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Background: This study describes a pharmacodynamic model during general anaesthesia in children relating the bispectral index (BIS) response to the anaesthetic dosing of propofol, fentanyl, and remifentanil., Methods: BIS, heart rate, mean arterial pressure, sedation scores, and anaesthetic protocols from 59 children aged 1-16 yr undergoing general surgery were considered for the study. Anaesthesia was performed with propofol, fentanyl, and remifentanil. A sigmoid model assuming additive interaction of propofol, fentanyl, and remifentanil was fitted to individual BIS as effect variable. The pharmacodynamic parameters were estimated by non-linear regression analysis. The ability of BIS to predict anaesthetic drug effect was quantified by the prediction probability Pk., Results: BIS started at a baseline of 90 (9), decreased during induction to 30 (14) and remained at 57 (10) during anaesthesia. BIS predicted the anaesthetic drug effect with a Pk of 0.79 (0.08). The EC(50 Propofol) and the k(e0 Propofol) were 5.2 (2.7) microg ml(-1) and 0.60 (0.45) min(-1), respectively. The k(e0 Propofol) decreased from approximately 0.91 min(-1) at 1 yr to 0.15 min(-1) at 16 yr. The EC(50 Remifentanil), k(e0 Remifentanil), EC(50 Fentanyl), and the k(e0 Fentanyl) were 24.1 (13.0) ng ml(-1), 0.71 (0.32) min(-1), 8.6 (7.4) ng ml(-1), and 0.28 (0.46) min(-1), respectively., Conclusions: The effect equilibration half-time of propofol in children was age dependent. The pharmacodynamics of fentanyl and remifentanil in children were similar to those reported in adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in children older than 1 yr.

Background: The authors investigated the suitability of different electroencephalographic parameters to quantify the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats., Methods: Ten male Sprague-Dawley rats were anesthetized in a randomized crossover design with maximum values of 11% desflurane, 2.1% isoflurane, and 3.5% sevoflurane. The electroencephalogram was recorded with implanted electrodes and a wireless telemetry system. Concentration-effect relations and signal-to-noise ratios were determined for the approximate entropy and for the median frequency and the spectral edge frequency, which were modified to account for spikes and burst suppression. The prediction probability Pk with respect to the response to a painful stimulus was determined., Results: All drugs produced deep anesthesia with burst suppression and no response at the highest concentrations. The occurrence of spikes and burst suppression made a modification of median frequency and spectral edge frequency necessary to obtain Pk values greater than 0.5 and monotonic sigmoid concentration-effect relations. The Pk values were between 0.89 and 0.98, with significantly higher values for modified median frequency and spectral edge frequency during desflurane and sevoflurane. The signal-to-noise ratios were between 3.0 and 6.4 dB, with significantly better values for modified spectral edge frequency and approximate entropy during sevoflurane., Conclusions: If modified for spikes and burst suppression, median frequency and spectral edge frequency as well as the unmodified approximate entropy were able to assess the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats. For sevoflurane, the modified spectral edge frequency was best with regard to signal-to-noise ratio and prediction probability.

Spontaneous or evoked electrical brain activity is increasingly used to monitor general anesthesia. Previous studies investigated the variables from spontaneous electroencephalogram (EEG), acoustic (AEP), or somatosensory evoked potentials (SSEP). But, by monitoring them separately, the available information from simultaneous gathering could be missed. We investigated whether the combination of simultaneous information from EEG, AEP, and SSEP shows a more discriminant power to differentiate between anesthesia states than from information derived from each measurement alone. Therefore, we assessed changes of 30 EEG, 21 SSEP, and 29 AEP variables recorded from 59 patients during four clinical states of general anesthesia: "awake," "light anesthesia," "surgical anesthesia," and "deep surgical anesthesia." The single and combined discriminant powers of EEG, AEP, and SSEP variables as predictors of these states were investigated by discriminant analysis. EEG variables showed a higher discriminant power than AEP or SSEP variables: 85%, 46%, and 32% correctly classified cases, respectively. The frequency of correctly classified cases increased to 90% and 91% with information from EEG + AEP and EEG + AEP + SSEP, respectively. Thus, future anesthesia monitoring should consider combined information simultaneously distributed on different electrophysiological measurements, rather than single variables or their combination from EEG or AEP or SSEP.

