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Background: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone., Methods: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations., Results: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml)., Conclusion: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

Background: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone., Methods: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations., Results: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly., Conclusions: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

Background: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach., Methods: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models., Results: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration., Conclusions: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

Unlabelled: The orofacial formalin test is established in rats and was recently transferred to mice. The aim of this study was to determine the ideal formalin concentration for testing analgesic drugs, to examine alternatives for the assessment of nociceptive and non-nociceptive behavior as well as the effects of morphine and age on formalin-induced nociception. Formalin (.5, 1, 2.5, 5, 7.5, 10, and 15%) was injected into the vibrissa of mice. The cumulative nociceptive behavior was measured as well as nociceptive and non-nociceptive behavior based on a score that was recorded over a 5-second observation period once per minute. We also examined the effects of morphine on the nociceptive response induced by 2.5% formalin. Age-dependent differences were tested in the third part of the experiment. NONMEM was used to model the pharmacodynamic effects of formalin and morphine. Injection of formalin lead to a concentration-dependent increase in cumulative nociceptive behavior ratings as well as the specific nociceptive behavior 3 of scratching injection site with hindpaw (score 3). The formalin concentrations that lead to 50% of the maximum effect were 2.6 and 3.3%, respectively, for the continuous rating method and the scoring method. Morphine dose dependently suppressed the nociceptive behavior and the number of score 3 ratings of the nociceptive behavior. Age differences in behavior could not be detected by either analytic method., Perspective: To improve the existing behavioral nociceptive assay for pain processed by the trigeminal system, we determined an ideal formalin concentration for the orofacial formalin test in mice, evaluated alternative timesaving analysis approaches, and investigated effects of morphine and age on formalin-induced nociception., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Studies with nondepolarizing neuromuscular blocking agents showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy. The objective of this study was to investigate if these alterations depend on disease progression., Methods: The authors studied 11 children (6-9 yr) with moderate Duchenne muscular dystrophy, 11 adolescents (12-16 yr) with advanced Duchenne muscular dystrophy, and 2 age-matched control groups of 8 patients each (5-9 and 10-17 yr). Anesthesia was performed with propofol and remifentanil. Patients received a single intravenous dose of 0.2 mg/kg mivacurium. Neuromuscular transmission was monitored by acceleromyography. The time course of neuromuscular blockade was characterized by the onset time and the times to different levels of recovery., Results: Onset and duration of neuromuscular blockade were significantly prolonged in adolescent Duchenne muscular dystrophy patients (onset time, 4.0 min; recovery index, 12.3 min; median), as compared with Duchenne muscular dystrophy children (onset time, 2.3 min; recovery index, 6.8 min), and also as compared with young controls (onset time, 2.0 min; recovery index, 4.4 min) and adolescent controls (onset time, 2.5 min; recovery index, 4.8 min). Within the Duchenne muscular dystrophy patients, onset time and recovery index increased significantly with age. In the control group, age had no effect., Conclusions: The neuromuscular blocking effects of mivacurium showed a significant age dependency in Duchenne muscular dystrophy patients, which was most probably caused by the progression of the disease.

Background and Objective: Studies with rocuronium showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy (DMD). The objective of this study was to identify the pharmacokinetic and/or pharmacodynamic origin of these alterations., Methods: Twenty-five male patients (15 with DMD, 10 controls, aged 10-18 years) were studied. Patients were anaesthetized with propofol and sufentanil. Neuromuscular transmission was monitored by acceleromyography. Patients received a single intravenous dose of 0.3 mg kg(-1) rocuronium. In five patients of the DMD group, pharmacokinetic modelling was performed from arterial rocuronium concentrations. The time course of neuromuscular block was analysed with a sigmoid E(max) model including an effect compartment., Results: The pharmacokinetics of rocuronium in DMD patients were Vc 63 +/- 14 ml kg(-1), Cl 3.0 +/- 1.0 ml min(-1) kg(-1), half-lives 2.0 +/- 0.6, 20 +/- 10 and 129 +/- 98 min, SE. For both the DMD and the control group, the time course of neuromuscular block could be described by a sigmoid E(max) model using the estimated pharmacokinetic parameters of the DMD group. In patients with DMD, the equilibration between the central and effect compartment was significantly slower (T(1/2)ke0: 9.7 +/- 0.3 vs. 1.3 +/- 0.1 min) and the EC(50) was significantly smaller (512 +/- 20 vs. 1170 +/- 64 ng ml(-1)), whereas the ED(50) was 0.16 +/- 0.02 mg kg(-1) in both groups., Conclusion: The pharmacodynamics of rocuronium were significantly altered in patients with DMD, whereas the pharmacokinetics seemed to be similar to those in healthy adults. Patients with DMD were more sensitive with respect to effect site concentration but not with respect to dose.

