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© 2001 International Anesthesia Research Society
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Abstract |
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Volatile anesthetics attenuate baroreflex function in a concentration-dependent manner. This study was designed to determine how long full recovery of baroreflex control of heart rate takes after isoflurane or sevoflurane anesthesia in healthy volunteers. We assessed baroreflex sensitivity in 20 subjects randomized to receive either isoflurane or sevoflurane (n = 10 each). After an 8- to 10-h fast and no premedication, mea- surements of R-R intervals obtained from the electrocardiogram (lead II) and systolic blood pressure (SBP) measured through a radial artery catheter were made at conscious baseline and 20, 60, and 120 min after the induction during end-tidal isoflurane 1.3% or sevoflurane 2.0% in air and oxygen, and 20, 60, 120, and 180 min after the emergence from general anesthesia. Baroreflex responses were triggered by bolus IV injection of phenylephrine and nitroprusside to increase and decrease SBP by 15–30 mm Hg, respectively. The linear portions of the baroreflex curves relating R-R intervals and SBP were determined to obtain baroreflex sensitivity. During anesthesia, baroreflex sensitivities of both the pressor and depressor tests were decreased by 50%–60% compared with conscious baseline values in both groups (P <0.05). Pressor test sensitivities returned to the baseline values at 120 min, whereas depressor test sensitivities returned to the baseline values at 60 min, after general anesthesia in both groups. There were no significant differences in baroreflex sensitivities between groups at any interval. Our results indicate that the recovery characteristics of baroreflex sensitivity are similar after isoflurane and sevoflurane anesthesia and that the depressor test sensitivity is restored more rapidly than the pressor test sensitivity after both anesthetic techniques.
IMPLICATIONS: Arterial baroreflex function is an important neural control system for maintaining cardiovascular stability. The authors found that 2 h was required for full recovery of baroreflex function and that recovery characteristics were similar after isoflurane and sevoflurane anesthesia in healthy volunteers not undergoing surgery.
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Introduction |
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Arterial baroreflex function is an important, short-term, neural control system for maintaining cardiovascular stability. The effects of contemporary available general anesthetics, such as isoflurane, sevoflurane, and desflurane, on baroreflex control of heart rate (HR) have been extensively investigated in humans (1–4). Increasing minimum alveolar anesthetic concentrations of these anesthetics results in similar and progressive decreases in baroreflex sensitivity (5). However, recovery characteristics of baroreflex function are poorly understood. More importantly, how long volatile anesthetics exert depressive effects on the baroreflex function after general anesthesia and, thus, how full recovery of baroreflex function actually takes place have not been addressed previously.
Previous studies suggest a rapid return of baroreflex sensitivities to preanesthesia, premedicated conditions after surgeries with halothane and isoflurane anesthesia (6,7). The results of these investigations, however, could be confounded by the use of morphine and atropine as premedication before baseline determinations of the baroreflex function (6,7). A more recent study in unpremedicated surgical patients demonstrated that baroreflex sensitivity to hypertensive, but not hypotensive, challenge returned to the conscious baseline level 20 min after sevoflurane anesthesia but was still depressed after isoflurane anesthesia (3). However, because noxious stimuli, sympathetic stimulation, and increased circulating catecholamine may all modify baroreflex-induced circulatory responses immediately after surgery (8–10), the effects of volatile anesthetics, per se, on the recovery profile of baroreflex function remain undetermined. To understand the extent and complex mechanism of prolonged postoperative depression of baroreflex activity, it is imperative that the isolated effects of volatile anesthetics be examined.
Accordingly, this study was designed to determine changes in baroreflex sensitivities to both hypertensive and hypotensive challenges during and after isoflurane or sevoflurane anesthesia in healthy young volunteers. To isolate the effects of volatile anesthetics, no other anesthetics, opioids, or premedications were administered during the entire course of the study.
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Methods |
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Twenty ASA physical status I volunteers, 22–32 yr old, were studied. Subjects who consumed alcoholic beverages daily, those with a history of cardiovascular, pulmonary, or neurologic disorders, and those who took any medication in the 2 weeks before the study were excluded. Volunteers also abstained from caffeine-containing beverages for at least 24 h before the study. The study protocol was approved by the institutional research committee, and informed, written consent was obtained from each subject. All subjects arrived at the operating room after an 8- to 10-h fast without premedication.