Over the past two decades, methods of processing the EEG for monitoring anaesthesia have greatly expanded. Whereas power spectral analysis was once the most important tool for extracting EEG monitoring variables, higher-order spectra, wavelet decomposition and especially methods used in the analysis of complex dynamical systems such as non-linear dissipative systems are nowadays attracting much attention. This chapter reviews some of these methods in brief. However, a comparison of some of the newer approaches with the more traditional ones with respect to clinical end-points by association measures and to the signal-to-noise ratio raises some doubt over whether the newer EEG-processing techniques really do better than the more traditional ones.

Background: A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect., Methods: Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC., Results: The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) microg ml(-1) at the beginning to 5.8 (3.8) microg ml(-1) at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg(-1) min(-1). The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg., Conclusions: The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

Background: Spontaneous EEG, mid-latency auditory evoked potentials (AEP) and somatosensory evoked potentials (SSEP) have been used to monitor anaesthesia. This poses the question as to whether or not EEG, AEP and SSEP vary in parallel with varying conditions during surgical anaesthesia., Methods: A total of 81 variables (31 EEG, 22 SSEP, 28 AEP) were simultaneously recorded in 48 surgical patients during anaesthesia. A total of 307 cases of the 81 variables in stable anaesthetic states were recorded. A factor analysis was performed for this data set., Results: Sixteen variables were excluded because of multicollinearity. We extracted 13 factors with eigenvalues >1, representing 78.3% of the total variance, from the remaining 65 x 307 matrix. The first three factors represented 12%, 11% and 10% of the total variance. Factor 1 had only significant loadings from EEG variables, factor 2 only significant loadings from AEP variables and factor 3 only significant loadings from SSEP variables., Conclusion: EEG, AEP and SSEP measure different aspects of neural processing during anaesthesia. This gives rise to the hypothesis that simultaneous monitoring of these quantities may give additional information compared with the monitoring of each quantity alone.

Bispectral analysis of the electroencephalogram (EEG) has been used for monitoring anesthesia. The estimation of bicoherence allows us to determine whether a given time series represents a linear random process in cases where the bicoherence is trivial, i.e., a mere constant independent of frequency. In this study, we investigated the proportion of EEG epochs with nontrivial bicoherence during surgical anesthesia with propofol and alfentanil as an indicator for the degree of nonlinearity in the EEG. We reanalyzed 90 h of EEG recorded from 20 patients undergoing abdominal surgery using the Hinich procedure, which provides a statistical test for the following hypothesis: the EEG is a linear random process. In approximately 90% of all artifact-free, stationary EEG epochs, the bicoherence was found to be zero or a mere constant. Under these conditions, the EEG can be considered as a linear random process. Our findings suggest that the spectral information in the frequency domain delivered by the EEG monitoring during anesthesia is largely contained in the power spectrum of the signal. This calls into question the benefit of EEG bispectral analysis for monitoring anesthesia effect.

The computer-aided detection of artefacts became an essential task with increasing automation of quantitative electroencephalogram (EEG) analysis during anaesthesiological applications. The different algorithms published so far required individual manual adjustment or have been based on limited decision criteria. In this study, we developed an artificial neural networks-(ANN-)aided method for automated detection of artefacts and EEG suppression periods. 72 hr EEG recorded before, during and after anaesthesia with propofol have been evaluated. Selected parameterized patterns of 0.25 s length were used to train the ANN (22 input, 8 hidden and 4 output neurons) with error back propagation. The detection performance of the ANN-aided method was tested with processing epochs between 1 to10 s. Related to examiner EEG evaluation, the average detection performance of the method was 72% sensitivity and 80% specificity for artefacts and 90% sensitivity and 92% specificity for EEG suppression. The improvement in signal-to-noise ratio with automated artefact processing was 1.39 times for the spectral edge frequency 95 (SEF95) and 1.89 times for the approximate entropy (ApEn). We conclude that ANN-aided preprocessing provide an useful tool for automated EEG evaluation in anaesthesiological applications.

