Anesth Analg 2003;96:336-343
© 2003 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Bispectral Index-Guided Anesthesia in Patients Undergoing Aortocoronary Bypass Grafting
Andreas Lehmann, MD*,
Julia Karzau*,
Joachim Boldt, MD*,
Elfi Thaler, MD*,
Johannes Lang*, and
Frank Isgro, MD
Departments of *Anesthesiology and Intensive Care Medicine and
Cardiac Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
Address correspondence and reprint requests to Andreas Lehmann, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Postfach 21 73 52, D-67073 Ludwigshafen, Germany. Address e-mail to Dr.A.Lehmann{at}web.de
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Abstract
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In this prospective, randomized study, we compared hemodynamics, oxygenation, possible intraoperative awareness, and costs in 62 patients undergoing first-time elective coronary artery bypass grafting at 2 different levels of anesthesia. Depth of anesthesia was assessed with bispectral index (BIS). All patients were anesthetized with sufentanil/midazolam. The dosage of sufentanil/midazolam was adjusted to achieve a BIS level of 45–55 in 32 patients (Group BIS 50), whereas in 30 patients a BIS level of 35–45 was intended (Group BIS 40). Data were obtained at six different time points before, during, and after surgery. All patients were asked about possible intraoperative awareness on the third postoperative day. There were no significant differences of any hemodynamic or oxygenation variables at any time between the two groups. BIS 40 patients received significantly (P < 0.05) more sufentanil (BIS 40, 888 ± 211 µg; BIS 50, 514 ± 99 µg) and midazolam (BIS 40, 22.4 ± 5.6 mg; BIS 50, 16.6 ± 3.7 mg) than BIS 50 patients. The reduction in anesthetic drugs used saved 
13.78/US$12.54 per patient (P < 0.05) in Group BIS 50, but one BIS electrode caused additional costs of 19.95/US$18.15. Time to extubation was not significantly prolonged in Group BIS 40 (BIS 40, 14.3 ± 4.6 h; BIS 50, 11.8 ± 3.8 h). There was no explicit memory during anesthesia in either group. BIS-guided reduction of anesthetic medication saved costs and did not increase the risk of intraoperative awareness. However, total costs were increased by monitoring BIS, because of the BIS electrodes.
IMPLICATIONS:Bispectral index (BIS)-guided anesthesia may allow reductions in anesthetic medication and costs without increasing the risk of intraoperative awareness. However, total costs may be increased by monitoring BIS.
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Introduction
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In October 1996, bispectral index (BIS) achieved approval by the Food and Drug Administration as the first electroencephalogram (EEG)-based monitor of anesthetic effect (1). BIS reduces complex EEG processing to a simple number ranging from 100 to 0. BIS decreases with increasing depth of anesthesia (1). An adequate level of anesthesia is achieved with BIS ranging from 40 to 60 (1). EEG processing by BIS includes time domain, frequency domain, and high-order spectral subparameters such as burst suppression ratio, QUAZI suppression, relative ß-ratio, power, and bispectral analysis (2). An excellent article about EEG processing and the calculation of BIS was recently published by Rampil (2).
Clinical evaluation of BIS is still controversial. Some authors state that anesthesia can be adapted by BIS to the patient’s individual needs R3-120332 (3,4). This optimal adaptation of anesthesia reduces the amount of anesthetics used, the time to extubation, the stay in the postanesthesia recovery area, and costs R3-120332 (3,4). However, it is yet not proven that monitoring the depth of anesthesia with BIS reduces the risk of intraoperative awareness (5). O’Connor et al. (5) stated that BIS might even increase costs and the risk of intraoperative awareness. Only a few studies using targeted BIS values in patients undergoing cardiac surgery have been published (6). During the induction of anesthesia in patients undergoing coronary artery bypass grafting (CABG), three different levels of BIS—BIS 40, BIS 50, and BIS 60—were compared. At BIS 40, patients had hemodynamic instability, and at BIS 60, they had signs of inadequate anesthesia. It was concluded that maintaining BIS near 50 would ensure hemodynamic stability with an adequate level of anesthesia (6).
The intention of this study was to compare, in patients undergoing CABG, two different levels of anesthesia assessed by BIS—deep anesthesia versus normal anesthesia. Is there any influence of deep anesthesia on hemodynamics, oxygenation, use of additional medication (catecholamines or vasodilators), time to extubation, adequacy of anesthesia, and costs during the whole procedure?
