Search

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 C 5 0 for the depression of CO 2 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 μg.kg - 1 .min - 1 , 14 patients, as published previously) or piritramide (17.9 μg.kg - 1 .min - 1 , nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO 2 (PaCO 2 ) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO 2 was used to describe the PaCO 2 data. Results: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k e l C O 2 (elimination rate constant of CO 2 ) 0.144 (-) min - 1 , F (gain of the CO 2 response) 4.0 (fixed according to literature values) (28%), C 5 0 (both drugs) 61.3 μg l - 1 (41%), k e o a l f e n t a n i l 0.654 (-) min - 1 and k e o p i r i t r a m i d e 0.023 (-) min - 1 . Assigning separate C 5 0 values for alfentanil and piritramide did not improve the fit compared with a model with the same C 5 0 . Conclusion: Since the C 5 0 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.

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

In dieser Studie haben wir die Interaktion von Enfluran und Stickoxidul bei einem konstanten EEG-Median untersucht. Registriert wurde bei 30 Patienten wahrend gynakologischer Laparotomien. Stickoxidul wurde randomisiert in Konzentrationen von 0, 20, 40, 60 und 75 Vol.-% bei jeweils 10 Patientinnen appliziert. Die Einstellungen des Enfluranverdampfers wurden so gewahlt, das der EEG-Median zwischen 2–3 Hz lag. Der Zusammenhang zwischen Stickoxidulkonzentrationen und den gemessenen endexspiratorischen Enflurankonzentrationen wurde mittels Regressionsanalyse bestimmt. Stickoxidul senkt den Enfluranbedarf linear um 0,042 Vol.-% pro 10 Vol.-% Stickoxidul. Die Interaktion von Enfluran und Stickoxidul im Dosisbereich von 0–75 Vol.-% entspricht einem additiven Synergismus. Die Interaktion beim EEG-Median 2–3 Hz ist jedoch geringer als bei den MAC-Werten. Je hoher die Stickoxidulkonzentration, desto groser ist der Bedarf an Anasthetika in MAC-Einheiten, um den EEG-Median zwischen 2–3 Hz konstant zu halten.

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

The authors describe intravenous anaesthesia with diethyl ether that has been in use for over 70 years as the only clinically useful form of anaesthesia with intravenously applied volatile anaesthetics. Intravenous ether anaesthesia, which had been introduced in 1909 by Burkhardt, was rarely but regularly used in Europe and the United States between 1910 and 1930. In the course of development of new intravenous anaesthetics such as hexobarbital and thiopental, which were easier to handle, intravenous ether narcosis was used only sporadically after 1930. The method, however, has certain "pros", such as: rapid and excitation-free introduction, good manageability, only mild postnarcotic disturbances and volume substitution by the carrier solution. The "cons" are a quite considerable incidence of venous irritations and thromboses, complicated and costly equipment and preparation of the solution as well as cardiovascular stress in case of cardiac insufficiency patients. Simulation confirmed the statements from literature in respect of the characteristic features concerning induction and manageability.

Closed-loop control of atracurium-induced neuromuscular blockade by a model-based adaptive feedback algorithm is described. Mean offsets (+/- s.d.) from setpoints at 50, 70 and 90% neuromuscular blocks using the Relaxograph were 1.1 +/- 1.3, 0.2 +/- 0.7 and 0.1 +/- 0.4%, respectively. Correspondingly, the mean steady-state rates of infusion of atracurium were 0.20 +/- 0.06, 0.25 +/- 0.03 and 0.39 +/- 0.10 mg.kg-1.h-1. The described controller provides reasonable control of atracurium dosing at different degrees of neuromuscular blockade. It gives a solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using population mean data as starting values for drug therapy.

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.

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.

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.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.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), P0.05]. 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.The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

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.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.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.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.

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.

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.

Automation of anaesthesia is a complex task but important with respect to patient health, improved quality of narcosis and cost reduction. Furthermore it will enhance our understanding of the complex mechanism underlying anaesthesia. Classical model based control concepts have been evaluated in the past. Those approaches were limited to univariate process control. As the objective of our studies we want to establish the feasibility of different real-valued reinforcement learning approaches for the task of multivariate adaptive control in anaesthesia. As a first step we present a series of experiments with a naive application of reinforcement learning. The appropriateness is demonstrated in the univariate case. Results are compared to a model based analytical controller.

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.

