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From the Department of Anesthesiology, Korea University Anam Hospital, Seoul, South Korea.
Address correspondence to: Dr. Hye-Won Lee, Department of Anesthesiology, Korea University Anam Hospital, 126–1, 5-Ka, Anam-dong, Sungbuk-Ku, Seoul, South Korea 136–705. Phone: +82-2-920-5632; Fax: +82-2-928-2275; E-mail: hyewonmd{at}unitel.co.kr
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Abstract |
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Methods: Forty women undergoing elective lower abdominal surgery received a propofol target controlled infusion (TCI) to maintain a modified Observer’s Assessment of Alertness/Sedation (OAA/S) score of 2 (sedation period). Subsequently anesthesia was induced with propofol TCI 5 µg·mL–1 and rocuronium 0.9 mg·kg–1, and propofol continued so as to maintain general anesthesia at a BIS of 50 (general anesthesia period). Intravenous epinephrine at a dose of 10 µg·5 mL–1 in normal saline (epinephrine group, n = 20) or normal saline 5 mL (control group, n = 20) was administered during both periods. The BIS, mean arterial pressure (MAP) and heart rate (HR) were measured immediately before, and one, two, three, four, six, eight, and ten minutes after injection. The modified OAA/S scale was evaluated during the sedation period.
Results: There was no significant change in the modified OAA/S scale, BIS, or hemodynamic variables compared to preinjection values during either sedation or general anesthesia in the control group. Intravenous epinephrine increased the BIS and modified OAA/S scale during sedation, but there was no increase in BIS during general anesthesia. Increases in HR and MAP were observed during both periods after iv epinephrine.
Conclusion: Intravenous epinephrine 10 µg resulted in an arousal effect and an increase in BIS during sedation, but did not change the BIS during general anesthesia. These results suggest that the arousal effect of iv epinephrine during propofol anesthesia depends on anesthetic depth.
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Introduction |
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It has been shown that iv isoprenaline5 or epinephrine6 injection induce arousal of the patient, and increase the BIS during propofol sedation. Thus, exogenous catecholamines may change anesthetic depth and the BIS. However, our preliminary study (abstract in the Korean Intravenous Anesthesia Journal 2002; 6: 55–9) found that a usual dose of epinephrine 10 µg, ephedrine 10 mg or phenylephrine 100 µg, did not increase the BIS in patients anesthetized with 1 minimum alveolar concentration enflurane. Thus, we hypothesized that the difference in anesthetic depth may have affected the effect of iv epinephrine on arousal and change of the BIS.
The aim of this study was to investigate whether the anesthetic depth affects the effect of iv epinephrine on changes of the BIS in patients anesthetized with propofol.
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Methods |
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Patients received no premedication before anesthesia. Standard monitors (non-invasive arterial blood pressure, heart rate (HR), and pulse oximetry (Agilent, Boblingen, Germany) were applied in the preoperative area. The BIS was monitored using a strip electrode BIS sensor (A-2000 BIS monitor, Aspect Medical Systems, Newton, MA, USA) placed on the forehead of the patient and connected to a BIS monitor. This monitor displays an active analogue waveform and a numerical BIS value, which is updated every five seconds.
A target controlled infusion (TCI) of propofol (Diprifusor,TM Fresenius Vial SA, Brézins, France) was initiated with an initial target blood concentration of 2 µg·mL–1 and the target concentration was subsequently increased by 0.2 µg·mL–1 every 20 sec until the patient failed to respond to loud verbal commands of the Observer’s Assessment of Alertness/Sedation (modified OAA/S scale of 2).
Sedation was maintained using propofol TCI to achieve a score of 2 on the modified OAA/S scale2 (0 = does not respond to noxious stimulus; 1 = does not respond to mild prodding or shaking; 2 = responds only after mild prodding or shaking; 3 = responds only after name is called loudly or repeatedly; 4 = lethargic response to name spoken in normal tone; and 5 = responds readily to name spoken in normal tone). Intravenous normal saline 5 mL (in the control group) or epinephrine 10 µg·5 mL–1 normal saline (in the epinephrine group) were administered during sedation after a stabilization period of at least five minutes. The modified OAA/S scale, BIS, HR and mean arterial pressure (MAP) were measured immediately before, and one, two, three, four, six, eight and ten minutes after the injection of normal saline or epinephrine. After completing the protocol for sedation, the propofol TCI was stopped.