Background: Based on previous pharmacokinetic and pharmacodynamic studies, we have developed an EEG-controlled closed-loop system for the i.v. hypnotic agent propofol in rats., Methods: Seven adult male Sprague-Dawley rats (weight 423-584 g) were included in the study. EEG was recorded with occipito-occipital needle electrodes and the EEG power spectrum was estimated. The median frequency (MEF) was extracted from the power spectrum and was modified MEF (mMEF) to account for the occurrence of spikes and burst suppression patterns in the EEG. Propofol infusion was controlled by a model-based adaptive control algorithm to maintain a set point of mMEF=3.0 (sd 0.5) Hz. The performance of the feedback system was characterized by the median performance error MDPE=median[(mMEF-set point)/set point] and the median absolute performance error (MDAPE). The effective therapeutic infusion (ETI) to maintain the set point was determined from the resulting infusion rates., Results: In all rats a feedback period of 90 min could be performed. Mean MDPE was 1.2 (se 0.4)% and MDAPE was 13.9 (0.3)%. The ETI was 0.73 (sd 0.20) mg kg(-1) min(-1). Mean arterial pressure before propofol infusion was 148 (14) mm Hg, with the lowest value during closed-loop infusion being 110 (20) mm Hg., Conclusions: The feedback system presented here may be a useful tool not only for automatic drug control to maintain a defined hypnotic effect but may also be a powerful device in pharmacological studies such as the determination of dose requirements or the assessment of drug-drug interactions.

Aims: We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791., Methods: Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum., Results: The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results., Conclusion: Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

Bispectral analysis of the electroencephalogram (EEG) has been used to monitor depth of anaesthesia. In the majority of publications this has involved the use of the so called BIS-Index TM (Aspect Medical Systems, Inc.). The exact relationship of this index to such bispectral parameters as the bispectrum and bicoherence has not yet been reported. If the EEG is considered as a linear random process, bicoherence is trivial, i.e. it is independent of the EEG frequency. The aim of this study was to determine the proportion of EEG epochs with non-trivial bicoherence during isoflurane/N20 anaesthesia. We reanalyzed 25.5 hours of digitalised EEG signal from 9 patients undergoing gynaecological surgery. The test developed by Hinich for Gaussian distribution and linearity was then applied. The test was validated using various synthetic surrogate data: Gaussian random data, the z-component of the Lorenz attractor, the phase randomized EEG and the phase randomized z-component of the Lorenz attractor. The percentage of epochs (8.192 s, 1024 data points) with non-trivial bicoherence was: Lorenz data 95.4%, phase randomized Lorenz data 9.4%, synthetic Gaussian data 14.8%, original EEG 9.1%, phase randomized EEG 5.1%. The original EEG data were not found to contain a higher percentage of epochs with non-trivial bicoherence than the phase randomized data and the synthetic Gaussian data. We conclude that bispectral analysis does not substantially add to the information obtained with other methods of quantitative EEG analysis.