An nahezu allen humanen Lebensvorgangen sind Rezeptoren beteiligt. Eine Vielzahl dieser Rezeptoren und Rezeptorsysteme werden im Rahmen der anasthesiologischen Therapie tangiert. Dieser „Refresher Course 2001“ beschrankt sich auf einige wenige Rezeptoren, von denen angenommen werden kann, dass sie fur die wesentlichen Therapieziele der Allgemeinanasthesie, Bewusst- und Schmerzlosigkeit, ursachlich von Bedeutung sind. Der Beitrag ist in 3 Abschnitte gegliedert.

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.

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.

In Germany a TCI-system for propofol (Disoprifusor-TCI) has been commercially available since spring 1997. We investigated the prediction error and precision of this TCI system as part of a multicentre study. Bias, precision, blood concentrations and dosage of propofol were compared with patients receiving propofol via a manually controlled infusion device.After approval by the local Ethics Committee and written informed consent, 21 patients of ASA-classification I to III scheduled for major abdominal surgery received either a target controlled infusion (group T, Disoprifusor-TCI) or a manually controlled infusion (group M) of propofol. The propofol plasma concentrations were measured by HPLC. The prediction error for each measurement, the median prediction error (MDPE) or bias, the median absolute prediction error (MDAPE) or precision and the divergence (change of the prediction error over infusion time) were calculated for both groups.For all patients in group T (n = 12) the bias of the TCI system was 6.7% and the precision 27.5%. For 70% of all measured plasma concentrations the absolute prediction error wasor = 37%. The divergence was -5.4% per hour. For all patients in group M (n = 9) the bias was 44.2% and the precision 50%. The mean amount of propofol infused per kilogram body weight and hour was significant higher in T (9.0 +/- 1.2 mg/kg/h) than in M (6.6 +/- 1.2 mg/kg/h, p0.005).With a precision of 27.5% the investigated TCI system (Diprifusor-TCI) showed an acceptable inaccuracy, as for TCI-systems a median prediction error of +/- 30% has to be expected due to the inherent variability of pharmacokinetic parameters. Further studies will be necessary to find out whether the investigated TCI system for propofol may offer substantial advantages.

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.

The objectives of the present study were to compare in a randomized double-blind crossover study design the concentration-effect relationships of Ro 48-6791, a new benzodiazepine agonist, and midazolam, following infusion in young and elderly male volunteers. Therefore, linearly increasing plasma concentrations were generated by computer controlled infusion pumps to achieve a deep hypnotic effect. The endpoint of the infusion was defined by loss of response to loud verbal commands and a median frequency of the recorded EEG power spectrum below 4 Hz. Arterial blood samples were collected in regular intervals up to 6 hours after cessation of the infusion. The method of pharmacokinetic-pharmacodynamic modeling was used to quantify the concentration-effect relationship, including age related differences, already in this early phase I study. The total clearance of Ro 48-6791 was found to be 1410 +/- 380 vs. 399 +/- 91 ml min-1 for midazolam (mean +/- SD; P0.005) and the central volume of distribution to be 20.5 +/- 7.1 vs. 7.9 +/- 3.0 l, respectively (P0.005). The comparison between young and elderly volunteers yielded for Ro 48-6791 a statistically not significant reduction of 16% for clearance with age and a slowed distribution of 47% for midazolam (P0.05). The recovery period for Ro 48-6791 was reduced by 66% (P0.005) in the young and 45% (P0.01) in the elderly, respectively, in comparison with midazolam. With respect to the total doses administered, Ro 48-6791 appeared to be 2.5 times as potent as midazolam in all volunteers (P0.001). Comparing both age groups, the doses necessary to cause similar effects were reduced by one half for both compounds in the elderly (P0.001). The major advantages of Ro 48-6791 compared to midazolam were its shorter duration of action as well as the faster recovery and thus the better controllability. Further investigations would have to confirm these results in a greater number of patients. The applied method of pharmacokinetic-pharmacodynamic modeling not only allowed to quantify the efficacy of Ro 48-6791 but also provided data to augment the safety for further investigations.