Once the patient’s modified OAA/S scale returned to 5, the patient was transferred to the operating room. The trachea was intubated after induction of anesthesia using propofol TCI, starting at an initial target blood concentration of 5 µg·mL–1, and rocuronium 0.9 mg·kg–1. General anesthesia was maintained at a BIS level of 50 by titrating propofol to a target concentration of 2.5 to 5 µg·mL–1. Intravenous normal saline 5 mL or epinephrine 10 µg·5 mL–1 normal saline were administered during general anesthesia after a stabilization period of at least five minutes. The BIS, HR and MAP were measured immediately before, and one, two, three, four, six, eight and ten minutes after the injection of normal saline or epinephrine.
A sample size calculation allowed us to determine that an elevation of the BIS value of 10 relative to the preinjection value would be detectable using a sample size of 17 patients per group (two groups for ANOVA) for 
= 0.05 and a study power of 0.8. Therefore, we decided to include 20 patients per group for the study.
All data are expressed as means ± SD. Demographic data were compared by unpaired t tests. Differences within the groups were tested by repeated measures ANOVA and post hoc comparisons were performed by Dunnett’s test. The differences between the groups were verified by unpaired t test or Mann-Whitney test. A P value < 0.05 was considered to be statistically significant.
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Results |
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No significant differences were found between the control group and the epinephrine group with respect to age, weight or height (Table
). The target concentrations of propofol did not differ between the two groups (Table). There was no significant difference in the preinjection value of the modified OAA/S scale, BIS, HR and MAP between groups at both study periods (Figures 1 and 2).
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). In the epinephrine group, the modified OAA/S scale increased at one to four minutes compared to preinjection value and to the control group and BIS increased at one to six minutes compared to preinjection value [maximum value in the epinephrine group: 75.6 ± 4.4 (69–84) vs preinjection value in the epinephrine group: 65.1 ± 1.8 (63–65)] and at one to four minutes compared to the control group [maximum value in the epinephrine group: 75.6 ± 4.4 (69–84) vs value at two minutes in the control group: 65.5 ± 3.0 (60–68; P < 0.05)]. HR and MAP increased after the injection of epinephrine (P < 0.05; Figure 1).
At the time of general anesthesia, there were no significant changes in BIS or hemodynamic variables compared to preinjection values in the control group (Figure 2). In the epinephrine group, the BIS did not increase (P > 0.05) but HR and MAP increased after the injection of epinephrine (P < 0.05; Figure 2).
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Discussion |
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The process of this observed arousal effect induced by epinephrine is not well understood, but it might be the result of a complex interplay of a number of neuropharmacological processes. The importance of an adrenergic system responsible for the modulation of consciousness has been known for many years.7 However, it is difficult to exclude arousal secondary to other indirect, or peripheral effects of epinephrine, such as the increase in cardiac output causing redistribution of blood flow or increased clearance, with resultant drop in the effect-site concentration of propofol.8
Johnson et al.5 reported an increase in MAP and HR and the arousal of patients after the infusion of isoprenaline at a dose of 0.03 µg·kg–1 ·min–1 during sedation with propofol TCI 1.2 µg·mL–1 and that, consequently, the dose of propofol had to be doubled to maintain sedation. Andrzejowski et al.6 studied patients sedated to a score of 2 on the modified OAA/S scale with propofol 3.1 µg·mL–1, and found that after the injection of iv epinephrine at a dose of 15 µg, the sedation score changed from 2 to 4 and the BIS increased from 63 to 79. It has been reported that pheochromocytoma patients may be very somnolent for the first 48 hr after surgery, possibly because of the sudden removal of the activating catecholamines, and this was found to result in a decreased requirement for narcotics.9 The above reports suggest that there might be some correlation between catecholamine levels and arousal. The arousal effect of iv epinephrine that had been demonstrated during sedation was not observed during general anesthesia in our study. Therefore we speculate that the state of anesthetic depth might influence the difference of this effect induced by epinephrine.
