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© 1999 International Anesthesia Research Society
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Abstract |
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Volatile anesthetics attenuate arterial baroreflex functions, whereas noxious stimuli may modify baroreflex-induced circulatory responses during anesthesia. We designed the present study to compare baroreflex control of heart rate during sevoflurane and isoflurane anesthesia in young healthy surgical patients. Baroreflex sensitivity was assessed in 24 patients randomized to receive either sevoflurane (n = 12) or isoflurane (n = 12) for general anesthesia. After an 8- to 10 -h fast and no premedication, measurements of RR intervals obtained from electrocardiography and systolic blood pressure (SBP) measured through a radial artery catheter were made at conscious baseline (Awake), during end-tidal sevoflurane 2% or isoflurane 1.2% plus 67% nitrous oxide before incision (Anesth), during surgery at end-tidal sevoflurane 2% or isoflurane 1.2% plus 67% nitrous oxide (Surg), and 20 min after tracheal extubation (Recov). Baroreflex responses were triggered by bolus IV injections of phenylephrine (100–150 µg) and nitroprusside (100–150 µg) to increase and decrease SBP by 15–30 mm Hg, respectively. The linear portions of the baroreflex curves relating RR intervals and SBP were determined to obtain baroreflex sensitivities. Baroreflex sensitivities to both pressor and depressor tests were significantly depressed during Anesth and Surg periods compared with Awake values in both anesthetic techniques. The pressor test sensitivity during the Recov period returned to the Awake value after sevoflurane (12.9 ± 3.7 vs 11.0 ± 8.7 ms/mm Hg [mean ± SD]) but was still depressed after isoflurane anesthesia (13.9 ± 8.0 vs 4.8 ± 3.2 ms/mm Hg; P < 0.05). The depressor test sensitivities during the Recov period remained depressed after both anesthetic techniques. We conclude that both sevoflurane and isoflurane depress arterial baroreflex function during anesthesia and surgery, but the pressor test sensitivity was restored more quickly after sevoflurane than after isoflurane anesthesia.
Implications: Arterial baroreflex function is an important neural control system for maintaining cardiovascular stability. We found that baroreflex control of heart rate due to hypertensive perturbation returned to the preanesthetic level more quickly after sevoflurane than after isoflurane anesthesia.
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Introduction |
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Arterial baroreflex function, an important neural control system for maintaining cardiovascular stability, is depressed by volatile anesthetics in both humans and animals (1–8). Halothane (1,2), enflurane (3), isoflurane (4,5), and desflurane (6) all attenuate baroreflex control of heart rate (HR) in humans, whereas nitrous oxide exerts minimal effects (1–3). The recently introduced volatile anesthetic sevoflurane was also found to be a depressant of baroreflex-sympathetic reflex system in rabbits (7) and of baroreflex control of HR in humans (8). However, changes and recovery of arterial baroreflex function during and after surgery under sevoflurane anesthesia have not been examined in humans.
In contrast to the isolated effect of each anesthetic, intraoperative alterations and postoperative recovery of arterial baroreflex function have not been well documented in humans. Previous studies suggest rapid return of baroreflex sensitivities to preanesthesia, premedicated conditions after surgeries using halothane (9) and isoflurane anesthesia (10), but not after enflurane anesthesia (10). However, the results of these studies could be confounded because of the use of morphine (9) and atropine (10) as premedication before baseline determinations of the baroreflex function, as well as for patients with advanced age (10).
In this study, we examined and compared the effects of sevoflurane and isoflurane anesthesia on arterial baroreflex control of HR through the entire course of clinical anesthesia, i.e., before induction of general anesthesia, after induction of anesthesia before surgery, during surgery, and on recovery from anesthesia. We hypothesized rapid recovery of baroreflex sensitivities to the conscious baseline level after sevoflurane anesthesia, because sevoflurane has relatively low blood and tissue solubilities compared with halothane, enflurane, and isoflurane (11). We chose young and healthy surgical patients and gave neither premedications nor opioids to eliminate possible confounding factors affecting baroreflex sensitivities.
