Ishiyama, Tadahiko MD, PhD; Oguchi, Takeshi MD, PhD; Iijima, Tetsuya MD; Matsukawa, Takashi MD, PhD; Kashimoto, Satoshi MD, PhD; Kumazawa, and Teruo MD, PhD
Hypotension sometimes occurs during combined general and epidural anesthesia. Ephedrine and phenylephrine are widely used to treat hypotension. Ephedrine has anticataleptic action (1), and may exert potent stimulating effects on the central nervous system (CNS). In addition, a previous study reported that the minimum alveolar concentration of halothane increased significantly during ephedrine infusion but did not increase during phenylephrine infusion (2). Thus, ephedrine may change anesthetic depth.
Bispectral index (BIS) is often used to assess anesthetic depth (3). BIS is a dimensionless number scaled from 100 (awake electroencephalogram) to 0 (complete electrical silence) (3). In clinical studies about BIS, ephedrine and phenylephrine were used to maintain arterial blood pressure (4). However, ephedrine and phenylephrine may influence BIS even though they are not anesthetics.
The aim of the present study was to investigate the effects of ephedrine and phenylephrine on BIS in patients anesthetized with general and epidural anesthesia.
The study was approved by the ethics committee of our institution, and written informed consent was obtained from all patients. We enrolled 44 ASA physical status I or II patients who were scheduled for elective surgery under combined general and epidural anesthesia. Patients with cerebral infarction, psychological disorders, neurologic disorders, or a history of alcohol or drug abuse were excluded.
Patients were premedicated with IM midazolam 0.02 mg/kg 30 min before entering the operating room. Before anesthesia, a venous catheter was inserted, and acetated Ringer’s solution was infused at a rate of 10 mL · kg−1 · h−1 throughout the study. Intraoperative monitoring consisted of a five-lead electrocardiogram, noninvasive measurement of blood pressure, and pulse oximetry (Spo2). With the patient in the lateral position, an epidural catheter was placed through an 18-gauge Tuohy needle at a vertebral level between T8 and L3. Thereafter, the patient was turned to the supine position. Then a disposable BIS Sensor® was applied to the forehead of each patient and a preinduction BIS value was obtained from an A-1050 monitor. The patient was given 5 mL of 0.75% ropivacaine through the epidural catheter, followed by an infusion of 10 mL/h. Sensory block was verified by loss of sensation to cold 5 min after the epidural injection.
General anesthesia was induced with propofol 2 mg/kg IV and the patient was ventilated with sevoflurane 5% in oxygen. Tracheal intubation was facilitated with vecuronium 0.15 mg/kg IV. After tracheal intubation, anesthesia was maintained with 0.75% sevoflurane (end-tidal) in an air/oxygen mixture. End-tidal sevoflurane concentration, Petco2, and rectal temperature were also monitored. The patient’s lungs were mechanically ventilated to maintain a Petco2 at 32–38 mm Hg. Fraction of inspired oxygen was adjusted to avoid Spo2 <97%.
Approximately 10 min after the intubation, BIS values were recorded as baseline values, and the patients were randomly allocated to 2 groups receiving either ephedrine 0.1 mg/kg IV (ephedrine group) or phenylephrine 2 μg/kg IV (phenylephrine group). If mean blood pressure did not decrease >30% of the preanesthetic values, each vasopressor was not administered. This group was defined as the control group. Therefore, the patients were divided into three groups according to which drug they received: none, ephedrine, or phenylephrine. BIS acquisition was made at 1-min intervals for 10 min. If a given patient had a BIS >60, the sevoflurane concentration was increased in 0.25% increments. When the BIS decreased to <50 after increasing sevoflurane concentration, the sevoflurane concentration was reduced in 0.25% decrements. Blood pressure was measured noninvasively every 2.5 min during the study period. No surgical procedure was performed during the study.
Data were expressed as mean ± sd, median, and 25th and 75th percentiles, or numbers. Patients’ age, height, weight, initial BIS values, mean blood pressure, heart rate, Spo2, Petco2, rectal temperature, and among-group comparisons in BIS values were compared using factorial analysis of variance. When a significant result was obtained, Fisher’s protected least significant difference test was performed for multiple comparisons. Sex and number of patients in whom sevoflurane concentration had been increased were compared by using a χ2 test. The Kruskal-Wallis test was used to analyze the spread of sensory anesthesia. Within-group comparisons in BIS values were performed using analysis of variance for repeated measurements, followed by the Dunnett post hoc test. A P value < 0.05 was considered significant.
