Ephedrine, but Not Phenylephrine, Increases Bispectral Index Values During Combined General and Epidural Anesthesia

Ephedrine, but Not Phenylephrine, Increases Bispectral Index Values During Combined General and Epidural Anesthesia Tadahiko Ishiyama, MD, PhD, Takeshi Oguchi, MD, PhD, Tetsuya Iijima, MD, Takashi Matsukawa, MD, PhD, Satoshi Kashimoto, MD, PhD, and Teruo Kumazawa, MD, PhD Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan Ephedrine and phenylephrine are used to treat hypotension during combined general and epidural anesthesia, and they may change anesthetic depth. In the current study, we evaluated the effects of ephedrine versus phenylephrine on bispectral index (BIS) during combined general and epidural anesthesia. After injection of ropivacaine through the epidural catheter, general anesthesia was induced with propofol and vecuronium, and was maintained with 0.75% sevoflurane. Approximately 10 min after the intubation, BIS was recorded as a baseline value. Patients with decreases in arterial blood pressure 30% of the preanesthetic values were defined as control group (n 9). Patients who had to be treated for larger decreases in arterial blood pressure were randomly assigned to receive ephedrine 0.1 mg/kg (n 17) or phenylephrine 2 g/kg (n 17). BIS values were recorded at 1-min intervals for 10 min. BIS in the ephedrine group was significantly larger from 7 to 10 min than that in the control and phenylephrine groups (P 0.05). Seven patients in the ephedrine group had BIS 60, whereas no patient in the control and phenylephrine groups had BIS 60 (P 0.005). Ephedrine, but not phenylephrine, increased BIS during general anesthesia combined with epidural anesthesia. (Anesth Analg 2003;97:780 4) 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 Support was provided solely from institutional and/or departmental sources. Accepted for publication April 8, 2003. Address correspondence and reprint requests to Tadahiko Ishiyama, MD, PhD, Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Tamaho, Nakakoma, Yamanashi 409-3898, Japan. Address e-mail to ishiyama@res.yamanashi-med.ac.jp. DOI: 10.1213/01.ANE.0000073355.63287.E4 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. Methods 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 (Spo 2 ). With the patient in 2003 by the International Anesthesia Research Society 780 Anesth Analg 2003;97:780 4 0003-2999/03

ANESTH ANALG TECHNOLOGY, COMPUTING, AND SIMULATION ISHIYAMA ET AL. 781 2003;97:780 4 EPHEDRINE, PHENYLEPHRINE, AND BIS 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, Petco 2, and rectal temperature were also monitored. The patient s lungs were mechanically ventilated to maintain a Petco 2 at 32 38 mm Hg. Fraction of inspired oxygen was adjusted to avoid Spo 2 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 g/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, Spo 2,Petco 2, 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 2 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. Results 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. Spo 2,Petco 2, 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. Discussion 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.

782 TECHNOLOGY, COMPUTING, AND SIMULATION ISHIYAMA ET AL. ANESTH ANALG EPHEDRINE, PHENYLEPHRINE, AND BIS 2003;97:780 4 Table 1. Patient Characteristics and Measurements During the Study Period Control Ephedrine Phenylephrine n 9 17 17 Age (yr) 67 3 61 14 63 14 Sex (female/male) 4/5 7/10 10/7 Height (cm) 154 10 158 9 156 12 Weight (kg) 48 1 53 10 56 13 BIS, pre-general anesth 94 4 94 3 94 1 Sensory block-cephalad limit T5 (T4-T8) T7 (T4-T8) T5 (T4-T9) Oxygen saturation (%) 99 1 99 1 99 1 P et co 2 (mm Hg) 34 6 34 4 34 3 Rectal temperature ( C) 36.2 0.3 36.3 0.2 36.5 0.3 BIS 60 0 7* 0 Data are mean sd, median (25th 75th percentile), or number. BIS bispectral index, pre-general anesth before induction of anesthesia, BIS 60 number of patients in whom bispectral index values were more than 60. * P 0.005 versus control and phenylephrine group. Figure 2. Changes in the bispectral index values after no vasopressor (control group), ephedrine (ephedrine group), or phenylephrine (phenylephrine group) injection in patients during sevoflurane anesthesia combined with epidural anesthesia. *P 0.05 versus the control group. P 0.05 versus the phenylephrine group. P 0.05 versus corresponding baseline values. Data are mean sd. Figure 1. Changes in mean blood pressure (A) and heart rate (B) before induction of general anesthesia and after no vasopressor (control group), ephedrine (ephedrine group), or phenylephrine (phenylephrine group) injection in patients during sevoflurane anesthesia combined with epidural anesthesia. Pre-general anesth before induction of general anesthesia. bpm beats per minutes. *P 0.05 versus the control group. P 0.05 versus the phenylephrine group. Data are mean sd. 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.

