Free
Clinical Science  |   November 2004
Impact of Bispectral Index Monitoring on Stress Response and Propofol Consumption in Patients Undergoing Coronary Artery Bypass Surgery
Author Affiliations & Notes
  • Michael Bauer, M.D.
    *
  • Wolfram Wilhelm, M.D.
  • Thomas Kraemer, Ph.D.
  • Sascha Kreuer, M.D.
    §
  • Andreas Brandt, M.D.
    §
  • Hans Anton Adams, M.D.
  • Gudrun Hoff, M.D.
    §
  • Reinhard Larsen, M.D.
    #
  • * Associate Professor, Department of Anesthesiology and Critical Care Medicine, University of Saarland. Current position: Associate Professor, Department of Anesthesiology and Critical Care Medicine, Friedrich-Schiller-University, Jena, Germany. † Assistant Professor, § Resident, # Professor and Chair, Department of Anesthesiology and Critical Care Medicine, ‡ Assistant Professor, Department of Pharmacology and Clinical Toxicology, University of Saarland. ∥Associate Professor, Department of Anesthesiology II, Hannover Medical School.
Article Information
Clinical Science
Clinical Science   |   November 2004
Impact of Bispectral Index Monitoring on Stress Response and Propofol Consumption in Patients Undergoing Coronary Artery Bypass Surgery
Anesthesiology 11 2004, Vol.101, 1096-1104. doi:
Anesthesiology 11 2004, Vol.101, 1096-1104. doi:
ELECTROENCEPHALOGRAPHIC monitoring may be used to assess effects of anesthetic drugs on the central nervous system, offering a tool to assess central nervous functional suppression or depth of anesthesia. More specifically, computerized electroencephalogram processing and display technology, such as Bispectral Index (BIS) monitoring, may be a useful tool to (1) titrate the hypnotic component of anesthesia1–6; (2) reduce drug consumption, thereby allowing faster recovery from anesthesia; and (3) avoid untoward side effects of anesthetics, such as hemodynamic instability.7–11 However, there might be a substantial discrepancy regarding chosen pharmacodynamic endpoints and their individual correlation with the degree of electroencephalographic depression. Although the latter correlates well with the magnitude of hemodynamic responses to noxious stimulation resulting, for example, from laryngoscopy12,13 as well as memory or awareness, the individual correlation with gross unpurposeful movement in response to surgical incision is less well defined.14,15 There is widespread agreement that these inconsistent results reflect various factors, including the lack of linear changes in electroencephalographic depression with changes in depth of anesthetic plane as well as the fact that the electroencephalogram is a phenomenon of rostral structures, most notably the cerebral cortex, whereas changes in neuronal circuits in the brainstem or spinal cord are poorly reflected.15 
The potential benefit of individual titration of anesthetic drugs based on electroencephalographic monitoring is particularly obvious in patients who are at risk of adverse effects of inadequate anesthesia, most notably hemodynamic instability. Therefore, the current study was designed to assess the impact of BIS-adjusted infusion of propofol on the stress response in patients undergoing coronary artery bypass surgery. This response to major surgery affects a variety of central nervous structures, such as the mesencephalon and diencephalon, which are influenced by central nervous networks involved in pain reception but which are not responsible per se  for the generation of the electroencephalographic signal.
Materials and Methods
All chemicals were obtained from Sigma Chemicals (Munich, Germany) if not otherwise specified.
Patients and Study Design
After obtaining approval from the local ethics committee (Ärztekammer des Saarlandes, Saarbrücken, Germany) and written informed consent, 40 consecutive patients scheduled to undergo elective coronary artery bypass grafting (CABG) were enrolled in a prospective, randomized design. Patients with a history of previous cardiac surgery, concomitant congestive (ejection fraction < 40%; New York Heart Association grades III and IV) or valvular heart disease, myocardial infarction during the last 3 months, or evidence of coexisting malignant or immunologic diseases were excluded, as well as diabetic patients or those with significant renal (creatinine > 1.5 mg%) or hepatic dysfunction (aspartate amino transferase, alanine amino transferase > 50% over normal range). Oral premedication consisted of 1 mg flunitrazepam 1.5 h before induction. In the operating room, intravenous and arterial lines were inserted during local anesthesia, and standard monitors were applied, including an Aspect A-2000 BIS® monitor (Version XP; Aspect Medical Systems B.V., Leiden, The Netherlands); electrodes were placed on the forehead according to the manufacturer’s instructions. Baseline readings of hemodynamics and BIS were taken 5–10 min after cannulation had been completed, and samples were obtained simultaneously for measurements of stress hormones and plasma propofol (baseline). Subsequently, patients were allowed to breathe oxygen and a remifentanil infusion was started at 0.1 μg · kg−1· min−1. The opioid was supplemented with propofol for hypnosis after 5 min using a commercial target-controlled infusion (TCI, Diprifusor; AstraZeneca, Wedel, Germany) initially adjusted to a target concentration of 3 μg/ml according to the model of Marsh et al.  16 After loss of consciousness, oxygen was given by facemask ventilation, and atracurium was used to provide neuromuscular blockade; neuromuscular blockade was controlled by train-of-four monitoring, and additional boluses of atracurium were provided to ensure relaxation throughout surgery. The trachea was intubated 3–5 min later at a BIS values of less than 60, and the lungs were ventilated with oxygen-enriched air (fraction of inspired oxygen = 0.5) to an end-tidal carbon dioxide concentration of 35 mmHg, which was adjusted to maintain normocapnia based on arterial blood gas analysis.