One of 44 patients was excluded because of an unintended dural puncture. Nine patients had decreased mean blood pressure <30% of preanesthetic values, and they were assigned to control group (n = 9). In the remaining 34 patients, 17 were allocated to each group (ephedrine group, n = 17; phenylephrine group, n = 17). Study groups were similar with regard to age, height, weight, preanesthetic BIS values, and spread of sensory blockade. Spo2, Petco2, and rectal temperature during the study period also did not differ in the three groups (Table 1).
Preanesthetic values of mean blood pressure and heart rate were similar in the three groups. Mean blood pressure during BIS value acquisition was comparable among the three groups except baseline. Heart rate during BIS value acquisition was significantly faster in the ephedrine group than in the other groups (P < 0.05) (Fig. 1).
Baseline BIS values were comparable among the three groups (Fig. 2). BIS values were significantly increased at 9 and 10 min from the baseline values in the control and the phenylephrine groups, and from 2 to 10 min in the ephedrine group (P < 0.05) (Fig. 2). BIS values in the ephedrine group were significantly larger from 7 to 10 min than those in the control and the phenylephrine groups (P < 0.05) (Fig. 2). Seven patients in the ephedrine group had BIS values >60 and were increased sevoflurane concentration at 1.0%–1.5%, whereas no patient in the control and the phenylephrine groups had BIS >60. This was statistically significant (P < 0.005) (Table 1). Mean ± sd end-tidal sevoflurane concentrations in the ephedrine group were 0.78 ± 0.08, 0.79 ± 0.06, and 0.85 ± 0.15, at 4, 8, and 10 min, respectively. End-tidal sevoflurane in the control and phenylephrine groups was 0.75% during the study period.
The main finding of this study was that ephedrine, but not phenylephrine, increases BIS values during sevoflurane anesthesia combined with ropivacaine epidural anesthesia.
We have sometimes witnessed hypotension during combined general and epidural anesthesia. Ephedrine and phenylephrine are used to treat hypotension. In the present study, both ephedrine and phenylephrine increased blood pressure, and only ephedrine increased BIS, which has been reported to correlate well with depth of sedation during sevoflurane anesthesia (5). It is postulated that a BIS <50 may be a sufficient depth of sedation, and that >60 would be an inadequate depth of sedation. The current study demonstrated that ephedrine increased mean BIS above 50. Furthermore, our study showed that ephedrine increased BIS >60 in 41% of the patients, and that their inhaled sevoflurane concentrations were increased. Our results concur with a previous report showing that ephedrine significantly increased minimum alveolar concentration of halothane (2). The sevoflurane requirement would be potentially increased after ephedrine injection. Therefore, we had to adjust the anesthetic gas concentration after ephedrine administration.
In the current study, the maximal effect of ephedrine on the BIS was seen at 10 minutes after the ephedrine injection, whereas peak blood pressure was at 2.5 minutes. There may be differences between the effects of ephedrine on cardiovascular systems and on the CNS. Because the CNS effect of ephedrine may persist for several hours (6), there was a discrepancy in the time course of ephedrine effects on the hemodynamics and on the CNS.
Indirect sympathomimetic drugs such as amphetamine and methamphetamine have powerful stimulant actions to the CNS in addition to the peripheral α and β actions. Ephedrine is closely related chemically to amphetamine and methamphetamine, and its action is similar to them (7). In addition, ephedrine has been reported to cross the blood-brain barrier (8). Indirect sympathomimetic drugs act indirectly by releasing endogenous norepinephrine. Central α1-adrenoceptor stimulation functionally antagonized the hypnotic response to dexmedetomidine (9). Norepinephrine stimulates cortical α1-adrenergic receptors to produce locomotor activation (10), and it may contribute to the amphetamine-type subjective effects on CNS stimulation in humans (11). In addition, dopamine is necessary for wake-promoting action (12). The increase in locomotion and turning behavior produced by ephedrine has been reported to be mediated through dopaminergic mechanism (13). Detection of both norepinephrine and dopamine is possible under ephedrine-stimulated conditions in the CNS (14). Release of norepinephrine and dopamine may be responsible for increasing the BIS after ephedrine injection.