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Methods
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Sixty-two patients undergoing first-time elective CABG with cardiopulmonary bypass (CPB) were enrolled in this study. Inclusion criteria were good or only slightly reduced left ventricular function (ejection fraction >40%; left ventricular end-diastolic pressure <15 mm Hg) and age less than 80 yr. Patients with valvular disease, former CABG, misuse of alcohol or drugs, or severe hepatic or renal insufficiency were excluded. The study was approved by the ethics committee of the hospital, and all patients gave written, informed consent.
The patients were prospectively randomized into two groups. In Group BIS 50 (n = 32), induction was performed with a bolus of midazolam (0.07 mg/kg) and sufentanil (1 µg/kg). Tracheal intubation was facilitated by pancuronium (0.1 mg/kg). After intubation, a continuous infusion of sufentanil (0.5–1.5 µg · kg-1 · h-1) was started. The lungs of all patients were normoventilated with oxygen in air (fraction of inspired oxygen, 0.5). Additional pancuronium (0.03 mg/kg) was given when necessary. The main target in this group was to achieve a BIS level of 45–55 by variation of the doses of the anesthetic drugs. In Group BIS 40 (n = 30), induction was performed with a bolus of midazolam (0.1 mg/kg) and sufentanil (1.5 µg/kg). Tracheal intubation was facilitated by pancuronium (0.1 mg/kg). After intubation, a continuous infusion of sufentanil (1.5–2 µg · kg-1 · h-1) was started. Ventilation and muscular relaxation were performed as in the other group. The main target in this group was to achieve a BIS level of 35–45 by variation of the doses of the anesthetic drugs. In both groups, additional boluses of midazolam (BIS 50, 0.03–0.07 mg/kg; BIS 40, 0.05–0.01 mg/kg) and sufentanil (BIS 50, 0.5–1 µg/kg; BIS 40, 1–2 µg/kg) were given if BIS increased above the upper limit of each group for >60 s. If BIS did not decrease within the next 60 s below the upper limit of each group by additional midazolam and sufentanil, propofol could be given as rescue medication.
CPB was performed by using mild hypothermia (core temperature, 32.5°–33.5°C), alpha-stat, and nonpulsatile flow (2.4 L · min-1 · m-2). Mean arterial blood pressure (MAP) was adjusted to 50 to 80 mm Hg by using vasopressors (norepinephrine) or vasodilators (nitroglycerin).
One hour before anesthesia, all patients were premedicated orally with 1 to 2 mg of flunitrazepam. Hemodynamic monitoring consisted of a five-lead electrocardiogram (ECG), radial artery cannulation, and a pulmonary artery catheter (7.5F, EFV/OTD catheter; Baxter, Irvine, CA) placed via the right internal jugular vein. Heart rate (HR), MAP, central venous pressure (CVP), mean pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and mixed venous oxygen saturation (SvO2) were measured. CO was measured by using the mean of three values obtained by the thermodilution technique (Explorer; Baxter). SvO2 was measured by fiberoptic reflectance spectrophotometry (Explorer; Baxter). Cardiac index (CI), stroke volume, left ventricular stroke work index (LVSWI), systemic vascular resistance (SVR), and pulmonary vascular resistance were calculated from standard formulas. Arterial and mixed venous blood gas analyses were performed to calculate the index of oxygen delivery and the index of oxygen consumption according to standard formulas. BIS (Version 2.21) was measured at the frontal lobe of the dominant hemisphere after skin preparation with disinfectant alcohol and slight rubbing with use of an Aspect 2000 EEG monitor and BIS-sensorTM (Aspect Medical Systems, Natick, MA). When electrode impedance exceeded 10 k
, the electrode was replaced, and skin preparation was repeated. Electrode impedance was tested repeatedly according to the software protocol of the Aspect 2000 EEG monitor. The following data points were defined: T0, awake before the induction of anesthesia (at T0, only HR, MAP, and BIS were recorded, because Swan-Ganz catheters were placed after the induction of anesthesia); T1, at steady-state after the induction of anesthesia; T2, after sternotomy; T3, 30 min after the start of CPB; T4, 5 min after CPB; and T5, at the end of surgery. Arterial plasma levels of cortisol, epinephrine and norepinephrine were measured at T0, T2, and T5 as stress markers by using standard laboratory techniques.
When MAP decreased to <60 mm Hg and right and left ventricular filling pressures (CVP and PCWP) were less than 12 mm Hg, colloids (hydroxyethyl starch, molecular weight 130.000 daltons) were infused. When CI decreased to <2.0 L · min-1 · m-2 despite adequate volume loading, a continuous infusion of dobutamine (2 µg · kg-1 · min-1) was started. The dose of dobutamine was increased until CI was more than 2.5 L · min-1 · m-2. Norepinephrine was used during and after CPB when MAP was <60 mm Hg (<50 mm Hg during CPB) and SVR was <850 dynes · s · cm-5. Nitroglycerine was used when MAP was >90 mm Hg, SVR was >1200 dynes · s · cm-5, and BIS was in the intended range.
