threshold precisely nor determine the range, operational point, and, more importantly, buffering capacity to hypotensive perturbation (16).
The unchanged operational point during sevoflurane anesthesia compared with the conscious baseline value rejected our hypothesis that the shift of the operational point might contribute to the reduced tangential baroslope at the operational point. However, an increase in BP by phenylephrine infusion was associated with an augmentation of measures of vagal activity during sevoflurane anesthesia, which in turn resulted in partial recoveries of maximum gain and range of the reflex relation. Moreover, alterations of maximum gain and range by sevoflurane with and without phenylephrine infusion correlated well with those of heart rate variability indices. These results suggest that depression of the efferent vagal nerve activity is the primary mechanism of reduced cardio-vagal baroreflex function during sevoflurane anesthesia and that hypotension-induced withdrawal of the vagal nerve activity only partially affected cardio-vagal baroreflex function.
Our results also demonstrated sustained, parallel depression of the maximum gain and range of the carotid-cardiac baroreflex responses for 60 minutes after emergence from sevoflurane anesthesia. Although vagal reflexes were not assessed during the recovery phase in the present study, prolonged suppressions of HF power of heart rate variability, together with spontaneous sequence baroreflex gain, have been reported after sevoflurane anesthesia in healthy volunteers (28). Therefore, sustained depression of cardio-vagal baroreflex function after sevoflurane anesthesia most likely reflects prolonged recovery of vagally mediated dynamic modulation of the cardiac cycle. Our findings, however, do not agree with a previous observation in which both phenylephrine pressor and nitroprusside depressor test gains returned to baseline values at 60 minutes after approximately two hours sevoflurane anesthesia in normothermic, healthy volunteers not undergoing surgery (11). Although a longer duration of anesthesia in the present study may be a possible explanation, the difference in the methodologies more likely explains these discrepancies. IV injections of vasoactive drugs, especially during hypotensive perturbation by nitroprusside, provoke sustained pressure changes, and thus, cardiac R-R interval responses reflect net effects of opposite, complex, reflex adjustments of primarily vagal, but to a lesser extent, sympathetic nerve efferent activities (29). However, the duration of the neck chamber pressure ramp is brief, and provokes small, biphasic arterial BP changes. Therefore, reflex changes in R-R intervals using the neck chamber device are less likely to be influenced by closed-loop adjustments than the pharmacological method and are considered to be mediated exclusively by vagal mechanisms (16,29). Based on these considerations, we can not exclude a possibility that earlier recovery of baroreflex control of heart rate assessed by the pharmacological method reflects more rapid recovery of the cardiac sympathetic baroreflex responses than the cardio-vagal baroreflex system.
It is not clear from the result of our study why fractional concentrations of sevoflurane exerted disproportionately profound depression of baroreflex function after emergence from sevoflurane anesthesia. A possible mechanism could be that partial pressure of sevoflurane in the brain was much higher than that in the lung, because equilibrium was never attained during the recovery phase. Whether subanesthetic concentrations of sevoflurane at equilibration cause depressions of baroreflex function remains to be determined.
Perioperative hypertension and postural hypotension are common after general anesthesia. In the supine position, cardiac output and total vascular resistance account for 25% and 75%, respectively, of carotid baroreflex-mediated changes in BP (1). The decreased range of the baroreceptor-cardiac reflex relation with the unchanged operational point seen in our study indicates compromised buffering capacity of vagally mediated hemodynamic control. Therefore, both the reduced gain and the range of the reflex may partially contribute to perioperative hemodynamic instability. In our study, vagal augmentation by a hypertensive stimulus was considerably affected during and after sevoflurane anesthesia, suggesting that inhibited vagal augmentation may play an important role in the genesis of perioperative hypertension. Indeed, the elderly and hypertensive patients, who are particularly prone to develop perioperative hypertension (30,31), are characterized by impairment of cardio-vagal reflex responses (3,4) but not arterial baroreflex control of sympathetic nerve traffic or dynamic vascular response (32,33).
The results of our study should be interpreted with some caution. First, brief carotid pressure-suction sequence specifically stimulates bilateral carotid baroreceptors, whereas physiological and pathological BP perturbations, seen perioperatively or by vasoactive drugs, activate several baroreceptor regions simultaneously (aortic, carotid, and cardiopulmonary) and induce integrated responses. In fact, absolute baroreflex gains determined by the pharmacological method, although correlating well with those calculated by the neck chamber technique, could be 5–10 times greater (7). Therefore, further studies would be warranted to confirm the present results using the pharmacological method. However, 40- to 50-mm Hg reductions of systolic BP would be required to define the threshold region by this method (34) and, thus, its application may be limited in hypotensive, anesthetized humans. Second, incomplete pressure transmission to carotid sinuses may produce erroneous carotid distending pressure. Actual determination of tissue pressure at carotid bifurcation by a percutaneously inserted catheter, however, revealed that 82% of negative and 89% of positive chamber pressure were transmitted to the periarterial tissue, and that correction of internal transmission resulted in minimum and nonsignificant changes in calculated carotid-cardiac baroreflex variables (35). Third, RMSSD, pNN50, and HF power of heart rate variability represent beat-to-beat cardio-vagal modulation of the cardiac cycle but do not directly estimate tonic activity of the vagal nerve. Except for certain experimental conditions including phenylephrine infusion and hypercapnia (36,37), tonic and phasic vagal nerve activities correlate well. In addition, our study protocol dictated normocapnia, and phenylephrine infusion resulted in significant increases in heart rate variability indices, suggesting that saturation of the vagal nerve activity was not achieved in our experimental setting. Finally, our results should be confined to young, healthy, mostly male individuals anesthetized with 2% end-tidal sevoflurane. Thus, further concentration-response studies and comparisons with other volatile or IV anesthetics would be warranted.
In conclusion, determination of carotid-cardiac baroreflex function revealed that sevoflurane anesthesia decreased maximum gain and range of the sigmoid-shaped reflex relation with the unchanged operational point in humans. Maintenance of BP by phenylephrine only partially restored baroreflex responses and heart rate variability indices, suggesting that reduced gain by sevoflurane is attributed primarily to decreased slope of the reflex relation secondary to depressed efferent vagal nerve activity, but not to the shift of the operational point or hypotension-induced vagal withdrawal. Significant inhibitions of cardio-vagal baroreflex function and, thus, of vagal nerve activity seem to last for longer than 60 minutes after emergence from sevoflurane anesthesia.
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Footnotes |
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) and without (Anesth, 
) phenylephrine infusion.
P < 0.05 versus Anesth values.
).