Background and Objective: For total intravenous anaesthesia an opioid is often combined with a hypnotic. A supra-additive interaction has been reported for clinical signs such as loss of consciousness or loss of the eyelash reflex. This study investigated the type of interaction of alfentanil and propofol on the electroencephalogram., Methods: Twenty patients scheduled for abdominal surgery were enrolled in the study. Anaesthesia was induced and maintained with alfentanil and propofol. Each patient received a target-controlled infusion of alfentanil. Three target concentrations of 150, 225 and 300 ng mL(-1) were applied to each patient in random order. Propofol was added to the alfentanil infusion by a feedback system. The set point was the range of 1.5-2.5 Hz median frequency of the electroencephalogram. Four arterial blood samples were taken within the last 20 min of each period. The mean drug concentrations were used to determine the type of interaction and an isobole was estimated by fitting Bernstein spline functions to the data., Results: In 17 patients, all three alfentanil target concentrations could be administered. The test for supra-additivity as well as the isobole construction resulted in an additive type of interaction. The line of additivity cA/cA0 + cP/cP0 = 1 was best fitted for the values (standard deviation) cA0 = 1240 (51)ng mL(-1) and cP0 = 5.21 (0.36) microg mL(-1)., Conclusions: The type of interaction between alfentanil and propofol on the electroencephalogram in the investigated dose range is additive. This gives the freedom and need to select the appropriate dosing ratio of alfentanil and propofol by other considerations.

Objective: Bispectral analysis of the electroencephalogram (EEG) has been used to monitor depth of anesthesia. In the majority of publications this has been done using the so called Bispectral (BIS) Index. The exact relation of this index to bispectral quantities like the bispectrum and its normalized version the bicoherence has not yet been published. In case the EEG is a linear random process the bicoherence is trivial. It is a mere constant independent of the EEG frequency. If the signal is a linear Gaussian random process this constant is zero. In this case both the bispectrum and bicoherence are zero. The aim of this study was to determine the proportion of EEG epochs with non-trivial bicoherence during anesthesia with isoflurane/nitrous oxide., Methods: We reanalyzed 26.4 hr of EEG signal recorded in 8 patients during anesthesia for general abdominal surgery which were stored in digitized form on CD-Rom. The test developed by Hinich for Gaussianity and linearity was applied to these data. The test was validated with various kinds of surrogate data; especially the phase randomized (pr) EEG, synthetic Gaussian random data and the z-component of the Lorenz attractor and its pr version., Results: The proportion of epochs for which a non-trivial bicoherence was detected by the test was as follows: Lorenz data 95%, pr Lorenz data 5%, synthetic Gaussian data 13.8%, pr EEG 5.4%, original EEG 6.2%., Conclusion: As expected the test procedure correctly identified for the Lorenz data for 95% of all epochs a non-trivial bicoherence. For the original EEG data we could not find a significant greater percentage of epochs with non-trivial bicoherence than for the pr data and the synthetic Gaussian data. We conclude that the EEG during anesthesia with isoflurane/alfentanil appears to be largely a linear random process.

Background and Objective: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance., Methods: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect., Results: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment., Conclusions: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

Study Objective: To identify and quantify the simultaneous interactions of isoflurane, nitrous oxide (N2O), and fentanyl during surgical procedures. The slowing of the EEG to a median power frequency of 2 Hz to 3 Hz was chosen as the measure of pharmacodynamic drug effect., Design: Prospective, randomized, open label., Setting: Operating room of a university hospital., Patients: 65 ASA physical status I and II patients undergoing gynecological laparatomies., Interventions: 25 patients received no fentanyl. 20 patients received a loading dose of 100 micrograms fentanyl and a continuous infusion of 70 micrograms.h-1 fentanyl. Calculated effect compartment concentrations were 0.7 ng.ml-1 between the first and second hours after induction of anesthesia. Another 20 patients received a loading dose of 200 micrograms fentanyl and a continuous infusion of 150 micrograms.h-1 fentanyl; the respective effect compartment concentrations were 1.5 ng.ml-1. N2O was randomly administered in concentrations of 0, 20, 40, and 60 vol%; in the group that did not receive fentanyl, we additionally investigated 75 vol% N2O. Each patient received two different N2O concentrations, with each combination of N2O and fentanyl finally applied to ten patients. Isoflurane vaporizer settings were chosen so that the median power frequency was held between 2 Hz and 3 Hz. The type and degree of interaction among the three anesthetic drugs was analyzed based on a generalized isobole approach., Measurements and Main Results: The interaction of isoflurane, N2O, and fentanyl is compatible with additivity. A model with regard to the relative potencies and age dependency is given by: [formula: see text] with C0,iso = 1.30 vol%, C0,N2O = 177 vol%, C0,fen = 10.6 ng.ml-1, and a = -0.0031 yr-1. where conc. = end-tidal or effect compartment concentrations., Conclusion: The potency of N2O and fentanyl to substitute isoflurane in maintaining a median power frequency of 2 Hz to 3 Hz during surgery is less than anticipated from minimum alveolar concentration studies.