Patients (n = 20/group) were randomly allocated to either standard practice, i.e.  , continuous infusion of propofol using a TCI target of 3 μg/ml (TCI group), or a BIS-controlled adjustment of the propofol infusion to achieve a BIS value of 40–50 during the whole surgical procedure (BIS group). Propofol infusion rates were adjusted in the BIS group in increments or decrements of 10% of the actual infusion rate every 5–10 min, so that actual measurement could be out of the defined range in between adjustments. However, propofol infusion rates were not reduced below a predicted target concentration of 1 μg/ml.
The remifentanil infusion was adjusted to 0.3 μg · kg−1· min−1with surgical incision in all patients. All data were analyzed on an intent-to-treat basis with respect to allocation to TCI and BIS groups, irrespective of the achieved BIS values in both groups.
The extracorporal circuit was primed with 1 l lactated Ringer’s solution and 0.5 l colloidal gelatin (Gelafundin; Braun, Melsungen, Germany), and cardiopulmonary bypass (CPB) was performed with moderate hypothermia (31°–32°C rectal temperature) and acid–base correction. A perfusion volume of 2.4 l · min−1· m−2was maintained throughout CPB, and myocardial protection was achieved by antegrade application of cooled St. Thomas’ solution into the aortic root after cross clamping. Norepinephrine (≤ 0.1 μg· kg−1· min−1) was used to restore systemic vascular resistance, i.e.  , the constant infusion was adjusted to a target mean arterial pressure of 60 mmHg at a CPB flow rate of 2.4 l · min−1· m−2while no other catecholamines were administered for weaning from CPB. All patients were transferred from the operating room to the surgical intensive care unit, where they were weaned from ventilation on the day of admission according to standard protocols and based on the decision of the attending cardiac surgeon. All measurements were repeated, and samples specified above for baseline were taken again after intubation of the trachea (intubation), after sternotomy (sternotomy), immediately before weaning from CPB (extracorporeal circulation), and after skin closure (end of operation). Patients were followed up with a standardized interview for intraoperative awareness on the first and third postoperative day as described by Dowd et al.  17 
Assessment of Plasma Propofol Concentration
Samples were taken from the arterial line into pyrogen-free serum tubes (Sarstedt Monovette, Nuembrecht, Germany), and serum was stored at −80°C after centrifugation until analysis.
Sample Preparation.
Serum samples (200 μl) in 1.5-ml reaction vials were mixed with toluol (200 μl). The reaction vials were sealed and left on a rotary shaker at room temperature for 10 min. Thereafter, the vials were centrifuged (10,000g  , 2 min), and 100 μl of the upper phase was transferred to autosampler vials. Aliquots (2 μl) were injected into the gas chromatography–mass spectroscopy system. Aliquots of blank serum (200 μl) were spiked with propofol to obtain calibration samples at concentrations of 0.1, 1.0, 2.5, 5.0, 7.5, and 10.0 μg/ml. Quality control samples were prepared at concentrations of 2.0 and 8.0 μg/ml.
Gas Chromatography–Mass Spectrometry.
The samples were analyzed using a Hewlett Packard HP 6890 Series GC system (Agilent, Waldbronn, Germany) combined with an HP 5972 Series mass selective detector, an HP 6890 Series injector, and an HP Chem Station G1701AA version A.03.00. The gas chromatography conditions were as follows: splitless injection mode; column, HP capillary (12 m × 0.2 mm ID), cross-linked methylsilicone, 330-nm film thickness; injection port temperature, 280°C, carrier gas, helium; flow-rate 1 ml/min; column temperature, programmed from 100° to 310°C at 30°/min, initial time 3 min, final time 8 min. Mass spectrometry conditions were as follows: transfer line heater, 280°C; source temperature, 140°C; electron ionization mode; ionization energy, 70 eV; selected-ion monitoring with the ions m/z 163 (target ion), 178, and 117 (qualifiers). The propofol concentrations in the serum samples were calculated via  daily prepared calibration curves. The method was selective and proved to be linear from 0.1 to 10 μg/ml. Accuracy and precision were within the required limits.