The need for better anaesthetic agents has led to the approval or the clinical studies of new compounds, which have or are assumed to have a higher degree of controllability or an improved spectrum of undesired side effects compared to other approved anaesthetics. For the i.v.-anaesthetics, different approaches have been used to achieve this. Among these are the new synthesis of a new chemical entity (NCE), the isolation of an isomer of a racemic mixture and the new galenic preparation of a known substance for i.v.-application. This review gives for all three approaches an example. Remifentanil is a NCE which has been released in Germany a few months ago. This compound has reached the highest degree of intraoperative controllability among all i.v. anaesthetics. Its context-sensitive half-life, that is the effective time for drug concentration to decline by 50% (ET50), is about 3-4 min even after several hours of continuous administration. One reason for this exceptional property is that its metabolism is independent of liver and kidney function and depends almost only on blood and tissue nonspecific esterases. S(+)-ketamine represents an example for the isolation of a specific isomer out of a known racemic mixture. Racemic ketamine was introduced into clinical practice in 1965. The clinical trials with the isolated S(+)-ketamine, which are finished now, showed that the racemic mixture of both isomer does not lead to an additive effect, but the action of S(+)-ketamine is weakened by the R(-)-compound. In volunteers studies it was not possible to achieve a complete loss of consciousness by administration of R(-)-ketamine only, whereby with S(+)-ketamine one could reduce the dose with respect to the racemic mixture by a factor of two to achieve complete consciousness. This dose reduction is accompanied by a faster offset time. For broader clinical applications one would therefore expect a higher degree of controllability and a shortened recovery period. With eltanolon a substance is presented which is known as the metabolite pregnanolon of the reductive metabolic pathway of progesterone since the 50s and which is known to possess strong hypnotic potency. However, because of its low water solubility it could not be studied as an i.v. agent until in 1990 one succeeded in making a water soluble emulsion in fat. The clearance of eltanolon is ca. 25 ml/kg/min and it has a terminal half-life of about 3 hr. It has, however, a pronounced hysteresis of 8 min between blood and effect site. This unfavourable pharmacokinetic property in conjunction with observed unvoluntary spontaneous movements and increased muscle tone during application has led to the cessation of its further clinical development. With the introduction of shorter acting compounds it is also necessary to improve the traditional techniques of i.v. drug delivery like manual bolus injections or drip infusions. After more than 16 years of research and development in the field of Target-Controlled Infusions (TCI), there has been recently introduced the so called Diprifusor-TCI, as a commercially available software module to control the delivery of propofol. TCI uses established pharmacokinetic data to determine infusion rates to achieve desired drug concentrations serving as the target, which can be chosen interactively. This way of dosing i.v. anesthetics is obviously not restricted to one specific compound but can be applied to any i.v.-drug if appropriate pharmacokinetic data are used.

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

Bei der Dosierung von Medikamenten spielen 3 pharmakokinetische Grosen eine wesentliche Rolle: 1) das intiale oder zentrale Verteilungsvolumen 2) das Gesamtverteilungsvolumen oder Volumen im Steady state 3) die Clearance.

The authors describe intravenous anaesthesia with diethyl ether that has been in use for over 70 years as the only clinically useful form of anaesthesia with intravenously applied volatile anaesthetics. Intravenous ether anaesthesia, which had been introduced in 1909 by Burkhardt, was rarely but regularly used in Europe and the United States between 1910 and 1930. In the course of development of new intravenous anaesthetics such as hexobarbital and thiopental, which were easier to handle, intravenous ether narcosis was used only sporadically after 1930. The method, however, has certain "pros", such as: rapid and excitation-free introduction, good manageability, only mild postnarcotic disturbances and volume substitution by the carrier solution. The "cons" are a quite considerable incidence of venous irritations and thromboses, complicated and costly equipment and preparation of the solution as well as cardiovascular stress in case of cardiac insufficiency patients. Simulation confirmed the statements from literature in respect of the characteristic features concerning induction and manageability.

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

Automatic feedback control of the delivery of volatile anesthetic agents has been realized in the past using inspired concentrations as well as expired concentrations (see D.R. Westenskow, this volume, pp 155–157) as feedback signal. These approaches used a proportional-integral-derivative (PID) controller for feedback control of the volatile anesthetic agents. This paper deals with a model-based adaptive feedback control system of the delivery of volatile anesthetics using the EEG as the pharmacodynamic response variable to be controlled. Specifically, we used the median EEG frequency.