Objective: We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect., Methods: Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model., Results: The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age., Conclusions: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

The objectives of this study were to explore, by a modelling approach, in nine young (24-28 yr) and nine elderly (67-81 yr) male subjects, the pharmacokinetics and pharmacodynamics of Ro 48-6791, a new water soluble benzodiazepine. A microprocessor-controlled i.v. infusion pump generated linearly increasing arterial plasma concentrations until predetermined EEG and clinical end-points were attained. This concentration was maintained for 15 min and thereafter the infusion was discontinued. Haemodynamic and respiratory variables were monitored continuously. At full reorientation of the subject, a second infusion cycle was started under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time profiles of Ro 48-6791 were fitted accurately to an open three-compartment model. Plasma concentrations of Ro 48-6792, an N-dealkylated metabolite, accumulated during the course of the study. Pharmacokinetic variables of Ro 48-6791 were similar for both groups. The largest differences between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h-1) and k12 (11 (7) vs 7 (3) h-1). The concentration-median EEG frequency relationship was described with a sigmoid Emax model. Elderly subjects showed slightly increased drug sensitivity compared with young subjects (EC50 72 (25) and 44 (15) micrograms litre-1 in young and elderly subjects, respectively). The concentration-response data of the second infusion cycle deviated from the fitted curve suggesting either development of acute tolerance to the EEG effects of Ro 48-6791 or a role for drug metabolites. Because of the differences in sensitivity and clearance, lower doses of Ro 48-6791 should be administered to elderly compared with young subjects in order to achieve similar effects.

Unlabelled: The aim of this study was to quantify the interaction of enflurane and nitrous oxide at a constant median EEG frequency., Methods: Thirty patients were studied during laparotomies. Nitrous oxide was randomly administered in concentrations of 0, 20, 40, 60, and 75 vol.-% for 10 patients for each nitrous oxide concentration. Enflurane vaporizer settings were chosen so that the median EEG frequency was kept constant at 2-3 Hz. The relationship between nitrous oxide concentrations and the required enflurane concentrations was examined with the isobole method., Results: Nitrous oxide decreases the enflurane requirement linearly. Addition of every 10 vol.-% of nitrous oxide decreases the enflurane requirement by 0.042 vol.-%. The total anaesthetic requirement of enflurane and nitrous oxide, expressed in terms of previously reported MAC values, increases significantly with increasing nitrous oxide concentrations., Conclusions: The interaction of enflurane and nitrous oxide in the dose range from 0 to 75 vol.-% on median EEG frequency is compatible with additivity. The potency of nitrous oxide as a substitute for enflurane is less than might be expected when adding up the MAC values.

Background: The volatile anesthetic sparing effect of nitrous oxide in clinical studies is less than might be expected from the additivity of minimum alveolar concentration values. Other studies identify nonadditive interactions between isoflurane and nitrous oxide. The aim of this study was to quantify the interaction of isoflurane and nitrous oxide at a constant median electroencephalographic frequency., Methods: Twenty-five patients were studied during laparotomies. Nitrous oxide was randomly administered in concentrations of 0, 20, 40, 60, and 75 vol%, to ten patients for each nitrous oxide concentration. Isoflurane vaporizer settings were chosen so that the median electroencephalographic frequency was held between 2 and 3 Hz. The relationship between nitrous oxide concentrations and required isoflurane concentrations was examined with the method of isoboles., Results: Nitrous oxide linearly decreased the isoflurane requirement. Addition of every 10 vol% of nitrous oxide decreases the isoflurane requirement by approximately 0.04 vol%. The total anesthetic requirement of isoflurane and nitrous oxide, expressed in terms of previously reported minimum alveolar concentration values, increased significantly with increasing nitrous oxide concentrations., Conclusions: The interaction of isoflurane and nitrous oxide in the dose range 0-75 vol% on median electroencephalographic frequency is compatible with additivity. The potency of nitrous oxide as a substitute for isoflurane is less than on a minimum alveolar concentration basis. Maintaining median electroencephalographic frequency more appropriately reflects the clinical usage of isoflurane and nitrous oxide than does maintaining minimum alveolar concentration.