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

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.

Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofol(G). The liberated propofol(G) compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater V(c), V(dss), significantly shorter alpha- and beta-half-life and a longer MRT (mean residence time) for propofol(G). The pharmacodynamic potency of propofol(G) appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation.

It belongs to the particularities of anaesthesia that the conscious response of the patient to drug therapy is not available for the adjustment of drug therapy and that the side-effects of anaesthetic drug therapy would be in general lethal if no special measures were taken such as artificial ventilation. Both conditions do not allow for a slow, time-consuming titration of drug effect towards the therapeutically effective window, but measures have to be taken to reach a therapeutic target fast (within seconds to a few minutes), reliably, and with precision. Integrated pharmacokinetic-pharmacodynamic models have proved to be a useful mathematical framework to institute such drug delivery to patients. The theory of model-based interactive drug dosing on the basis of common pharmacokinetic-pharmacodynamic (pk-pd) models is outlined and the target-controlled infusion system (TCI) is presented as a new anaesthetic dosing technique that has developed during the last decade. Whereas TCI presents an open-loop dosing strategy (the past output does not influence the future input), current research deals with the model-based adaptive closed-loop administration of anaesthetics. In these systems the past output is used to adapt and individualize the initial pk-pd model to the patients and thus has an influence on future drug dosing which is based on the adapted model.

Objective: Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability., Methods: We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1'-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring., Results: Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration-dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1'-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively., Conclusions: The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 +/- 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.

Background: The objective of this pilot study was to investigate the feasibility of an EEG-controlled closed-loop administration of propofol over a long distance of about 200 km., Methods: We performed a teletherapeutic propofol infusion during total intravenous anaesthesia with propofol in 11 patients undergoing general surgery. The teletherapeutic system consisted of a computer at the patient site in Munich and a computer at the control site in Erlangen, which were connected via the internet through a virtual private network. The patient's EEG signal was sent to the control site computer, where the median frequency (MEF) of the EEG power spectrum was calculated. The propofol infusion, determined by a model-based adaptive feedback algorithm to maintain a MEF of 1.5 to 2 Hz, was sent to the patient site computer connected to the infusion pump. The quality of the control was assessed by the performance error defined as the percentage deviation of the measured MEF from the set point and the necessity of interventions by the anaesthetist at the patient site., Results: During closed-loop administration of propofol [83 (52) min] the median performance error of the system was - 4.6 (4.4)% and the median absolute performance error was 18.8 (5.7)%. From a total number of 10 905 transmitted EEG epochs, there were five epochs with transmission errors, without further consequences for drug control. In one patient, teletherapy was stopped because the internet connection was interrupted., Conclusions: Teletherapeutic drug administration could be realized over a longer distance. Further studies have to investigate the practicability and safety of teletherapeutic drug control in anaesthesia.

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.

Background: Propofol is nowadays available in various lipid formulations. We compared two different propofol formulations with respect to pharmacodynamics, using the EEG and clinical signs., Materials and Methods: Ten volunteers received Diprivan 1% and Propofol 1% MCT Fresenius as a computer controlled infusion with increasing propofol target concentrations. A sigmoid E(max) model with effect compartment was estimated for the median frequency of the EEG power spectrum, based on measured arterial propofol plasma concentrations. Clinical pharmacodynamics were assessed by reaction on acoustic stimuli, eyelid reflex and corneal reflex., Results: The drugs did not differ in pharmacodynamics with respect to EEG (EC(50) 2.1+/-0.6 for Diprivan and 2.1+/-0.5 microg/ml for Propofol Fresenius) and clinical signs. The pharmacodynamic model was characterized by a steep concentration effect relationship and a distinct hysteresis between propofol plasma concentration and effect (k(e0) 0.12+/-0.04 and 0.12+/-0.5 min(-1))., Conclusions: The investigated lipid formulations have no influence on the pharmacodynamics of propofol.

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.

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

The binding properties of the short-acting hypnotic agent propofol (CAS 2078-54-8) to human serum albumin were studied in vitro. Using centrifugation through ultrafiltration membranes the ratio of free and bound propofol as a function of the human serum albumin concentration was determined. In addition, a biomathematical approach was tested that allowed the determination of the number of binding sites from the measured binding profile. At a total propofol concentration of 8.81 +/- 0.25 microg/mL the concentration of the free fraction of propofol ranged from 338 +/- 11 ng/mL (mean +/- SE) at an albumin concentration of 0.5% to 15 +/- 2 ng/ mL at an albumin concentration of 8.0%. The corresponding percentage of propofol binding ranged from 96.07 +/- 0.14% to 99.83 +/- 0.02%. From this binding profile the binding site was estimated to be n(0) = 2. The measured influence of the albumin concentration on propofol binding might be of relevance in states of hypo- or hyperalbuminaemia which could result in an altered demand of propofol.

