Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

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.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.

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.

Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children.

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.

Target controlled anaesthetic drug dosing.

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.

Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection) - a water-soluble propofol prodrug.

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.

The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.

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.

Isoflurane, nitrous oxide, and fentanyl pharmacodynamic interactions in surgical patients as measured by effects on median power frequency.

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.

Awareness during laryngoscopy and intubation: quantitating incidence following induction of balanced anesthesia with etomidate and cisatracurium as detected with the isolated forearm technique.

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.

Present state of closed-loop drug delivery in anesthesia and intensive care.

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.

[Pharmacokinetics of drugs in single and multiple organ failure]. / Pharmacocinétique des médicaments en cas de défaillance mono et multiviscérale.

Organ failure modifies the pharmacokinetics of drugs and usually requires a decrease in their dosage. A decrease in cardiac output, in protein binding and extraction ratio, hepatic and renal insufficiency, a modification in acid-base balance are the main factors regulating pharmacokinetics of drugs used in anaesthesia and intensive therapy.

[Bispectral analysis does not differentiate between anaesthesia EEG and a linear random process]. / Die bispektrale Analyse unterscheidet das Narkose-EEG nicht von einem linearen Zufallsprozess.

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.

Automated EEG preprocessing during anaesthesia: new aspects using artificial neural networks.

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.

Teletherapeutic drug administration by long distance closed-loop control of propofol.

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.

[Pharmacodynamics of two different propofol formulations]. / Pharmakodynamik zweier unterschiedlicher Propofolformulierungen.

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.

Development of acute tolerance to the EEG effect of propofol in rats.

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.

Concurrent recording of AEP, SSEP and EEG parameters during anaesthesia: a factor analysis.

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.

[Optimization of the dosage of volatile anesthetics based on pharmacokinetic and dynamic models]. / Optimierung der Dosierung volatiler Anästhetika auf der Grundlage pharmakokinetisch-dynamischer Modelle.

The quantitative aspects of dosing of volatile anaesthetics to establish and maintain constant alveolar concentrations are in general only discussed in the framework of closed circuit anaesthesia. A systematic approach to determine the appropriate dosage for arbitrary flows on the basis of pharmacokinetic models and to adjust the parameters of the model to the individual patient is described. A pharmacodynamic model of the volatile agents isoflurane, enflurane and halothane based on the electroencephalogram is worked out and added to the kinetic model. The median of the EEG power spectrum serves as a monoparametric correlate of depth of anaesthesia. A system theoretic consideration of the coupled subsystems, anaesthesia machine and patient, enables the establishment of interactive dosing strategies, thus offering the possibility of adapting dosage to the different painful phases of surgery. The implications of these dosing strategies for feed back control of anaesthesia by electroencephalographic means are discussed.

[Anesthesiology]. / Anästhesiologie.

During the past three decades anaesthesia-related mortality has been reduced to an extent which is more or less exclusively governed by human error. This improvement has been achieved by nearly equal progresses in drug development as well as in the development of technical devices, especially in monitoring. Nearly 80% of all anaesthetics which are used today in an anaesthetic university department were developed in the last 30 years. The search and research for better controllable compounds has caused the necessity to develop also devices which are able to deliver these substances continuously. One might therefore reason that the term pharmaceutical which today is entirely based on the term compound has in the future to be based on a combination of compound and device. The pharmacist of today and yesterday may in the future become a high-tech microsystems engineer. From an academic point of view it is unsatisfactory that the degree of therapeutic success can only be achieved and documented very incompletely. Partially this is due to the fact that the anaesthesiologists are not able to formulate their therapeutic goals, stating which higher integrative brain functions have to be reduced to what degree to guarantee an optimum therapeutic level.