Nitrous oxide is delivered during most cases of general anaesthesia. Though it has a history of approx. 150 years there is no univocal understanding about its clinical potency. Research studies during the last 10 years support, however, the view that 1. the potency of nitrous oxide in the clinical settings is only 1/3 of the potency as estimated from the MAC value; 2. the potency of combinations of nitrous oxide and volatile anaesthetics is represented more appropriately by quantities which are derived from the EEG than by the addition of MAC fractions. The findings of the last 10 years do not support the hypothesis, that the addition of nitrous oxide to the breathing gas is more beneficial than waiving the use of nitrous oxide.

The determination of MAC values (minimum alveolar concentrations) for inhalation anesthetics and, correspondingly, of MIR values (minimum infusion rates) for i.v. anesthetics necessarily requires the use of therapeutically ineffective doses so that reactions to skin incision can be observed. EEG feedback-controlled dosing systems for i.v. anesthetics make it possible to determine dose requirement curves, allowing the definition of effective therapeutic infusion rates (ETI). During total i.v. anesthesia in 11 patients treated with fentanyl the mean effective infusion rate for methohexitone was found to be 4.68 +/- 1.39 mg/min, while for propofol the mean ETI in 11 volunteers was determined at 9.90 +/- 2.46 mg/min. The implications of feedback-controlled dosing systems for the study of clinico-pharmacologic problems in anesthesia are discussed.

Anaesthesia has significant effects on circulation and oxidative metabolism which are closely related to each other. Usually there is a marked reduction of oxygen uptake (VO2) and energy expenditure. A controversial discussion on the effects of the drugs administered and the degree of metabolic depression has continued in the literature fuelled by a lack of studies in patients under standardized conditions. 18 patients (ASA I-II) scheduled for major abdominal surgery were given closed-loop feedback control anaesthesia by quantitative EEG analysis. Group 1 received a total intravenous anaesthesia with methohexital and fentanyl whereas group 2 was given a combined anaesthesia with alfentanil and N2O. The aim of this comparative study was to evaluate the effects of different techniques for general anaesthesia on oxygen uptake and on the cardiovascular system. Preanaesthetic values of VO2 taken after flunitrazepam premedication were slightly below the predicted range determined by indirect calorimetry for basal metabolism. Steady-state general anaesthesia led to an approximately 30% reduction of VO2 for both groups. In contrast to oxygen uptake, blood pressure and especially heart rate were defined by the type of anaesthesia as in the methohexital fentanyl group higher values of both blood pressure and heart rate were observed.

A combined pharmacokinetic and pharmacodynamic model of methohexital was used to establish and evaluate feedback control of methohexital delivery during total intravenous anesthesia with fentanyl in 11 surgical patients. The median frequency of the EEG power spectrum served as the pharmacodynamic variable constituting feedback. Based on previous investigations a median frequency from 2-3 Hz was chosen as the desired EEG set point. In addition to methohexital, patients were given a 10-min loading infusion of 0.5 mg of fentanyl followed by a constant-rate infusion of 0.22 mg/h. In agreement with an earlier similar study in volunteers given only methohexital and aiming at the same set point, identical distribution of EEG power was achieved in the current study. The decrease of median EEG frequency to 2-3 Hz was primarily induced by an increase in fractional power in the 0.5-2- Hz frequency band to 46 +/- 4%. The average requirement of methohexital during the first 2 h was 675 +/- 250 mg. The authors conclude that model-based feedback control of intravenous methohexital delivery can help establish and quantitate methohexital requirements during total intravenous anesthesia with fentanyl.