The plot of the BIS against anesthetic depth follows an ‘S’ shaped slope from the awake state to the anesthetic state, starting with a steep slope at the BIS values of around 60 to 70 which then level off at BIS values of around 30 to 50 during propofol anesthesia.10 This implies that the magnitude of the change in BIS would be different according to the initial value of the BIS. Therefore it would be expected that there would be a large change in the value of the BIS during a period of light anesthesia, where the value of the BIS is 60 to 70, but only a small change, if any, in the BIS value during a period of deep anesthesia where the value of the BIS is 30 to 50. As a result, the injection of epinephrine during general anesthesia, in which the BIS level is maintained at 50, may not have induced any change in the value of BIS.
Myburgh et al.8 reported a pharmacokinetic interaction between iv epinephrine and propofol, where an induced hyperdynamic circulatory state decreased propofol concentrations. The hemodynamic effects of epinephrine may cause redistribution of blood flow or increase the clearance of propofol, with a resultant drop in the effect site concentration of propofol. Intravenous epinephrine may have lowered the effect site concentration of propofol and caused a large change of the BIS during sedation, leading to arousal, but this effect may not have been sufficient to decrease higher propofol concentration and increase the BIS during general anesthesia.
In our study, the BIS response to epinephrine was delayed compared to hemodynamic response during sedation (Figure 1). It is not a matter of BIS calculation time constant, since the modified OAA/S scale reacted similarly. Gunnells et al.11 reported that the hemodynamic response to iv epinephrine induced the alteration in the status of arousal of the central nervous system. Dahlgren et al.12 concluded that iv epinephrine infusion increased cerebral metabolic and circulatory effects and the rise of MAP induced the translocation of the amine from blood to cerebral extracellular fluids and evoked the changes in the EEG. Catecholamines poorly penetrate the blood-brain barrier but high arterial pressure induced by iv epinephrine transiently opens the barrier to allow translocation of epinephrine with subsequent activation of the reticular formation. Therefore, the increase of the BIS required that iv epinephrine first increase MAP.
The use of a catecholamine in patients receiving propofol anesthesia is common. After the injection of epinephrine, we consider that the anesthetic depth of the patient may change and anesthetic requirements increase because epinephrine induces arousal of patients undergoing sedation with propofol. The dose of epinephrine (10 µg) used in our study was very low, but larger doses are commonly used in other situations. This may be of clinical significance and require further study.
In conclusion, iv epinephrine 10 µg induced arousal and an increase in the BIS during sedation with propofol, but did not change the BIS during general anesthesia. The arousal effect of iv epinephrine may depend on anesthetic depth during propofol anesthesia.
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Footnotes |
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References |
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2 Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836–47.[Medline]
3 Mychaskiw G, Heath BJ, Eichhorn JH. Falsely elevated bispectral index during deep hypothermic circulatory arrest. Br J Anaesth 2000; 85: 798–800.
4 Puri GD. Paradoxical changes in bispectral index during nitrous oxide administration. Br J Anaesth 2001; 86: 141–2.
5 Johnson IA, Andrzejowski J, Sikiotis L. Arousal following isoprenaline (Letter). Anaesth Intensive Care 1999; 27: 221.
6 Andrzejowski J, Sleigh JW, Johnson IA, Sikiotis L. The effect of intravenous epinephrine on the bispectral index and sedation. Anaesthesia 2000; 55: 761–3.[Medline]
7 Berridge CW, Foote SL. Enhancement of behavioral and electroencephalographic indices of waking following stimulation of noradrenergic ß-receptors whthin the medial septal region of the basal forebrain. J Neurosci 1996; 16: 6999–7009.
8 Myburgh JA, Upton RN, Grant C, Martinez A. Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model. Intensive Care Med 2001; 27: 276–82.[Medline]
9 Yao FF. Yao and Artusio’s Anesthesiolgy, 4th ed. Philadelphia: Lippincott-Raven Publishers; 1998: 595.
10 Kazama T, Ikeda K, Morita K, et al. Comparion of the effect-site keos of propofol for blood pressure and EEG bispectral index in elderly and younger patients. Anesthesiology 1999; 90: 1517–27.[Medline]
11 Gunnells JC, Gorten R, Bogdonoff MD, Warren JV, Durham NC. The effect of alterations in arousal of the central nervous system upon cardiovascular response to intravenous epinephrine. Am Heart J 1960; 60: 231–6.[Medline]
12 Dahlgren N, Rosen I, Sakabe T, Siesjo BK. Cerebral functional, metabolic and circulatory effets of intravenous infusion of adrenaline in the rat. Brain Res 1980; 184: 143–52.[Medline]
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