Measurements of Epinephrine, Norepinephrine, and Cortisol
Samples were taken from the arterial line into pyrogen-free EDTA (for assessment of epinephrine and norepinephrine)– or heparin (for assessment of cortisol)–containing tubes (Sarstedt Monovette) and kept on ice until centrifugation. Supernatants were subsequently frozen in liquid nitrogen and stored at −80°C until analysis. Epinephrine, norepinephrine, and cortisol plasma concentrations were measured in the supernatant using commercially available kits and standards (Clin Rep; Recipe, Munich, Germany; Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA) by means of high-performance liquid chromatography (epinephrine, norepinephrine) or radioimmunoassay (cortisol) as we have described in detail previously.18 
Measurement of Interleukins 6 and 10
Samples were taken from the arterial line into pyrogen-free citrate-anticoagulated tubes (Sarstedt Monovette) and kept on ice until centrifugation. Supernatants were frozen immediately in liquid nitrogen and kept at −80°C until analysis. Interleukin (IL)-6 and IL-10 concentrations were determined in supernatants by means of an enzyme-linked immunosorbent assay (Medgenix/Biosource, Ratingen, Germany). A detailed protocol including intraassay and interassay coefficients of variance for our laboratory has been published previously.18,19 
Statistical Analysis
All data are presented as mean and SD, median, 25th and 75th percentile and range, or as individual data points for nonlinear regression analysis. Median prediction error (bias, equation 1) and median absolute prediction error (precision, equation 2) of the Diprifusor system were calculated according to the equations
where the prediction error of the jth measurement of the ith patient was calculated according to
where Niequals number of measurements of the ith patient, and k equals the number of patients.
Differences between the two groups were tested using the Mann–Whitney U test, whereas statistical differences from baseline were determined by Friedman repeated-measures analysis of variance on ranks, followed when significant by the Dunnett post hoc  test. A priori  power analysis indicated that a total of 20 patients/group would be sufficient to detect a 20–25% change in the stress hormone release with a power greater than 90% at α= 0.05. To assess for intersubject variability, nonlinear regression analysis for BIS, propofol concentration, and parameters of the stress response with a sigmoidal model were performed for the individual patients during the course of the operation using SigmaPlot 5.0 software (Jandel GmbH, Erkrath, Germany), and the best, worst, and median fits are shown. All other statistical tests were performed using the SigmaStat software package (Jandel GmbH). All P  values are two-sided and are considered significant if P  is less than 0.05.
Results
Demographic Data, Duration of Surgery, and Evidence of Awareness
Both groups were comparable with respect to age, weight, height, body mass index, duration of surgery, extracorporal circulation, and ischemia. Biometric data and patient characteristics are summarized in table 1. None of the patients reported intraoperative recall during the standardized interview on postoperative days 1 and 3.
Table 1. Demographic Data and Duration of Surgery, CPB, and AXC 
Image not available
Table 1. Demographic Data and Duration of Surgery, CPB, and AXC 
×
Propofol Requirement, Plasma Concentrations, and Resulting BIS Values
A reduction of the infusion rates of propofol was required to maintain BIS values in the range of 40–50 in 16 of 20 patients in the BIS group, whereas 10 of 20 patients in the TCI group displayed BIS values of less than 40. Two patients in the BIS-guided group had BIS values repeatedly less than 40 because the study protocol prevented a further reduction of the infusion rate of propofol to a predicted target concentration of less than 1 μg/ml. The median propofol infusion rate including the induction dose equaled 6.8 mg · kg−1· h−1for TCI, whereas electroencephalographic monitoring allowed for a reduction of the infusion rate to 4.3 mg · kg−1· h−1in the BIS group (P  < 0.05). Plasma concentrations of propofol displayed a similar reduction of roughly 30% as compared with standard practice when the propofol infusion was adjusted to achieve a BIS value of 40–50 (fig. 1). The higher propofol plasma concentrations in the TCI group were paralleled by lower BIS values reaching statistical significance after weaning from CPB (fig. 1). A significant correlation of TCI-predicted and measured propofol concentrations for the group mean was observed (r  2= 0.36, P  < 0.01; fig. 2), whereas no correlation between measured propofol concentration and BIS values (r  2= 0.003) was established for individual patients (fig. 3). Bias and precision of the Diprifusor system were calculated as 39.4% and 40%, respectively. Figure 2Bshows the results of nonlinear regression analysis for measured and predicted propofol concentrations in individual patients over time, with a median R  of 0.73. The line of identity between measured and predicted plasma propofol concentration confirms a predominant underestimation of the measured plasma concentration for this patient group by the Diprifusor system. The individual correlation for measured propofol and BIS is summarized in figures 3B and C, indicating a median of −0.7 to −0.8 for the correlation of plasma propofol and electroencephalographic suppression.