Propofol was administered for 2 h to 11 volunteers by an adaptive feedback control algorithm based on quantitative EEG analysis. Median EEG frequency served as the control variable. The range 2-3 Hz was chosen as the target range of control. During the feedback period, volunteers did not respond to commands and eyelash reflex was abolished. An average median frequency of 2.5 (SD 0.3) Hz was obtained by administering propofol 1452 (262) mg within 2 h. Time to recovery was 17.9 (8.0) min. Compared with a study with methohexitone using the same approach, the relative potency of propofol was 0.72. The mean recovery time was less than half that observed after methohexitone.

32 cases with Etomidate-, Ethrane- and Fentanyl-application have been investigated in order to evaluate a common EEG-index indicating the depth of anaesthesia. The following parameters are regarded: the mean amplitude, the relative parts of the powerspectrum for the frequency bands 0.5--2 Hz, 2--5 Hz, 5--8 Hz, 8--13 Hz, 13--24 Hz, alpha-delta-index, the beta-delta-index, the median of the powerspectrum. The median of the powerspectrum gains the best correlation to anaesthetic depth for adequate anaesthesia, which is determined by the common clinical vegetative signs. Anaesthesia which is unnecessarily deep is better indicated by a biparametric representation of both median and mean amplitude.

A combined pharmacokinetic and pharmacodynamic model of methohexital was used to establish and evaluate feedback control of methohexital anesthesia in 13 volunteers. The median frequency of the EEG power spectrum served as the pharmacodynamic variable constituting feedback. Median frequency values from 2-3 Hz were chosen as the desired EEG level (set-point). In 11 volunteers, the feedback system succeeded in maintaining a satisfactory depth of anesthesia (i.e., unresponsiveness to verbal commands and tactile stimuli). During feedback control, 75% of all measured median frequency values were in the preset range of 2-3 Hz. This distribution of median frequency was obtained by applying random stimulation (six different acoustic and tactile stimuli) to the volunteers approximately every 1.5 min. The decrease of median frequency from baseline to anesthetic values was primarily induced by increasing the fractional power in the frequency band of 0.5-2 Hz from 12.6 +/- 4.5% (mean +/- SD) to 46.0 +/- 2.5%. The median time to recovery (as defined by opening eyes on command) after cessation of the feedback control period was 20.6 min (10.7-44.5 min) when median EEG frequency was 5.2 Hz (4.7-8.4 Hz). The average requirement of methohexital (mean +/- SD) during the 2 h was 1.02 +/- 0.16 g. It is concluded that pharmacokinetic-pharmacodynamic models of intravenous anesthetics established previously may be used to form a suitable background for model-based feedback control of anesthesia by quantitative EEG analysis. This approach gives a possible solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using population mean data as starting values for drug therapy.

In 14 patients undergoing elective surgery the EEG was studied during anaesthesia with isoflurane and nitrous oxide (in oxygen) at 1.3 and 1.5 MAC. The distribution of spectral EEG indices of the baseline EEG, during the intraoperative and recovery periods were established and compared. Median frequency exhibited the most clear separation between the distributions during recovery and the intraoperative period. During anaesthesia, the median values were found to be lower than 5 Hz; when the patient was conscious, the EEG median frequency values were greater than 6 Hz. Time to recovery was 13.4 +/- 2.9 min and 30.0 +/- 8.5 min for the groups treated with 1.3 and 1.5 MAC, respectively. Burst suppression was observed during the loading period in all patients treated with 1.5 MAC and in five patients out of seven receiving 1.3 MAC. The average duration of the period of burst suppression was markedly greater in the group receiving 1.5 MAC than in the group receiving 1.3 MAC. It is concluded that devices designed for EEG trend monitoring during anaesthesia should preferably depict a frequency measure, and allow for burst suppression recognition before spectral analysis.