An electrocardiograph monitor (lead II), a peripheral IV catheter, and an arterial (radial) blood pressure catheter were placed in each subject while they breathed room air supplemented with oxygen 2 L/min via a face mask while lying in the supine position. The electrocardiogram, HR, and systolic blood pressure (SBP) were continuously recorded on a polygraph. Tympanic temperature was measured throughout the study period. Pressor and depressor tests were performed by using IV bolus injections of phenylephrine (100–250 µg) and nitroprusside (100–300 µg) to increase and decrease SBP by 15–30 mm Hg, respectively, before the induction of general anesthesia (awake). These doses were chosen on the basis of our pilot study of a similar age group. The pressor test was always performed first. A period of stabilization, usually 5 min, between the pressor and depressor tests allowed HR and SBP to return to the pretest values ±5% (3).
The volunteers were then randomly assigned to either the Isoflurane or Sevoflurane group (n = 10 each). General anesthesia was induced by using stepwise increments of isoflurane or sevoflurane concentrations in air (5 L/min) and oxygen (1 L/min), and a laryngeal mask airway (LMA) was inserted without any other adjuvant. Then, their lungs were mechanically ventilated (tidal volume 10–12 mL/kg at a respiratory rate of 8–10 breaths/min). Anesthesia was maintained with end-tidal isoflurane 1.3% or sevoflurane 2% in air and oxygen (fraction of inspired oxygen = 34%), and end-tidal CO2 tension was maintained at 35 mm Hg throughout the anesthesia period. To ensure anesthetic equilibration, end-tidal isoflurane and sevoflurane concentrations were maintained at 1.3% and 2%, respectively, for 20 min by frequently adjusting inspiratory concentrations before the second set of the pressor and depressor tests were performed (anesthesia-20). These tests were repeated in a similar manner after the desired end-tidal concentrations were maintained for 60 and 120 min (anesthesia-60 and -120, respectively). Then, isoflurane and sevoflurane were discontinued, and after the return of adequate spontaneous respiration and responses to verbal commands was confirmed, the LMA airway was removed. The volunteers were left undisturbed with supplemental oxygen 2 L/min via face mask. The pressor and depressor tests were repeated at 20, 60, 120, and 180 min after the removal of the LMA (recovery-20, -60, -120, and -180, respectively). Each set of the tests was preceded by determining end-tidal isoflurane or sevoflurane concentration through a cannula advanced 2–3 cm into a naris and by having subjects take five or six deep and regular breaths separated by 2–3 s. Arterial blood samples were collected for measurements of arterial blood gas tensions and plasma concentrations of potassium, sodium, ionized calcium, and glucose before each set of the tests. All subjects received balanced salt solution containing 5% dextrose at a rate of 2 mL · kg-1 · h-1 throughout the study. The ambient temperature was set to 20°C before and 25°C–30°C during and after general anesthesia to avoid causing shivering. A circulating-water mattress was not used. No other anesthetics, sedatives, or opioids were used throughout the study.
A power analysis based on a previous similar study revealed that eight patients would provide a power of >0.8 (P = 0.05) for a 50% difference in temporal baroslope changes and baroslopes of regression lines between groups (5). On completion of the study and all the data collection, the pressor and depressor test data were analyzed by a blinded observer (MT), who used least-square regression analysis on the linear portion of the sigmoid relation between SBP and the R-R interval, when each R-R interval was plotted as a function of the preceding SBP. We used 7–11 pairs of corresponding SBP and R-R intervals at the end-expiratory phase to analyze each test result. The square values of all the correlation coefficients were >0.8. Data are presented as mean ± SD throughout the article. Changes in baroslopes during various stages were first analyzed by two-way analysis of variance for repeated measurements, and if a significant difference was detected with respect to time or group, it was followed by Fisher’s protected least significance difference test as a post hoc test to compare pretest hemodynamic data and baroslopes between and within groups. The 
2 test and unpaired t-test were used to compare volunteers’ demographic data between groups. A P value <0.05 was considered statistically significant.