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
×
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
×
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
×
Neurohumoral Stress Response
Total intravenous anesthesia using propofol–remifentanil prevented the substantial induction of a neurohumoral stress response with significant increases in the concentrations of circulating cortisol and catecholamines to CABG reported by us18 and others,20 which is likely to be influenced by suppression of nociceptive stimuli.20 Plasma epinephrine concentrations were largely unaffected by surgery, whereas cortisol concentrations even decreased as compared with respective baseline values without differences between TCI and BIS groups for the group mean. Nonlinear regression analysis also revealed only a moderate or barely any correlation between plasma propofol concentration (fig. 4) or BIS (fig. 5) and the stress hormones epinephrine or cortisol. The significantly increased plasma norepinephrine concentrations at the end of extracorporal circulation and before discharge from the operating room reflect similar requirements of exogenous norepinephrine for weaning from CPB (table 2).
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
×
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
×
Table 2. Stress Response to CABG and BIS-titrated Reduction of Propofol Infusion Rates 
Image not available
Table 2. Stress Response to CABG and BIS-titrated Reduction of Propofol Infusion Rates 
×
Hemodynamics and Catecholamine Support
Patients displayed stable macrohemodynamics throughout as reflected by mean arterial pressure and heart rates (table 3), and none of the patients required catecholamines before CPB. Central venous (TCI group, 4.5 [2.7/6.4]; BIS group, 3.3 [1.4/5.2] mmHg) and left atrial (TCI group, 3.2 [2.0/4.4]; BIS group, 3.5 [2.5/ 4.3] mmHg) filling pressures were similar after weaning from CPB. At this time point, lower BIS values (< 40), which are indicative of an inappropriate depth of anesthesia, were observed more frequently in the TCI group and tended to result in higher norepinephrine requirements, although this difference did not reach statistical significance. The body temperature was restored to approximately 36°C before weaning from CPB, and there were no differences regarding body temperature during the course of the investigation between the two groups (table 3).
Table 3. Macrohemodynamic Variables and Body Temperature in Patients Undergoing CABG during Propofol–Remifentanil TIVA 
Image not available
Table 3. Macrohemodynamic Variables and Body Temperature in Patients Undergoing CABG during Propofol–Remifentanil TIVA 
×
Plasma Cytokine Concentrations
Coronary artery bypass grafting and CPB during propofol–remifentanil anesthetic evoked a significant IL-6 and IL-10 release, which was in a similar order of magnitude as we have described previously under total intravenous anesthesia with midazolam–fentanyl.18 Similar to what was observed for the neurohumoral stress hormones, this response was not affected by BIS-guided reduction of propofol infusion rates (table 4).
Table 4. Cytokine Response to CABG/CPB 
Image not available
Table 4. Cytokine Response to CABG/CPB 
×
Discussion
In the current study, using propofol–remifentanil anesthesia, we aimed to assess the influence of adjusting propofol infusion rates by means of BIS monitoring on the stress response to CABG, i.e.  , a response potentially affecting morbidity and outcome in cardiac risk patients.21 BIS monitoring allowed for a reduction of approximately 30% in propofol infusion rates and plasma concentrations compared with TCI, whereas the stress response as reflected by plasma epinephrine, cortisol, and cytokine concentrations was identical in both groups. Furthermore, the comparable plasma norepinephrine concentrations in both groups reflect similar requirements of norepinephrine support to restore mean arterial pressure irrespective of the allocation to either the BIS or the TCI group. In addition, none of the patients reported awareness in a standardized interview. Plasma concentrations of propofol correlated with the concentrations predicted by the TCI system particularly during and after CPB, with prediction errors similar to previous reports in different patient populations,22 whereas they correlated only moderately with the pharmacodynamic effect, i.e.  , electroencephalographic depression as assessed by BIS when data were analyzed for patients individually over time. This reflects an overall good performance of the TCI system despite a broad spectrum of confounding factors, such as changes in body temperature and cardiac output in this patient population. In particular, the known increase in cardiac output during and after CPB might explain the better performance of the TCI system during and after CPB. Lower BIS values after weaning from CPB in the TCI group tended to be paralleled by higher requirements of catecholamine support, although this effect did not reach statistical significance. Therefore, titration of propofol based on BIS monitoring allowed for a significant reduction of propofol requirements without negatively affecting the stress response to CABG/CPB.