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Methods |
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We studied 24 ASA physical status I patients, 24–42 yr of age, scheduled to undergo general anesthesia for elective minor surgeries. Surgery primarily involved minor procedures of the head and neck, such as mandibular joint exploration, mandibular tumor resection, mandibular plate removal, maxillary sinus surgery, and partial thyroidectomy. These procedures were evenly distributed in the two groups of patients receiving either sevoflurane or isoflurane. Patients who consumed alcoholic beverages daily; those with a history of cardiovascular, pulmonary, or neurological disorders; or those who had taken any medication in the 2 wk before the study were excluded. Patients were not allowed to have any caffeine for at least 48 h before the study. The study protocol was approved by the institutional research committee, and informed consent was obtained from each patient. All patients arrived at the operating room after an 8- to 10 -h fast. No premedication was given.
An electrocardiograph monitor (lead II), a peripheral IV catheter, an arterial (radial) blood pressure catheter, and a beat-to-beat basic HR monitor (tachometer) were established with each patient in the supine position breathing supplemental oxygen 6 L/min via a face mask. End-tidal CO2 was monitored through a 20 -gauge cannula advanced 2–3 cm into either naris. The electrocardiogram, the capnogram, HR, and systolic blood pressure (SBP) were continuously recorded on a polygraph. Bladder temperature was measured throughout the study period. Pressor and depressor tests were performed using IV injections of phenylephrine (100–150 µg) and nitroprusside (100–150 µg) to increase and decrease SBP by 15–30 mm Hg, respectively, before the induction of general anesthesia (Awake). These doses were chosen based on a previous study (10) and our pilot study in a similar age group. A period of stabilization (usually 5 min) between the pressor and the depressor tests allowed HR and SBP to return within 5% of the pretest values.
The patients were then anesthetized in the supine position with IV thiamylal 5 mg/kg, and tracheal intubation was facilitated with IV vecuronium 0.1 mg/kg. After endotracheal intubation, patients’ lungs were mechanically ventilated (tidal volume 10–12 mL/kg at a respiratory rate of 8–10 breaths/min). All patients were then randomized to received either sevoflurane (n = 12) or isoflurane (n = 12). Anesthesia was maintained with 67% nitrous oxide, end-tidal sevoflurane 2%, or isoflurane 1.2% in oxygen, while end-tidal CO2 was maintained at 30–35 mm Hg. To ensure anesthetic equilibration, the desired end-tidal anesthetic concentrations were maintained constant for at least 20 min before the next test was performed. The second pressor and the depressor tests were then performed in a similar manner before the beginning of surgical procedures in the supine position (Anesth). End-tidal anesthetic concentrations, sevoflurane at 2% and isoflurane at 1.2%, were maintained constant for the entire course of surgery. The third sets of the tests were performed 60 min after the start of surgery (Surg).
After surgery, sustained tetanic contracture for 5 s was documented by a nerve stimulator with its electrodes located over the ulnar nerve; hence, muscle relaxant was not antagonized. After confirming the return of adequate spontaneous respiration, responses to verbal commands, and end-tidal sevoflurane and isoflurane concentrations <0.4% and <0.2%, respectively, tracheal extubation was performed. Patients were then left undisturbed with supplemental oxygen 6 L/min via a face mask for 20 min, and had stable HR and SBP. End-tidal anesthetic concentrations were determined in all patients through a cannula advanced 2–3 cm into a naris, and by having patients take several regular deep breaths. The last sets of the pressor and the depressor tests were then performed (Recov). No opioids were given throughout the study.
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. During surgery, all patients received lactated Ringer’s solution, but no other crystalloid solutions, at a rate adjusted to maintain urinary output >1 mL · kg-1 · h-1, and none received blood or blood products during surgery.
Power analysis based on a previous similar study revealed that eight patients would provide a power >0.8 (P = 0.05) for 50% difference for temporal baroslope changes (10), and our pilot study revealed that at least 12 patients in each group would provide a power >0.8 (P = 0.05) for 50% difference in baroslopes and intercepts of regression lines between groups. The pressor and the depressor tests data were analyzed using least-square linear regression analysis on the linear portion of the sigmoid relation between SBP and RR interval, when each RR interval was plotted as a function of the preceding SBP during expiration. We used 7–14 pairs of corresponding SBP and RR interval to analyze each test result. The square values of all correlation coefficients were >0.8. Data are presented as mean ± SD throughout the article. Changes in baroreflex sensitivities during various stages were first analyzed by using repeated measures of analysis of variance, followed by paired t-test with Bonferroni’s correction to adjust for multiple comparisons. 