During a 5-year period, 1997 to 2002, therapeutic drug monitoring of midazolam plasma concentrations in combination with the level of sedation as assessed by the Ramsay sedation scale was performed in 648 critically ill patients requiring artificial ventilation. In a subgroup of 189 patients sepsis-related organ failure assessment procedure was additionally performed. A total number of 3354 samples were analyzed. Significantly reduced clearance of midazolam was observed within the first 4 days of midazolam treatment of critically ill patients. As a result, accumulation of midazolam and its metabolites occurred within the first week of treatment. In contrast, parameters such as serum bilirubin or creatinine, which are commonly used to adapt drug therapy to organ dysfunction, showed significant changes with a delay of more than 10 days as compared with the findings of midazolam monitoring. Midazolam plasma concentrations showed a good correlation with the sedative capacity of the drug (r2 = 0.906). However, a great variability of the drug effect between patients could be demonstrated, which, as a consequence, may complicate the development of dosing strategies based on midazolam plasma concentrations to better control sedation in critically ill patients. Furthermore, patient age seems to be an important factor for the considerable variability of the sedative effect of midazolam. To achieve a certain levels of sedation, significantly lower midazolam infusion rates as well as plasma concentrations were required as the patients age increased. No significant sex-related differences could be observed for any pharmacologic parameter obtained in this study. Our findings suggest that midazolam therapeutic drug monitoring might be a useful tool to individualize midazolam therapy, especially in critically ill patients developing organ dysfunction and requiring long-term sedation to minimize the risk of drug accumulation and excessive sedation.

Background: Target-controlled infusion (TCI) of propofol was initially realized as a device for prefilled syringes (Diprifusor). New TCI systems can be used with any propofol formulation. We compared two different propofol formulations with respect to accuracy of TCI and pharmacokinetics., Materials and Methods: A total of 10 volunteers received Diprivan 1% and Propofol 1% MCT Fresenius as TCI using the pharmacokinetic model of the Diprifusor. The prediction error was determined from measured arterial concentrations. A three-compartment model was fitted to the concentration data., Results: The median prediction error and the median absolute prediction error were -1.4% and 23.3% for Diprivan, and -5.9% and 17.8% for Propofol Fresenius. The drugs did not differ in pharmacokinetics but showed a smaller central volume of distribution than used for infusion control., Conclusions: The pharmacokinetic model of Diprifusor can also be used for TCI of Propofol Fresenius. The large volume of distribution in this model may cause an overshoot in concentration.

Background: GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion., Methods: In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 microg/ml. Subsequently, the targets were reduced to 3 microg/ml and 1.5 microg/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data., Results: Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 microg/ml for GPI 15715 and 3.0 +/- 0.7 microg/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect., Conclusions: Compared with propofol emulsion, propofol from GPI 15715 showed different pharmacokinetics and pharmacodynamics, particularly a higher potency with respect to concentration. These differences may indicate an influence of the formulation.

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.

Background: The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action., Methods: Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data., Results: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50., Conclusion: Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.

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: GPI 15715 (AQUAVAN injection) is a new water-soluble prodrug which is hydrolyzed to release propofol. The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715., Methods: Three groups of three healthy male volunteers (aged 19-35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h. Pharmacokinetics were analyzed with compartment models. Pharmacodynamics were assessed by clinical signs., Results: GPI 15715 was well tolerated without pain on injection. Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion. Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg. After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 +/- 0.6 microg/ml. A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml. kg-1 min-1; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data. The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%. There were no significant laboratory abnormalities., Conclusions: Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose. Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.

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.

Background and Objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis., Methods: Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum., Results: A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1))., Conclusions: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

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.

The history of nitrous oxide is more than 200 years old and its clinical use as anaesthetic is more than 150 years old. The symposium discussed the question whether nitrous oxide should maintain its traditional role as a component of the anaesthetic breathing gas in everdays anaesthetic procedure or whether there are indications not to continue the regular use of nitrous oxide. As a matter of fact the continued use of nitrous oxide will not change its clinical pharmacology and one may argue that every year of additional experience with this drug is likely to increase the safety of its application. However, one has steadily to judge the risks of this drug against its alternatives and these have changed dramatically over the past decades. The new anaesthesia machines allow the combination of oxygen and air as breathing gas, there are new inhalational agents (e. g. desflurane, xenon) as controllable as nitrous oxide and new i. v. agents. As a conclusion of these developments the Department of Anaesthesiology at the Universität Erlangen-Nürnberg has decided to cease the traditional use of nitrous oxide.