ANESTH ANALG TECHNOLOGY, COMPUTING, AND SIMULATION ISHIYAMA ET AL. 783 2003;97:780 4 EPHEDRINE, PHENYLEPHRINE, AND BIS Indirect sympathomimetic drugs such as amphetamine and methamphetamine have powerful stimulant actions to the CNS in addition to the peripheral and 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 bloodbrain barrier (8). Indirect sympathomimetic drugs act indirectly by releasing endogenous norepinephrine. Central 1-adrenoceptor stimulation functionally antagonized the hypnotic response to dexmedetomidine (9). Norepinephrine stimulates cortical 1-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 1-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 g/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 effectsite 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.

784 TECHNOLOGY, COMPUTING, AND SIMULATION ISHIYAMA ET AL. ANESTH ANALG EPHEDRINE, PHENYLEPHRINE, AND BIS 2003;97:780 4 References 1. Malec D, Langwinski R. Anticataleptic action of psychostimulating drugs and serotonin in brain. Acta Physiol Pol 1979;30: 589 95. 2. Steffey EP, Eger EI II. The effect of seven vasopressors of halothane MAC in dogs. Br J Anaesth 1975;47:435 8. 3. Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 2000;93:1336 44. 4. Hodgson PS, Liu SS. Epidural lidocaine decreases sevoflurane requirement for adequate depth of anesthesia as measured by the Bispectral Index monitor. Anesthesiology 2001;94:799 803. 5. Katoh T, Suzuki A, Ikeda K. Electroencephalographic derivatives as a tool for predicting the depth of sedation and anesthesia induced by sevoflurane. Anesthesiology 1998;88:642 50. 6. Hoffmann BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Gilman AG, ed. Goodman & Gilman s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:199 248. 7. Bowyer JF, Newport GD, Slikker W Jr, et al. An evaluation of l-ephedrine neurotoxicity with respect to hyperthermia and caudate/putamen microdialysate levels of ephedrine, dopamine, serotonin, and glutamate. Toxicol Sci 2000;55:133 42. 8. Domer FR, Wolf CL. Effects of lead on movement of albumin into brain. Res Commun Chem Pathol Pharmacol 1980;29:381 4. 9. Guo T-Z, Tinklenberg J, Oliker R, Maze M. Central alpha 1-adrenoceptor stimulation functionally antagonizes the hypnotic response to dexmedetomidine, an alpha 2-adrenoceptor agonist. Anesthesiology 1991;75:252 6. 10. Darracq L, Blanc G, Glowinski J, Tassin J-P. Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of d-amphetamine. J Neurosci 1998;18:2729 39. 11. Rothman RB, Baumann MH, Dersch CM, et al. Amphetaminetype central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 2001;39:32 41. 12. Wisor JP, Nishino S, Sora I, et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci 2001;21:1787 94. 13. Zarrindast MR. Dopamine-like properties of ephedrine in rat brain. Br J Pharmacol 1981;74:119 22. 14. Ruwe WD, Naylor AM, Bauce L, Veale WL. Determination of the endogenous and evoked release of catecholamines from the hypothalamus and caudate nucleus of the conscious and unrestrained rat. Life Sci 1985;37:1749 56. 15. Sarmento A, Borges N, Azevedo I. Adrenergic influences on the control of blood-brain barrier permeability. Naunyn Schmiedebergs Arch Pharmacol 1991;343:633 7. 16. Mayhan WG. Role of nitric oxide in disruption of the bloodbrain barrier during acute hypertension. Brain Res 1995;686: 99 103. 17. Berridge CW, O Neill J. Differential sensitivity to the wakepromoting actions of norepinephrine within the medial preoptic area and the substantia innominata. Behav Neurosci 2001;115: 165 74. 18. Adachi YU, Watanabe K, Higuchi H, Satoh T. The determinants of propofol induction of anesthesia dose. Anesth Analg 2001;92: 656 61. 19. Eger EI II. Uptake and distribution. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000:74 95. 20. Storm H, Myre K, Rostrup M, et al. Skin conductance correlates with perioperative stress. Acta Anaesthesiol Scand 2002;46: 887 95. 21. Yamamoto K, Ozawa N, Shinba T, Hoshino T. Functional influence of the central noradrenergic system on the skin conductance activity in rats. Schizophr Res 1994;13:145 50. 22. Reves JG, Glass PS, Lubarsky DA. Nonbarbiturate intravenous anesthetics. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000:228 72. 23. Olofsen E, Dahan A. The dynamic relationship between endtidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999;90:1345 53. 24. De Deyne C, Struys M, Heylen R, et al. Influence of intravenous clonidine pretreatment on anesthetic requirements during bispectral EEG-guided sevoflurane anesthesia. J Clin Anesth 2000;12:52 7. 25. Hodgson PS, Liu SS, Gras TW. Does epidural anesthesia have general anesthetic effects? A prospective, randomized, doubleblind, placebo-controlled trial. Anesthesiology 1999;91:1687 92.