2 tests and unpaired t-tests were used to compare patients’ demographic, surgical, and hemodynamic data, as well as determinants of baroreflex functions, such as baroslopes and 
intercepts, 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 patients’ demographic and surgical data between groups (Table 1). Patients’ temperature decreased significantly during anesthesia and surgery compared with the Awake period but returned to Awake values during the recovery period in both groups (Table 1). Arterial blood gas analysis revealed that PaCO2 decreased significantly during Anesth and Surg and significantly increased during the Recov period in both groups (Table 1). Oxygen saturation was >98% in all patients throughout the study. Sodium, potassium, and ionized calcium concentrations were within normal ranges in all patients, and blood glucose levels ranged from 84 to 144 mg/dL.
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Pretest SBP values were significantly lower during anesthesia and surgery than the Awake values in both groups (Table 2). Compared with the Awake period, HR significantly increased during anesthesia in the sevoflurane group, whereas HR was unchanged during anesthesia and surgery in the isoflurane group. During the recovery period, both SBP and HR were significantly greater than Awake values in both groups (Table 2). No significant differences in pretest SBP or HR were seen between groups at any interval.
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There were no significant differences in the pressor and the depressor test sensitivities (baroslopes) during the Awake period between groups (Table 2, Figures 1 and 2). Compared with Awake values, both sensitivities were significantly depressed after the induction of general anesthesia and during surgery in both groups. During the Recov period, the pressor test sensitivity of the sevoflurane group recovered and increased significantly compared with that during surgery, whereas that of the isoflurane group during the Recov period was still depressed compared with the Awake value. As a result, the pressor test sensitivity of the sevoflurane group was significantly greater than that of the isoflurane group during the Recov period (P = 0.03) (Figure 1). However, the depressor test sensitivities in both groups remained depressed during the Recov period (Figure 2). End-tidal concentrations of sevoflurane and isoflurane immediately before the pressor and the depressor tests during the Recov period were 0.20% ± 0.04% and 0.12% ± 0.02%, respectively.
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P < 0.05 versus Awake. 
P < 0.05 versus Surg.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major finding of our study is that arterial baroreflex sensitivity, determined by both the pressor and the depressor tests, was significantly depressed during sevoflurane and isoflurane anesthesia, and that the pressor test sensitivity was restored more quickly after sevoflurane than isoflurane anesthesia. According to previous similar works using halothane (1,2) and enflurane (3), concomitant administration of nitrous oxide exerts either minimal or slightly stimulatory effect on the baroreflex sensitivities. Although thiamylal was used for the induction of anesthesia, its depressive effect on arterial baroreflex function is dissipated within 10 min of its administration (4). In our study, more than 20 minutes had elapsed before the second sets of the tests (Anesth), not only to eliminate confounding effects of thiamylal, but also for the equilibrium of anesthetics to be reached. Hyperoxia seen while patients were awake and during anesthesia in our study would not have played a role in modulating baroreflex functions because hyperoxia either alone or in combination with halothane does not significantly alter baroreflex sensitivities (1,12). These results, together with previous reports, indicate that depression of the baroreflex function during anesthesia seen in our study is primarily due to the effects of sevoflurane and isoflurane.
Our results also indicate that surgical stimulation does not alter the primary depressive effect of volatile drugs on the baroreflex function. Although noxious stimuli by surgery, which produces "cortical arousal," may modify baroreceptor-mediated circulatory responses (13) and may evoke sensitization of baroreceptors through increases in plasma catecholamine concentrations (14,15), depression of baroreflex sensitivities were found to be similar to those determined during anesthesia before surgery, during which end-tidal sevoflurane and isoflurane concentrations were maintained constant. These results suggest that theoretically possible antagonizing effects of neurological and endocrinological alterations elicited by surgery on baroreflex functions are overridden by the predominantly depressive effect of simultaneously administered volatile anesthetics. Indeed, previous clinical studies failed to demonstrate changes in arterial baroreflex functions during surgery with methohexital, halothane, enflurane, and isoflurane anesthesia (9,10). We cannot exclude a possibility, however, that with procedures more invasive than those in the present study, surgical stimulation may have modulated the baroreflex function.