The use of a feedback system to control intravenous anesthetic drug delivery based on the spontaneous EEG requires at first mapping the anesthesia-induced EEG changes onto a figure which can be easily calculated and used for control. The power spectrum of the EEG signal has been widely investigated as a basis for the derivation of EEG parameters. The power spectrum is nothing but a distribution; thus, the derivation of spectral EEG parameters is equivalent to the derivation of descriptors of a distribution. It should, however, be mentioned here that the estimation of the power spectrum is not a unique procedure. The transformation from the time domain into the frequency domain requires a signal extending from −∞ to +∞ in time. Because an EEG epoch is finite in time, methods for extrapolating the signal to the future and into the past are required. Fourier transformation assumes that the epoch under consideration is repeated indefinitely to ±00, while other methods of power spectrum estimation, such as maximum entropy analysis [28], assume other methods of extrapolation. For the purpose of EEG monitoring during anesthesia, these differences in estimating the power spectrum are of minor importance if the EEG epoch is long enough. Figure 1 gives the scheme of an EEG power spectrum and the three monoparametric descriptors of distribution which were used. The simplest one is mean EEG frequency, defined as the mean of the power spectrum regarded as a distribution. As is known from ordinary statistics, the mean can give inappropriate measures of the center in the case of skew symmetric distributions and is, in addition, rather sensitive to outliers.

The relationship between drug dosing and the induced time course of effect is of major interest for the anesthetist when aiming at inducing and maintaining an anesthetic state. Especially when the patient is treated with neuromuscular blocking agents, there are only very limited apparent clinical signs for detecting awareness. A reliable estimation and prediction of drug dosing to prevent intra-operative awareness is therefore required.

The combination of propofol and ketamine for total intravenous anesthesia was investigated; the intention was to minimize the side effects of each drug by the concomitant application of the other drug. METHODS. Twenty patients scheduled for lower abdominal interventions were divided into two groups. In the first group anesthesia was induced and maintained by a simple administration regimen based upon pharmacokinetic principles. Ketamine and propofol were given as bolus injections (60 mg each) with a time interval of 60 s for induction followed by a two-step infusion regimen for propofol (15.5 mg/min) and later on by an additional ketamine infusion (1-2 mg/min). Bolus injections (20 mg) of ketamine were administered to increase the depth of anesthesia if necessary (Fig. 1). The second group received propofol and ketamine by microprocessor-controlled infusion pumps requiring the anesthetist to operate a single dial to preset the desired blood levels of both drugs according to the needs of the individual patient (Fig. 2). RESULTS. There were no difference (Table 1) between the two groups in the demographic data of the patients or duration of surgery (30-120 min). The total doses of propofol (750 +/- 262 vs 624 +/- 468 mg) and ketamine (158 +/- 41 vs 99 +/- 48 mg) were smaller in the computer-controlled infusion group, though this difference just failed to be significant. The hemodynamic changes during induction were minor, with a small nonsignificant increase in all parameters (Fig. 3) for 10 min. The controllability of the pharmacodynamic effects of both drugs during anesthesia was very satisfactory in the computer-assisted infusion group and quite satisfactory in the first group. There were no psychic disturbances during induction of or recovery from anesthesia. Respiration was adequate within a few minutes after the end of surgery. The patients were awake about 10 min later and fully oriented after 20 min. No major side effects were observed with this anesthetic technique. CONCLUSION. Total intravenous anesthesia with propofol and ketamine proved to be very satisfactory from a clinical point of view. The major known side effects of propofol (reduced hemodynamics during induction) and ketamine (psychic disturbances and cardiovascular stimulation) were absent and respiratory function was adequate after the end of surgery. This technique, therefore, can be used in risk patients and under disaster conditions when i.v. access is the only possible route of drug administration. The use of computer-assisted infusion pumps markedly enhances handling and controllability of total i.v. anesthesia.

An adaptive closed-loop control of neuromuscular block by pharmacokinetic dynamic model-based feedback is described. Mean (+/- SD) offsets from setpoints at 70, 80 and 90% neuromuscular blockade were 2.2 +/- 1.1, 1.8 +/- 0.6 and 0.4 +/- 0.4%, respectively. Correspondingly, the mean standard deviations from mean neuro-muscular blockade were 3.9 +/- 2.3, 2.7 +/- 0.6 and 1.3 +/- 0.2% and the mean average vecuronium requirements 0.5 +/- 0.2, 0.7 +/- 0.2 and 1.0 +/- 0.5 micrograms kg-1 min-1. The described closed-loop vecuronium administration system gives a solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using mean data as starting values for drug therapy.

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