After surgery, all patients were transferred to the intensive care unit (ICU). Controlled mechanical ventilation was continued in the ICU. The fraction of inspired oxygen and ventilation patterns were adjusted to keep PaO2 between 80 and 120 mm Hg and PaCO2 between 38 and 45 mm Hg. The patients were tracheally extubated when no major blood loss occurred and hemodynamic and respiratory variables remained stable for at least 30 min. Time to extubation was documented. No fast-track procedures were performed. Postoperative analgesia used nurse-based IV injections of piritramide, a morphine analog. The analgesic potency of piritramide in comparison to morphine (with a potency of 1) is 0.7. The patients received 3.75 to 7.5 mg of IV piritramide as determined by the attending staff nurse.
On the third postoperative day, all patients were visited and were asked to answer a standardized questionnaire (Appendix 1) to measure explicit intraoperative recall. If the patient was unable to answer the questionnaire, the event was noted as a neurological disorder.
The total amount of used and wasted drugs was documented. The costs for the anesthetic drugs were analyzed by using the hospital’s actual pharmacy list (midazolam 5 mg, 0.60/US$0.54; sufentanil 250 µg, 6.29/US$5.72). Our institution was charged for one BIS electrode with 19.95/US$18.15. The exchange rate from US dollars to Euros was 0.91. Cost analyses did not include costs for other disposables, staff, anesthesia machines, or monitoring equipment.
Data are presented as mean ± SD unless otherwise indicated. For statistical analysis, SPSS/PC+ software (Version 4.0; SPSS, Inc., Chicago, IL) was used. Hemodynamics and BIS were analyzed by using two-factorial analysis of variance for repeated measurements. For significant findings, post hoc Student’s t-tests were applied at the end-point of each mea-surement. In case of multiple comparisons, P values were corrected according to Bonferroni. Fisher’s exact tests, 
2 tests, Mann-Whitney U-tests, or unpaired Student’s t-tests were also used when appropriate. P values <0.05 were considered significant.
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Results
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Patients in both groups were similar with respect to age, weight, height, sex, and ejection fraction (Table 1). All 62 patients were classified as ASA status III, and the mean New York Heart Association classification was 2.3 ± 0.9 in Group BIS 50 and 2.5 ± 0.9 in Group BIS 40 (not significant). The duration of anesthesia, surgery, CPB, and aortic cross-clamping did not differ between the two groups (Table 1). Time to extubation was not significantly prolonged in the BIS 40 group (14.3 ± 4.6 h) compared with the BIS 50 group (11.8 ± 3.8 h). There was no difference in the volume management (crystalloids: BIS 50, 1273 ± 366 mL; BIS 40, 1410 ± 362 mL; colloids: BIS 50, 449 ± 269 mL; BIS 40, 583 ± 456 mL) or the number of patients transfused (BIS 50, n = 9; BIS 40, n = 10) between the two groups.
BIS was 86 ± 6 in Group BIS 50 and 89 ± 6 in Group BIS 40 while the premedicated patients were awake before the induction of anesthesia (T0). During anesthesia, BIS was always significantly higher (P < 0.05) in Group BIS 50 compared with Group BIS 40 (Table 2).
There was no significant difference at any time between the two groups with regard to hemodynamics (Table 3). In both groups, HR increased from the baseline value before the induction of anesthesia (T0) (P < 0.05) after CPB. At T4, CI was higher (P < 0.05) than the baseline value in both groups. MAP decreased (P < 0.05) during CPB (T3) and 5 min after CPB (T4) from the baseline value (T0). Mean pulmonary artery pressure, CVP, and PCWP remained unchanged throughout the whole study period. SVR decreased during and after CPB (T3 to T5) (P < 0.05) in both groups. There was no change of pulmonary vascular resistance. LVSWI decreased (P < 0.05) after CPB (T4 and T5) in both groups. However, LVSWI did not show any significant differences between the two groups. There was no change of SvO2, index of oxygen delivery, or index of oxygen consumption from the baseline value nor between the two groups (Table 3).
In both groups, no patient needed dobutamine before CPB (not significant). There was no difference in the need for dobutamine between the two groups to increase CI to >2 L · min-1 · m-2 after CPB. In Group BIS 40, significantly more patients needed norepinephrine during and 5 min after CPB (T3 and T4). The use of nitroglycerine did not differ between the two groups, except at T4 (BIS 50, 9%; BIS 40, 27%; P < 0.05) (Table 4).