Total intravenous anesthesia using propofol and remifentanil has been proposed as a safe anesthetic procedure for patients undergoing cardiac surgery, even in those with substantially impaired left ventricular function.23,24 Attenuation of the neuroendocrine stress response, most notably release of catecholamines, to noxious stimulation as it may result from intubation, sternotomy, and initiation of CPB is an important concern in the anesthetic treatment of these patients. Regarding the latter, propofol–remifentanil completely prevented the release of the stress hormones epinephrine and cortisol in response to the above-mentioned stimuli. In contrast, a marked release of stress hormones in response to CABG has been reported for other anesthetics, e.g.  , midazolam combined with high-dose fentanyl.18 It has been shown that propofol and remifentanil synergize to decrease BIS.25 Nevertheless, the lack of effect on the neuroendocrine stress response of reducing the propofol infusion rate according to the BIS values in the current study would suggest that this effect is attributable primarily to fixed remifentanil administration. Consistent with this notion, a recent study demonstrated that remifentanil blunted the catecholamine response to laparoscopic fundoplication in a dose-dependent fashion,26 and intravenous anesthesia with propofol–remifentanil results in a favorable hemodynamic profile in patients undergoing cardiac surgery,27 indicative of excellent stress protection. Although blunting the neuroendocrine response to painful or noxious stimuli seems intuitively opportune in the operating room setting, data obtained for sedation using etomidate for several days in intensive care patients28 —which inhibits 11β-hydroxylase activity and thus cortisol biosynthesis—would suggest that the pronounced effects of propofol–remifentanil on the neuroendocrine stress response might be of concern in long-term application in the intensive care unit.
Whereas propofol–remifentanil completely blunted the neuroendocrine response to bypass surgery, a cytokine response as reflected in a significant appearance of IL-6 and IL-10 in plasma paralleled CABG. Moreover, the concentrations of IL-6 and IL-10 were in a similar order of magnitude to those we had observed previously during midazolam–fentanyl anesthesia.18 Therefore, although the neuroendocrine and immunologic stress responses are known to interfere with each other in this patient population,18 effective attenuation of the neurohumoral stress response with propofol–remifentanil did not prevent a cytokine response to CABG/CPB. Reducing the propofol administration rate according to BIS also failed to affect the plasma IL-6 and IL-10 response, although we have shown in previous studies that propofol has a permissive effect on tumor necrosis factor α release, i.e.  , an “upstream” cytokine that regulates IL-6 and IL-10 gene expression, by human peripheral blood mononuclear cells in vitro  .19 
Computerized infusion systems using internal pharmacokinetic models are becoming increasingly popular in cardiac surgery,29 although their benefit with respect to required doses of propofol30 or maintenance of a stable anesthetic depth, when compared with titration against traditional clinical signs,31 has been questioned. Advantages over manual application include the rapid achievement of a desired blood concentration while avoiding “overshoot” seen with bolus administration. In addition, they may provide advisory information regarding calculated blood and effect site concentrations. Nevertheless, all pharmacokinetic models, such as the pharmacokinetic model of Marsh et al.  16 incorporated into the Diprifusor TCI used in the current study, have an inherent prediction error. This error may result in systematic overestimation or underestimation for certain patient populations, leading to an inappropriate infusion rate of propofol in elderly patients,24 but this unavoidable problem may also change during the course of surgery as observed in the current study. Although the Diprifusor TCI constantly underestimated measured plasma propofol concentrations before CPB, the precision of predicted plasma concentrations was better after weaning from CPB, which might reflect, for example, increases of cardiac output after CPB as a typical confounding factor. In any case, a Diprifusor-predicted target concentration of 3 μg/ml propofol resulted in measured propofol concentrations in our patient population between 0.7 and 6.5 μg/ml and BIS values below 40. Therefore, an inadequately deep plane of anesthesia was observed in approximately 50% of the patients in the TCI group. Conversely, a reduction of propofol infusion rates below a target concentration of 3 μg/ml was possible in 16 of 20 patients when the propofol infusion rate was adjusted according to BIS readings. Interestingly, none of the patients reported intraoperative recall, not even those in whom actual plasma concentrations below 1.5 μg/ml were measured. Therefore, our data support the notion that titration of propofol based on pharmacodynamic effects, such as electroencephalographic suppression, is superior to administration based on pharmacokinetic modeling.