Although the end-tidal concentrations of both volatile drugs were comparable after tracheal extubation, the recovery of the pressor test sensitivity was considerably delayed after isoflurane anesthesia compared with sevoflurane anesthesia. The difference in the speed of recovery of the pressor test sensitivity may be attributed to the lower blood and tissue solubilities of sevoflurane compared with isoflurane (11). However, Seagard et al. (16) demonstrated, in isoflurane-anesthetized dogs, that volatile anesthetics known to act at several sites along the baroreceptor pathway, including the baroreceptors, afferent and efferent nerve pathways, central nervous system, peripheral ganglia, and heart, depressed cardiac chronotropic responses to direct sympathetic fiber stimulation more than vagal fiber stimulation. These results suggest that efferent postganglionic sympathetic fiber recovers more slowly from isoflurane than vagal fiber, resulting in slower recovery of the depressor than the pressor test sensitivity.
Takeshima and Dohi (10) determined baroreflex sensitivity in the immediate postoperative period and found that both the pressor and the depressor test sensitivities incompletely recovered toward the awake baseline level 10–15 min after isoflurane anesthesia. However, both test sensitivities remained depressed after enflurane anesthesia. In contrast to their work, we measured end-tidal concentrations of volatile anesthetics during the recovery period and demonstrated that depressor test sensitivities were profoundly depressed even at subanesthetic concentrations (-40% and -60% depression after sevoflurane and isoflurane, respectively). Whether subanesthetic concentrations of volatile anesthetics per se caused depression of arterial baroreflex function remains to be seen. More importantly, it is of clinical relevance to determine how long full recovery of baroreflex function takes after various techniques of general anesthesia.
Poorly preserved baroreflex regulation of HR in response to a decreasing pressure stimulus after sevoflurane or isoflurane anesthesia may be detrimental in some clinical circumstances but advantageous in others. Depression of homeostatic cardiovascular reflexes may have undesirable sequelae after postural changes or sudden loss of circulating blood volume, as may occur during recovery from anesthesia. Hypovolemia superimposed on poorly preserved baroreflex function may also exaggerate such hemodynamic perturbations. In contrast, diminished reflex tachycardia in response to decreased blood pressure would attenuate increases in myocardial oxygen demand in patients with myocardial ischemia. However, rapid recovery of the pressor test sensitivity after sevoflurane may be advantageous in patients with myocardial ischemia because slowing of HR would prevent further increases in myocardial oxygen demand.
In conclusion, arterial baroreflex function, determined by the pressor (phenylephrine) and the depressor tests (nitroprusside), was significantly depressed during anesthesia and surgery under sevoflurane and isoflurane plus nitrous oxide in healthy surgical patients. Whereas depressor test sensitivities remained depressed after both sevoflurane and isoflurane anesthesia, the pressor test sensitivity returned to the awake baseline value more quickly on recovery from sevoflurane versus isoflurane anesthesia.
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References |
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- Duke PC, Fownes D, Wade JG. Halothane depresses baroreflex control of heart rate in man. Anesthesiology 1977;46:184–7.[Web of Science][Medline]
- Duke PC, Trosky S. The effect of halothane with nitrous oxide on baroreflex control of heart rate in man. Can Anaesth Soc J 1980;27:531–4.[Web of Science][Medline]
- Morton M, Duke PC, Ong B. Baroreflex control of heart rate in man awake and during enflurane and enflurane-nitrous oxide anesthesia. Anesthesiology 1980;52:221–3.[Web of Science][Medline]
- Kotrly KJ, Ebert TJ, Vucins E, et al. Baroreceptor reflex control of heart rate during isoflurane anesthesia in humans. Anesthesiology 1984;60:173–9.[Web of Science][Medline]
- 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]
- 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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- Ebert TJ, Harkin CP, Muzi M. Cardiovascular responses to sevoflurane: a review. Anesth Analg 1995;81:S11–22.[Abstract]
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Bristow JD, Brown EB, Cunningham DJC, et al. The effects of hypercapnia, hypoxia and ventilation on the baroreflex regulation of the pulse interval. J Physiol 1971;216:281–302.
[Abstract/Free Full Text] - Biber B, Martner J, Werner O. Modification by baroreceptor feedback of circulatory responses to noxious stimuli during anaesthesia in cats. Acta Anaesthesiol Scand 1983;27:391–5.[Web of Science][Medline]
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