Cortisol, epinephrine, and norepinephrine did not differ between the two groups before, during, or after surgery (Fig. 1). Epinephrine and norepinephrine were analyzed only before CPB (T0 and T2), because several patients received catecholamines after CPB. Epinephrine was smaller in Group BIS 40 and increased in Group BIS 50. However, this trend did not reach statistical significance.
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Figure 1. Changes in arterial plasma levels of cortisol (µg/dL), epinephrine (ng/L), and norepinephrine (ng/L) (mean ± SD). BIS 50 = bispectral index (BIS) ranging from 45 to 55; BIS 40 = BIS ranging from 35 to 45; T0 = awake, T2 = after sternotomy, T5 = at the end of surgery. Epinephrine and norepinephrine were analyzed only before cardiopulmonary bypass (CPB) (T0 and T2), because several patients received external catecholamines after CPB. #P < 0.05 between the two groups.
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The postoperative interview at the third postoperative day did not show any significant differences in patient satisfaction. In both groups, all patients were able to answer. Nearly all patients wanted the same type of anesthesia if they required cardiac surgery again. In neither group was there any sign of explicit intraoperative memory during anesthesia (Table 5).
Patients in Group BIS 40 received significantly more sufentanil and midazolam than patients in Group BIS 50 (Table 6). In both groups, 16 patients needed propofol as rescue medication for BIS values above the intended limit (BIS 40, BIS >45; BIS 50, BIS >55). The amount of propofol used was significantly larger in Group BIS 40 (BIS 40, 2.2 ± 3.4 mg/kg; BIS 50, 0.9 ± 1.9 mg/kg). The reduction in the amount of used anesthetics saved 13.78/US$12.54 per patient (P < 0.05) in Group BIS 50. One BIS electrode caused additional costs of 19.95/US$18.15 (Table 6).
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Discussion
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BIS is the only monitor for anesthetic depth evaluated by a multicenter study (7). It had a sensitivity of 97.3% and a specificity of 94.4% (8). An adequate level of anesthesia is achieved with BIS ranging between 40 and 60 R1-120332 (1,9). Monitoring BIS is proposed to reduce the risk of intraoperative awareness (10). Jones (11) described different levels of intraoperative awareness: conscious awareness with pain, conscious awareness without pain, and perception without conscious awareness (implicit memory). In a series of >11,000 patients, Sandin et al. (12) reported an incidence of intraoperative awareness with explicit intraoperative recall of 0.1% without neuromuscular blockade and 0.18% with neuromuscular blocking drugs. Studies in patients undergoing cardiac surgery reported an incidence of intraoperative awareness of 0.3% to 4% R13-120332 R14-120332 (13–15). Intraoperative awareness with explicit intraoperative recall was not increased in fast-track cardiac anesthesia (15); only 1 patient out of 617 had conscious awareness with pain, and another patient had conscious awareness without pain. The authors suggest that this small incidence of intraoperative awareness might be related to the continuous administration of volatile or IV hypnotic drugs (15). Recently, explicit intraoperative recall at a BIS of 47 was reported in a patient undergoing cardiac surgery with inhaled anesthesia (16). In our series of 62 patients with 2 different levels of anesthesia, as indicated by BIS, no patient had any signs of intraoperative explicit memory.
A BIS level of 40 reflects deep anesthesia, because BIS 40 is the lower recommended range for adequate anesthesia R1-120332 (1,9). A BIS level of 50 reflects adequate anesthesia R1-120332 R9-120332 (1,9,17)—it does not reflect light anesthesia. Light anesthesia might cause the patient to experience intraoperative awareness. In a series of 45 patients undergoing the induction of anesthesia for CABG, 3 different levels of anesthesia assessed by BIS were studied (6). At BIS 40, patients had a significant decrease of MAP requiring intravascular volume load and a vasopressor. At BIS 50 and BIS 60, stable hemodynamics during the induction of anesthesia were reported (6). Patients at BIS 40 and BIS 50 had no signs of inadequate anesthesia, whereas at BIS 60, >90% of the patients coughed and had tear production. These are clinical signs of inadequate anesthesia as proposed by Evans (18). Therefore, we did not compare deep versus light anesthesia, reflected by BIS 60, in patients undergoing cardiac surgery.
A monitor for depth of anesthesia might even paradoxically cause an increased incidence of intraoperative awareness. If the sensitivity of this monitor is not near 100% and the patient is anesthetized at the upper safety limits of this monitoring device, it might lead the anesthesiologist to believe that his or her patient is anesthetized, although the patient is not and is experiencing intraoperative awareness (5). Interestingly, the studies reporting reduced drug doses and faster recovery by monitoring the depth of anesthesia advocate lighter levels of anesthesia for patients R3-120332 R4-120332 (3,4,19).