A variety of electroencephalogram-derived parameters and monitoring devices are now being evaluated with respect to measuring anesthetic depth. Among these, the BIS® monitor can currently be considered the accepted standard, although other algorithms and devices may provide similar information.11 Interestingly, the differences in BIS between the study groups of the current investigation were fairly small, reaching statistical difference only in the late phase of the investigation, although a 30% reduction of propofol consumption was achieved. This reflects primarily two phenomena: All data were analyzed on an intent-to-treat basis, and the study protocol prevented a reduction of propofol administration below a predicted target of 1 μg/ml, resulting in BIS values repeatedly less than 40 in two patients of the BIS group. Because adjustments of the infusion rate were made intermittently every 5–10 min, outliers could be observed between adjustments. Similarly, 10 of 20 patients in the TCI group had BIS values in the target range of 40–50. Moreover, in the range of 35–55, the BIS algorithm results in a broad plateau underestimating any changes in the plasma or effect site concentration of an anesthetic.11,32 Consequently, substantial changes in propofol infusion rates or anesthetic depth might result in only moderate changes of the numerical values in this given BIS range. This relation, together with the study design, which involved repeated adjustments of the propofol infusion rates over time, would also explain the delayed evolving difference between the BIS values in the two study groups. Conversely, our current data reflect a substantial interindividual variability with respect to the required plasma propofol concentration to achieve a given BIS value, which may result in part from the high number of confounding variables, such as changes in cardiac output or body temperature in this particular patient population.
In summary, total intravenous anesthesia using propofol and remifentanil substantially attenuates the stress response to cardiac surgery. Titration of propofol based on BIS monitoring under these conditions allows for a reduction in drug consumption, which is paralleled by a similar decrease in propofol plasma concentrations compared with TCI. However, titration of propofol did not induce an augmented release of stress hormones in response to CABG in the presence of a potent narcotic, i.e.  , background remifentanil infusion in the current study.
References
Liu J, Singh H, White PF: Electroencephalogram bispectral analysis predicts the depth of midazolam-induced sedation. Anesthesiology 1996; 84:64–9Liu, J Singh, H White, PF
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; 86:836–47Glass, PS Bloom, M Kearse, L Rosow, C Sebel, P Manberg, P
Gan TJ, Glass PS, Windsor A, Payne F, Rosow C, Sebel P, Manberg P: Bispectral Index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Anesthesiology 1997; 87:808–15Gan, TJ Glass, PS Windsor, A Payne, F Rosow, C Sebel, P Manberg, P
Iselin-Chaves I, Flaishon R, Sebel P, Howell S, Gan T, Sigl J, Ginsberg B, Glass PS: The effect of the interaction of propofol and alfentanil on recall, loss of consciousness and the bispectral index. Anesth Analg 1998; 87:949–55Iselin-Chaves, I Flaishon, R Sebel, P Howell, S Gan, T Sigl, J Ginsberg, B Glass, PS
Katoh T, Suzuki A, Ikeda K: Electroencephalographic derivatives as a tool for predicting the depth of sedation and anesthesia induced by sevoflurane. Anesthesiology 1998; 88:642–50Katoh, T Suzuki, A Ikeda, K
Kearse L, Rosow C, Zaslavsky A, Connors P, Dershwitz M, Denman W: Bispectral analysis of the electroencephalogram predicts conscious processing of information during propofol sedation and hypnosis. Anesthesiology 1998; 88:25–34Kearse, L Rosow, C Zaslavsky, A Connors, P Dershwitz, M Denman, W
Bannister CF, Brosius KK, Sigl JC, Meyer BJ, Sebel PS: The effect of bispectral index monitoring on anesthetic use and recovery in children anesthetized with sevoflurane in nitrous oxide. Anesth Analg 2001; 92:877–81Bannister, CF Brosius, KK Sigl, JC Meyer, BJ Sebel, PS
Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M: The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2001; 90:161–7Guignard, B Menigaux, C Dupont, X Fletcher, D Chauvin, M
Johansen JW, Sebel PS, Sigl JC: Clinical impact of hypnotic-titration guidelines based on EEG bispectral index (BIS) monitoring during routine anesthetic care. J Clin Anesth 2000; 12:433–43Johansen, JW Sebel, PS Sigl, JC
Pavlin DJ, Hong JY, Freund PR, Koerschgen ME, Bower JO, Bowdle TA: The effect of bispectral index monitoring on end-tidal gas concentration and recovery duration after outpatient anesthesia. Anesth Analg 2001; 93:613–9Pavlin, DJ Hong, JY Freund, PR Koerschgen, ME Bower, JO Bowdle, TA