Because central α1-adrenoceptor has an important role in awaking action, phenylephrine may also exert wake-promoting action. In animal studies using rats, phenylephrine infusion increased the blood-brain barrier’s permeability (15), and produced disruption of the blood-brain barrier (16). Actually, infusion of phenylephrine directly into the medial preoptic area elicited a robust increase in waking in rats (17). On the contrary, Guo et al. (9) showed that IV administration of phenylephrine did not attenuate dexmedetomidine’s hypnotic effect in humans. Their findings are consistent with our results demonstrating that phenylephrine did not influence the BIS. Because phenylephrine does not cross the blood-brain barrier in humans (9), it is unlikely that phenylephrine would influence depth of sedation.
Although the BIS is an electroencephalogram-based monitor of the depth of anesthesia (3), several factors can modify the BIS. Cardiac output influences the pharmacokinetics for anesthetic drugs (18). When the cardiac output increases, blood concentrations of propofol decrease (18). An increase in cardiac output also decreases alveolar concentration of high blood soluble volatile anesthetics such as halothane by augmenting uptake (19). Therefore, a sudden increase in cardiac output may affect anesthetic depth during propofol or halothane anesthesia. However, cardiac output shows the least effect on alveolar concentration of poorly soluble drugs like sevoflurane (19). Increased cardiac output induced by ephedrine might produce a minor influence on the increase of the BIS after ephedrine injection during sevoflurane anesthesia.
Because the BIS monitor strip is pasted on the skin, and skin conductance correlates with emotional state and arousal (20), skin conductance could have influenced the BIS in the current study. Stimulation of the central noradrenergic activity affects the skin conductance (21). Thus, ephedrine would influence skin conductance via the CNS effects. However, skin conductance is chiefly affected by sweat production, which is controlled by postganglionic, cholinergic neurons (20). Because ephedrine enhances the release of norepinephrine, but not acetylcholine, from sympathetic nerves, it would induce a little effect on skin conductance. Although change of skin conductance could change the BIS, its effect might be minimal.
The BIS increased at 9 and 10 minutes in the control and phenylephrine groups. In the current study, anesthesia was induced with propofol 2 mg/kg IV. After a bolus injection, plasma concentrations of propofol decrease rapidly as a result of redistribution and elimination (22). The measurements of BIS were performed approximately 15–25 minutes after the propofol injection. Plasma concentration of propofol 15 minutes after the bolus 2 mg/kg IV should have been smaller than 1 μg/kg, but not zero (22). Propofol concentrations at the start of the BIS measurements should have been larger than those at the end of the BIS measurements. Carryover effects of propofol might have been involved in the increases of the BIS in the control and phenylephrine groups.
We used 0.75% as end-tidal sevoflurane concentration. One study demonstrated that estimated effect-site sevoflurane concentration to induce a BIS value of 50 was 1.14% ± 0.31%(23). Another reported that the maintenance dose of sevoflurane was 1.46% ± 0.60%(24). However, epidural anesthesia has been shown to possess general anesthetic effects (25). In combined general and epidural anesthesia, the minimum alveolar concentration of sevoflurane was reduced by 50% and was 0.52% ± 0.18%(25), and sevoflurane requirement to produce a BIS value of <50 was 0.59%(4). In the current study, mean BIS during the study period in the control group was between 42 and 48 under sevoflurane 0.75% inhalation. Our findings agree with those of a previous study showing that the end-tidal sevoflurane concentration related to a BIS of 50 was 0.73%(4). A sevoflurane concentration of 0.75% was thought to be clinically relevant.
In conclusion, a clinical dose of ephedrine, but not phenylephrine, increases the BIS during sevoflurane anesthesia combined with ropivacaine epidural anesthesia. Ephedrine-induced increases in the BIS may have been produced by the increased electroencephalographic activity attributed to the central stimulatory effects of ephedrine. The increased cardiac output, or the changes in skin conductance produced by ephedrine could have caused small effects on the increase of the BIS.
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