Purpose: The present study investigated the interaction between the cumulative dose requirements of cisatracurium and anesthesia with isoflurane, sevoflurane, desflurane or propofol using closed-loop feedback control., Methods: Fifty-six patients (18-85 yr, vitrectomies of more than one hour) were studied. In the volatile anesthetics groups, anesthesia was maintained by 1.3 MAC of isoflurane, sevoflurane or desflurane; in the propofol group, anesthesia was maintained by a continuous infusion of 6-8 mg.kg(-1).hr(-1) propofol. After bolus application of 0.1 mg.kg(-1) cisatracurium, a T1%-level of 10% of control level (train-of-four stimulation every 20 sec) was maintained using closed-loop feedback controlled infusion of cisatracurium. The effective therapeutic infusion rate (ETI) was estimated from the asymptotic steady-state infusion rate Iss. The Iss was derived from fitting an asymptotic line to the measured cumulative dose requirement curve. The ETI of the different groups was compared using Kruskal-Wallis- test, followed by rank sum test, corrected for the number of comparisons, P <0.05 was regarded as showing significant difference., Results: ETI in the isoflurane group was 35.6 +/- 8.6 microg.m(-2).min(-1), in the sevoflurane group 36.4+/- 11.9 microg m(-2).min(-1), in the desflurane group 23.8 +/- 6.3 microg.m(-2).min(-1). The ETI of the volatile anesthetic groups were all significantly lower than the ETI in the propofol group at 61.7 +/- 25.3 microg.m(-2).min(-1) (P <0.002). The ETI in the desflurane group was significantly lower than in all other groups (P <0.02)., Conclusion: In comparison to propofol, isoflurane, sevoflurane and desflurane reduce the cumulative dose requirements of cisatracurium to maintain a 90% neuromuscular blockade by 42%, 41% and 60%, respectively.

Study Objective: To measure the incidence of awareness during induction of anesthesia with etomidate and fentanyl, and to model its frequency as a function of dose of etomidate., Design: Prospective cohort study., Setting: Anesthesia department of a university hospital., Patients: 30 ASA physical status I, II, and III patients undergoing elective general surgery., Interventions: Patients were assigned to one of three groups of etomidate (0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg) and received fentanyl (2 microg/kg) and 2 x ED(95) of cisatracurium (0.1 mg/kg). Neuromuscular block was monitored with a peripheral nerve stimulator. Intubation was performed after maximum T(1)-depression. To identify awareness, the isolated forearm technique (IFT) was used. The IFT was performed by prompting the patient every 20 seconds. Only a verified response was considered a positive IFT response. Anesthesia was maintained with isoflurane in oxygen/air and fentanyl., Measurements and Main Results: Maximum neuromuscular block occurred after 352 +/- 96 seconds and intubation was performed 424 +/- 86 seconds after loss of consciousness (LOC). Awareness was dose dependent: 80% of patients receiving 0.2 mg/kg etomidate, 70% of patients receiving 0.3 mg/kg etomidate, and 20% of patients receiving 0.4 mg/kg etomidate had a positive IFT response. Awareness occurred in one patient 3 minutes after LOC, in 65% during laryngoscopy, and in 30% within the following 120 seconds. One patient had explicit recall without finding awareness unpleasant. Hemodynamic parameters did not differ between patients with a positive or a negative IFT response., Conclusions: The incidence of awareness during bolus induction can be modeled as dose dependent. However, when combining a short-acting induction drug and a delayed-onset neuromuscular blocker, the continuous infusion of the hypnotic drug may prevent awareness during induction.

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.

Especially for medical disciplines like anesthesiology, which represent only a small economic market, drug development is a cost intensive and with respect to financial aspects a high risk task. This situation requires methods, which in the early stages of the drug development process of an interesting compound allow the establishment of a reliable and valid data set, in order to make decisions on the continuation or discontinuation of a project. Given a compound out of the group of benzodiazepines as an example this paper represents todays methods of integrated pharmacokinetic-pharmacodynamic modelling as well as the special computer aided strategies of drug dosing as powerful tools in the anaesthetic drug development process. It is shown that one can generate data concerning differences in drug requirement and drug duration in the therapeutic dose range between different groups of possible patients, e.g. young and elderly, as early as the early phase II. It is concluded that these clinical pharmacological tools and the high resolution data generated by them facilitate the Go/No-Go decision to proceed to phase III and enhance the likelihood of passing phase III successfully.

Background: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study., Methods: After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations., Results: The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid., Conclusions: The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.

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.

Although closed-loop systems have a long tradition in engineering, their continued use for patient care is limited to the last 20 years, with the exception of BICKFORD's pioneering work in 1950. During the past 2 years it has been shown that automated closed-loop systems for drug delivery can provide unique study designs for clinical research allowing experimental setups not realizable by traditional means. It is, however, evident that a lot of research and development has to be done on therapeutic closed-loop systems to solve the many questions related to their reliability, safety and use in the routine clinical setting.