Kreuer S, Biedler A, Larsen R, Altmann S, Wilhelm W: Narcotrend monitoring allows faster emergence and reduction of drug consumption in propofol–remifentanil anesthesia. Anesthesiology 2003; 99:34–41Kreuer, S Biedler, A Larsen, R Altmann, S Wilhelm, W
Rampil IJ, Matteo RS: Changes in EEG spectral edge frequency correlates with the hemodynamic response to laryngoscopy and intubation. Anesthesiology 1987; 67:139–42Rampil, IJ Matteo, RS
Sidi A, Halimi P, Cotev S: Estimating anesthetic depth by electroencephalography during anesthetic induction and intubation in patients undergoing cardiac surgery. J Clin Anesth 1990; 2:101–7Sidi, A Halimi, P Cotev, S
Dwyer RC, Rampil IJ, Eger EI II, Bennett HL: The electroencephalogram does not predict depth of isoflurane anesthesia. Anesthesiology 1994; 81:403–9Dwyer, RC Rampil, IJ Eger, EI Bennett, HL
Rampil IJ: A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89:980–1002Rampil, IJ
Marsh B, White M, Morton N, Kenny GN: Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67:41–8Marsh, B White, M Morton, N Kenny, GN
Dowd NP, Cheng DCH, Karski JM, Wong DT, Munro JAC, Sandler AN: Intraoperative awareness in fast-track cardiac anesthesia. Anesthesiology 1998; 89:1068–73Dowd, NP Cheng, DCH Karski, JM Wong, DT Munro, JAC Sandler, AN
Grundmann U, Rensing H, Adams HA, Falk S, Wendler O, Ebinger N, Bauer M: Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: Role of humoral factors. Anesthesiology 2000; 93:359–69Grundmann, U Rensing, H Adams, HA Falk, S Wendler, O Ebinger, N Bauer, M
Larsen B, Hoff G, Wilhelm W, Buchinger H, Wanner G, Bauer M: Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood. Anesthesiology 1998; 89:1218–27Larsen, B Hoff, G Wilhelm, W Buchinger, H Wanner, G Bauer, M
Lee TW, Grocott HP, Schwinn D, Jacobsohn E, Winnipeg High-Spinal Anesthesia Group: High spinal anesthesia for cardiac surgery: Effects on β-adrenergic receptor function, stress response, and hemodynamics. Anesthesiology 2003; 98:499–510Lee, TW Grocott, HP Schwinn, D Jacobsohn, E Winnipeg High-Spinal Anesthesia Group,
Louagie Y, Jamart J, Broka S, Collard E, Scavee V, Gonzalez M: Off-pump coronary artery bypass grafting: A case-matched comparison of hemodynamic outcome. Eur J Cardiothorac Surg 2002; 22:552–8Louagie, Y Jamart, J Broka, S Collard, E Scavee, V Gonzalez, M
Hoymork SC, Raeder J, Grimsmo B, Steen PA: Bispectral index, predicted and measured drug levels of target controlled infusions of remifentanil and propofol during laparoscopic cholecystectomy and emergence. Acta Anaesthesiol Scand 2000; 44:1138–44Hoymork, SC Raeder, J Grimsmo, B Steen, PA
Lehmann A, Boldt J, Zeitler C, Thaler E, Werling C: Total intravenous anesthesia with remifentanil and propofol for implantation of cardioverter-defibrillators in patients with severely reduced left ventricular function. J Cardiothorac Vasc Anesth 1999; 13:15–9Lehmann, A Boldt, J Zeitler, C Thaler, E Werling, C
Outtara A, Boccara G, Lemaire S, Köckler U, Landi M, Vaissier E, Leger P, Coriat P: Target-controlled infusion of propofol and remifentanil in cardiac anesthesia: Influence of age on predicted effect-site concentrations. Br J Anaesth 2003; 90:617–22Outtara, A Boccara, G Lemaire, S Köckler, U Landi, M Vaissier, E Leger, P Coriat, P
Röpcke H, Konen-Bergmann M, Cuhls M, Bouillon T, Hoeft A: Propofol and remifentanil pharmacodynamic interaction during orthopedic surgical procedures as measured by effects on bispectral index. J Clin Anesth 2001; 13:198–207Röpcke, H Konen-Bergmann, M Cuhls, M Bouillon, T Hoeft, A
Myre K, Raeder J, Rostrup M, Buanes T, Stokland O: Catecholamine release during laparoscopic fundoplication with high and low doses of remifentanil. Acta Anaesthesiol Scand 2003; 47:267–73Myre, K Raeder, J Rostrup, M Buanes, T Stokland, O
Olivier P, Sirieix D, D’Attellis N, Baron JF: Continuous infusion of remifentanil and target-controlled infusion of propofol for patients undergoing cardiac surgery: A new approach for scheduled early extubation. J Cardiothorac Vasc Anesth 2000; 14:29–35Olivier, P Sirieix, D D’Attellis, N Baron, JF
Ledingham IM, Watt I: Influence of sedation on mortality in critically ill multiple trauma patients (letter). Lancet 1983; 1:1270Ledingham, IM Watt, I
Theil DR, Stanley TE, White WD Goodman DK, Glass PS, Bai SA, Jacobs JR, Reves JG: Midazolam and fentanyl continuous infusion anesthesia for cardiac surgery: A comparison of computer-assisted versus manual infusion systems. J Cardiothorac Vasc Anesth 1993; 7:300–6Theil, DR Stanley, TE White, WD Goodman, DK Glass, PS Bai, SA Jacobs, JR Reves, JG