Six volunteers were subjected to an infusion of etomidate designed to generate linearly increasing plasma concentrations with a slope of 0.05 microgram ml-1 min-1. Cessation of infusion was determined by the occurrence of burst suppression patterns on the EEG. Infusion was restarted when the volunteers recovered personal and temporal orientation. This cycle was repeated twice. The drug input function, the pharmacokinetic parameters of etomidate as derived from a 'least squares' fit, and the median EEG frequency were used to establish a pharmacological model of etomidate. Two modelling procedures, the pharmacokinetic-pharmacodynamic, and the input-output modelling procedure, are compared. These procedures yield different results with respect to the kinetic data. As one possible explanation, a different pharmacokinetic behaviour of etomidate in the venous blood and at the site of drug action is discussed.

To evaluate the efficacy of flumazenil in intensive care medicine, the benzodiazepine antagonist was administered to 20 intubated and ventilated patients. In 18 cases the drug was used to interrupt long-term sedation (midazolam in combination with piritramide) for a short period of neurological examination. In two cases it was used to diagnose a coma of unknown origin. The patient's alertness was evaluated by clinical observation and electroencephalography. Blood pressure and heart rate were monitored continuously. The two patients with coma of unknown origin demonstrated no clinical response to flumazenil at a dosage of 2 mg. However, there was a change in the EEG: before administration of the antagonist, slow delta waves predominated; after administration there was an increase in theta activity. This activity shift was associated with a slight increase in the median frequency from 1.6 to 2.1 Hz. Serum level analysis confirmed a non-benzodiazepine-induced coma. The other 18 patients (average serum midazolam concentration: 0.27 microgram/ml) were awake and oriented after a dose of between 0.3 and 0.6 mg flumazenil. This clinical finding correlated with the EEG which showed an increase in the median frequency from 2 Hz to 6-7 Hz. Even after receiving the antagonist, the patients were able to tolerate intubation and ventilation without problem. No significant adverse effects were observed.

The objectives of the present study were to compare in a randomized double-blind crossover study design the concentration-effect relationships of Ro 48-6791, a new benzodiazepine agonist, and midazolam, following infusion in young and elderly male volunteers. Therefore, linearly increasing plasma concentrations were generated by computer controlled infusion pumps to achieve a deep hypnotic effect. The endpoint of the infusion was defined by loss of response to loud verbal commands and a median frequency of the recorded EEG power spectrum below 4 Hz. Arterial blood samples were collected in regular intervals up to 6 hours after cessation of the infusion. The method of pharmacokinetic-pharmacodynamic modeling was used to quantify the concentration-effect relationship, including age related differences, already in this early phase I study. The total clearance of Ro 48-6791 was found to be 1410 +/- 380 vs. 399 +/- 91 ml min-1 for midazolam (mean +/- SD; P < 0.005) and the central volume of distribution to be 20.5 +/- 7.1 vs. 7.9 +/- 3.0 l, respectively (P < 0.005). The comparison between young and elderly volunteers yielded for Ro 48-6791 a statistically not significant reduction of 16% for clearance with age and a slowed distribution of 47% for midazolam (P < 0.05). The recovery period for Ro 48-6791 was reduced by 66% (P < 0.005) in the young and 45% (P < 0.01) in the elderly, respectively, in comparison with midazolam. With respect to the total doses administered, Ro 48-6791 appeared to be 2.5 times as potent as midazolam in all volunteers (P < 0.001). Comparing both age groups, the doses necessary to cause similar effects were reduced by one half for both compounds in the elderly (P < 0.001). The major advantages of Ro 48-6791 compared to midazolam were its shorter duration of action as well as the faster recovery and thus the better controllability. Further investigations would have to confirm these results in a greater number of patients. The applied method of pharmacokinetic-pharmacodynamic modeling not only allowed to quantify the efficacy of Ro 48-6791 but also provided data to augment the safety for further investigations. [ABSTRACT FROM AUTHOR]