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Results |
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There were no significant differences in volunteers’ demographic data, awake pretest SBP and HR, and awake tympanic temperature between groups (Table 1). After general anesthesia induction, SBP significantly decreased and HR significantly increased compared with awake values in the Sevoflurane group. In the Isoflurane group, SBPs were significantly less during anesthesia than the awake value, whereas significantly increased HR was seen only at the anesthesia-120 period. In both groups, SBP returned to the baseline values after emergence from general anesthesia, whereas significantly increased HR were seen during the immediate postanesthesia period (recovery-20). Tympanic temperatures were significantly less than the baseline values during, but returned to the baseline levels after, general anesthesia in both groups (Table 1). There were no significant differences in the pretest SBP, HR, and tympanic temperatures between groups at any interval.
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Baroslopes of the pressor and depressor tests were significantly depressed compared with awake values in both groups during the entire course of general anesthesia, except for the baroslope of the pressor test in the Sevoflurane group at the anesthesia-20 period (Fig. 1). The smallest baroslope values were always seen at the anesthesia-120 period in all subjects and were decreased by 50%–60% compared with awake values in both groups (no significant difference between groups). Pressor test sensitivities of both groups remained depressed for 60 min after the removal of the LMA. However, depressor test sensitivities returned to the awake levels at the recovery-60 period and thereafter in both groups (Fig. 1). No significant difference in baroreflex sensitivity was seen between groups at any study interval.
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No significant difference was seen in arterial pH, PaCO2, and PaO2 values; sodium, potassium, or ionized calcium concentrations; or blood glucose values between groups at any study interval (data not shown). Oxygen saturation was >98% in all subjects throughout the study. The mean times from the discontinuance of isoflurane and sevoflurane until the LMA removal were 23.3 ± 8.7 and 20.9 ± 6.2 min, respectively, and were similar between groups (P = 0.49). No ventricular or supraventricular arrhythmia was observed at any time during the study.
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Discussion |
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One of the major findings of our study is that both pressor and depressor test sensitivities were significantly depressed in the immediate recovery period even at the fractional end-tidal concentrations of isoflurane and sevoflurane. Similar degrees of depression in baroreflex sensitivities to both the pressor and depressor tests at the anesthesia-20 and recovery-20 periods with almost 10-fold differences in end-tidal isoflurane and sevoflurane concentrations suggest that there is significant hysteresis in the concentration-response profile of baroreflex function, depending on whether the depth of general anesthesia is being deepened or vice versa (Fig. 1). It is not clear from our results, however, whether prolonged depression of arterial baroreflex function is attributed to subanesthetic end-tidal concentrations of volatile anesthetics, because effects of fractional concentrations of volatile anesthetics on baroreflex function have not been addressed previously. One may argue that, without validating the accuracy of our method in measuring end-tidal concentrations, reported end-tidal isoflurane and sevoflurane values may have been underestimated during the recovery period because of dilution with room air. Furthermore, there may be a difference in the central nervous system and alveolar partial pressures of volatile anesthetics, because the equilibrium has never been reached during the emergence from general anesthesia. A more precise mechanism of prolonged depression of baroreflex function after general anesthesia remains to be determined.
Our results also demonstrated that two hours was required until full recovery of baroreflex function, determined by both the pressor and depressor test sensitivities after both anesthetic techniques. These results suggest that patients remain at increased risk for developing hemodynamic instability in response to sudden bleeding or postural changes for at least two hours after surgery. However, interpretation of these results should be confined to the circumstance of our investigation, by using healthy young volunteers without noxious stimulation. In actual surgical patients, other IV anesthetics, opioids, or sedative medications, all of which potentially attenuate baroreflex control of HR in humans (11–13), may be administered. In addition, high thoracic sympathetic blockade by cervical epidural anesthesia attenuates (14), but lumbar epidural anesthesia augments (15), baroreflex sensitivities in humans. Mild hypothermia depresses both the pressor and depressor test sensitivities during, and prolongs their recovery after, sevoflurane anesthesia in healthy young volunteers (16). These previous results suggest that the recovery profile of baroreflex function may be a more complex process in surgical patients. Whether the recovery characteristics of baroreflex function are influenced by the subjects’ age remains to be determined.