Lehmann A, Boldt J, Thaler E, Piper S, Weisse U: Bispectral index in patients with target-controlled or manually-controlled infusion of propofol. Anesth Analg 2002; 95:639–44Lehmann, A Boldt, J Thaler, E Piper, S Weisse, U
Gale T, Leslie K, Kluger M: Propofol anesthesia via target controlled infusion or manually controlled infusion: Effects on the bispectral index as a measure of anesthetic depth. Anaesth Intensive Care 2001; 29:579–84Gale, T Leslie, K Kluger, M
Olofsen E, Dahan A: The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and Bispectral Index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999; 90:1345–53Olofsen, E Dahan, A
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
Fig. 1. Bispectral Index (BIS) values (  A  ) and corresponding propofol plasma concentrations (  B  ) in patients undergoing coronary artery bypass grafting during total intravenous anesthesia with propofol and remifentanil. Patients were randomly allocated to receive propofol either as a “fixed” target-controlled infusion with a target of 3 μg/ml (standard care;  empty bars  ) or as a BIS-titrated infusion to maintain a BIS value of 40–50 (  hatched bars  ).  Box plots  indicate median and 25th and 75th percentiles. #  P  < 0.05 as compared with respective baseline value for repeated-measures analysis of variance on ranks followed by Dunnett test. *  P  < 0.05 between standard care and BIS-titrated anesthesia. 
×
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
Fig. 2. (  A  ) Pharmacokinetic performance of the target-controlled infusion (TCI) system according to the Marsh model in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.  Empty symbols  indicate measurements in the fixed TCI group.  Filled symbols  indicate correlation of TCI-calculated and measured propofol plasma concentrations in patients who underwent Bispectral Index–titrated adjustment of propofol infusion rates. (  B  ) (  Inset  ) Individual relations between measured and TCI-predicted plasma propofol concentrations for the patient with best (  circle  ), median (  square  ), and worst (  triangle  ) fits.  Dashed lines  indicate line of identity. 
×
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
Fig. 3. Correlation of measured plasma propofol concentration and Bispectral Index (BIS) at different time points (  empty symbols  indicate target-controlled infusion/fixed infusion rate;  filled symbols  indicate BIS-titrated adjustment;  circles, triangles, squares,  and  diamonds  indicate the group mean ± SD for intubation, sternotomy, end of extracorporeal circulation, and end of operation, respectively). Data indicate a leftward (lower propofol) and upward (higher BIS) displacement with BIS-titrated propofol infusion as compared with target-controlled infusion according to the Marsh model (  A  ). To address intersubject variability, individual correlations of measured plasma propofol concentrations  versus  BIS were performed for each patient over time indicating a moderate negative correlation for the group mean in both groups (  B  : target-controlled infusion;  C  : BIS).  Circle  indicates patient with best fit,  square  indicates patient with median fit, and  triangle  indicates patient with worst fit. 
×
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
Fig. 4. Nonlinear regression analysis of measured propofol plasma concentration and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ).  R  = coefficient of correlation. 
×
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
Fig. 5. Nonlinear regression analysis of Bispectral Index and stress hormones epinephrine (  A  ) and cortisol (  B  ) in plasma during coronary artery bypass grafting involving cardiopulmonary bypass for each patient over time. Individual relations between measured plasma propofol and the stress hormones are shown for the patient with best (  circle  ), median (  square  ), and worst fit (  triangle  ). 
×
Table 1. Demographic Data and Duration of Surgery, CPB, and AXC 
Image not available
Table 1. Demographic Data and Duration of Surgery, CPB, and AXC 
×
Table 2. Stress Response to CABG and BIS-titrated Reduction of Propofol Infusion Rates 
Image not available
Table 2. Stress Response to CABG and BIS-titrated Reduction of Propofol Infusion Rates 
×
Table 3. Macrohemodynamic Variables and Body Temperature in Patients Undergoing CABG during Propofol–Remifentanil TIVA 
Image not available
Table 3. Macrohemodynamic Variables and Body Temperature in Patients Undergoing CABG during Propofol–Remifentanil TIVA 
×
Table 4. Cytokine Response to CABG/CPB 
Image not available
Table 4. Cytokine Response to CABG/CPB 
×