In our series of patients, comparing deep versus normal levels of anesthesia, BIS 50 patients received less sufentanil and midazolam than BIS 40 patients. Thus, BIS may help to reduce drug costs. However, with BIS, overall costs per patient were increased. One BIS electrode (19.95/US$18.15) is more expensive than the amount of saved costs for anesthetic drugs (13.78/US$12.54). This result is in good agreement with those of Yli-Hankala et al. (4). An interesting theoretical calculation was published by O’Connor et al. (5). They studied the costs required for preventing a single case of intraoperative awareness. With an incidence of 0.2% (14), and if monitoring BIS reduced the incidence of awareness by 90%, it would cost 6.105 (US$5.556) to prevent one case; if BIS reduces the incidence of awareness by 50%, it would cost 10.990 (US$10.000) to prevent one case (5). O’Connor et al. (5) concluded that BIS monitoring’s reducing the risk of intraoperative awareness is unproven and that it might be difficult to justify the additional costs caused by BIS monitoring. Recently, a study was published stating that ECG electrodes provide the same results as expensive special sensors in the routine monitoring of anesthetic depth (20). This might dramatically reduce costs for BIS monitoring.
Anesthetic maintenance at BIS values between 50 and 65 was associated with shortened emergence and recovery from general anesthesia in 1552 adult patients (17). BIS values constantly <50 showed no clinical advantage over unmonitored cases in this study (17). All these patients were tracheally extubated at the end of the surgical procedure or immediately afterward in the postanesthesia care unit (17). These data are confirmed by others R3-120332 (3,19) showing that maintaining BIS between 45 and 60 during anesthesia resulted in faster extubation and earlier discharge from the postanesthesia care unit. However, all these patients underwent noncardiac surgery and were not scheduled for postoperative ventilation R3-120332 (3,19). In the present study, time to extubation in cardiac surgical patients anesthetized at a BIS level of <45 (BIS 40) was not prolonged compared with that in patients with a BIS level of >45 (BIS 50). Our patients did not undergo fast-track extubation and were scheduled for postoperative ventilation. In cardiac surgery, time to extubation depends on many different factors, such as weaning protocol, preoperative status, and postoperative bleeding (21). Anesthesia only partly influences the time to extubation (22). In a study comparing fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia, all three different opioids produced equally rapid extubation, similar stays at the ICU and in the hospital, and even similar pain scores the morning after surgery (22). Anesthesia influences the postoperative period of cardiac surgical patients, but postoperative therapeutic strategies have a major effect on the time to extubation and the length of stay in the ICU or in the hospital R21-120332 (21,22).
Anesthesia at a BIS level of 50 or 40 did not influence hemodynamics, oxygenation, or stress response in patients undergoing CABG. In patients with low CO, propofol and small-dose fentanyl were compared with a large-dose fentanyl regimen (23). Except for a slower HR in propofol patients, no other differences were found in hemodynamics and myocardial contractility (23). In children undergoing CPB, different doses of fentanyl varying from 2 to 150 µg/kg and their effect on stress response were tested (23). Only in children receiving 2 µg/kg of fentanyl did glucose, cortisol, and catecholamines increase. In all other children, who received 25 to 150 µg/kg of fentanyl, there was no significant increase in any of these variables (24). Therefore, in 1993, Hall (25) advocated a goal-directed approach in cardiac anesthesia to maintain hemodynamic stability and myocardial oxygen balance, minimize ischemic episodes, and facilitate early extubation.
It is concluded that varying the depth of anesthesia from BIS 40 to BIS 50 in patients undergoing CABG with postoperative ventilation had no influence on hemodynamics, oxygenation, or time to extubation. BIS-guided reduction of anesthetic medication is possible without explicit intraoperative recall; thus, drug costs can be reduced. However, overall costs were increased by monitoring BIS because of the BIS electrodes.
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Appendix 1: Standardized Questionnaire
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On the third postoperative day, all patients were visited and asked to answer the following six questions:
- Were you satisfied with the anesthesia you received? (Satisfaction was evaluated with a scoring system ranging from 1 [best] to 6 [worst].)
- What was your last memory before the operation?
- What was your first memory after the operation?
- What of your anesthesia was very pleasant?
- What of your anesthesia did you not like at all?
- If you need anesthesia again, would you like the type of anesthesia you had, or do you prefer another type of anesthesia?
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References
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Accepted for publication October 21, 2002.
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Abstract
Introduction
