Bispectral Index (BIS)-titrated administration allows a reduction of propofol infusion rates in patients undergoing surgery. Resulting differences in anesthetic depth might affect the stress response to surgery involving neural circuitry not reflected in the electroencephalogram.
Forty patients scheduled to undergo elective coronary artery bypass grafting receiving a background infusion of remifentanil (0.3 microg . kg . min) were anesthetized with intravenous propofol delivered by target-controlled infusion according to the Marsh pharmacokinetic model under BIS monitoring. In a randomized, prospective design, 20 patients received propofol at a target concentration of 3 microg/ml, whereas in 20 patients propofol was titrated to maintain a BIS value of 40-50. Plasma concentrations of propofol (by means of gas chromatography-mass spectrometry), epinephrine, norepinephrine (by means of high-pressure liquid chromatography), cortisol (by means of radioimmunoassay), and interleukins 6 and 10 (by means of enzyme-linked immunosorbent assay) were measured repeatedly throughout surgery.
BIS monitoring allowed a 30% reduction of propofol infusion rates and a similar decrease in plasma propofol concentrations in the BIS group without affecting the stress response to surgery for the group mean. None of the patients reported awareness during a standardized interview. Interestingly, propofol-remifentanil anesthesia blunted the release of epinephrine and cortisol to bypass surgery completely even when the propofol infusion rate was reduced according to BIS values.
Total intravenous anesthesia using propofol-remifentanil effectively attenuates the neurohumoral stress response to coronary bypass surgery involving cardiopulmonary bypass. Titration of propofol using BIS allows for significant reduction of propofol consumption, with only minor effects on stress response under these conditions.
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.7–11However, 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 laryngoscopy12,13as well as memory or awareness, the individual correlation with gross unpurposeful movement in response to surgical incision is less well defined.14,15There 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. 16After 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.
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
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.
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.
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.
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 us18and others,20which is likely to be influenced by suppression of nociceptive stimuli.20Plasma 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).
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).
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.18Similar to what was observed for the neurohumoral stress hormones, this response was not affected by BIS-guided reduction of propofol infusion rates (table 4).
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.21BIS 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,22whereas 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.23,24Attenuation 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.18It has been shown that propofol and remifentanil synergize to decrease BIS.25Nevertheless, 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,26and intravenous anesthesia with propofol–remifentanil results in a favorable hemodynamic profile in patients undergoing cardiac surgery,27indicative 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.18Therefore, although the neuroendocrine and immunologic stress responses are known to interfere with each other in this patient population,18effective 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,29although their benefit with respect to required doses of propofol30or maintenance of a stable anesthetic depth, when compared with titration against traditional clinical signs,31has 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. 16incorporated 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,24but 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.11Interestingly, 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.11,32Consequently, 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.