Our data are in clear contrast with a previous study, in which pressor test sensitivity returned to the preanesthesia, unmedicated condition 20 minutes after minor surgical procedures performed under sevoflurane/N2O anesthesia, but it was still significantly depressed after isoflurane/N2O anesthesia (3). Postganglionic sympathetic efferent nerve stimulation directly sensitizes carotid sinus baroreceptors in cats (9), and clinically relevant plasma norepinephrine concentrations increase impulse frequency of carotid baroreceptor afferent (depressor branch) fibers in rabbits (10). Therefore, neurologic or endocrinologic alterations elicited by surgery and noxious stimulation may have accelerated recovery of the pressor test sensitivity after surgery compared with the sevoflurane-anesthetized subjects in this study. However, the absence of differential recovery characteristics with or without surgery under isoflurane anesthesia is not clear from our results. Theoretically, possible stimulatory effects of neuro-endocrinologic environment on the baroreflex function may have been differentially overridden by the predominantly depressive effect of subtle concentrations of two volatile anesthetics.
Seagard et al. (17) have shown, in isoflurane-anesthetized dogs, that volatile anesthetics act at several sites along the baroreceptor pathway, including the baroreceptors, afferent and efferent nerve pathways, the central nervous system, peripheral ganglia, and the heart, and they demonstrated that efferent postganglionic sympathetic fibers recovered more slowly than vagal fibers. In addition, isoflurane-induced depression of vagal tone approaches the conscious level more quickly (30 min) than sympathetic tone after anesthesia (18). On the basis of these previous results before we performed this study, we assumed that the pressor test sensitivity would recover more rapidly than the depressor test sensitivity, as seen in sevoflurane-anesthetized surgical patients (3). However, more rapid recovery of the depressor test than the pressor test sensitivity of our study suggests that HR increase caused by hypotensive challenge is not simply a manifestation of sympathetic stimulation. Indeed, blockade of cardiac accelerator nerve by cervical epidural anesthesia resulted in a significant decrease in the pressor test sensitivity, but unaltered depressor test sensitivity, in humans (14). The relative contribution of sympathetic and parasympathetic nervous system to the immediate HR changes associated with baroreflex responses remains to be seen in humans.
Our results must be interpreted with some caution. Even though no significant difference was detected in the recovery times after the discontinuance of anesthetics until the removal of the LMA, retrospective sample size calculation revealed that at least 65 patients would be required in each group to demonstrate a statistically significant difference in this variable (
= 0.05, ß = 0.8). It is more important to note that measurement timings of baroslopes after the discontinuance of sevoflurane were approximately 2.5 min earlier than those of isoflurane, and this may partly explain the absence of significant differences in baroreflex sensitivities after isoflurane and sevoflurane anesthesia.
In conclusion, the recovery profile of baroreflex control of HR is similar to, and full recovery takes two hours after, isoflurane and sevoflurane anesthesia in healthy volunteers not undergoing surgery. The depressor test sensitivity recovers more rapidly than the pressor test sensitivity after both anesthetic techniques.
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References |
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- Murat I, Lapeyre G, Saint-Maurice C. Isoflurane attenuates baroreflex control of heart rate in human neonates. Anesthesiology 1989; 70: 395–400.[Web of Science][Medline]
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Tanaka M, Nishikawa T. Sevoflurane speeds recovery of baroreflex control of heart rate after minor surgical procedures compared with isoflurane. Anesth Analg 1999; 89: 284–9.
[Abstract/Free Full Text] - Muzi M, Ebert TJ. A comparison of baroreflex sensitivity during isoflurane and desflurane anesthesia in humans. Anesthesiology 1995; 82: 919–25.[Web of Science][Medline]
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Carter JA, Clarke TNS, Prys-Roberts C, Spelina KR. Restoration of baroreflex control of heart rate during recovery from anaesthesia. Br J Anaesth 1986; 58: 415–21.
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Sampson SR, Mills E. Effects of sympathetic stimulation on discharges of carotid sinus baroreceptors. Am J Physiol 1970; 218: 1650–3.
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[Abstract/Free Full Text] - Takeshima R, Dohi S. Circulatory responses to baroreflexes, Valsalva maneuver, coughing, swallowing, and nasal stimulation during acute cardiac sympathectomy by epidural blockade in awake humans. Anesthesiology 1985; 63: 500–8.[Web of Science][Medline]
- Baron JF, Decaux-Jacolot A, Edouard A, et al. influence of venous return on baroreflex control of heart rate during lumbar epidural anesthesia in humans. Anesthesiology 1986; 64: 188–93.[Web of Science][Medline]
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