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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.

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.

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.

The predictability of the inspiratory and endexpiratory concentrations of the volatile anaesthetics isoflurane and enflurane by pharmacokinetic models was investigated. 67 patients of ASA-classes 1-2 that underwent minor surgical procedures were studied. The pharmacokinetic model consisted of two parts, a model of the anaesthesia machine and a model of the patient. The mean values of the predicted/measured concentrations of isoflurane had an amount of 1.01 +/- 0.13 (inspiratory) and 0.97 +/- 0.13 (endexpiratory), the mean values of enflurane showed a value of 1.00 +/- 0.11 (inspiratory) and 0.97 +/- 0.13 (endexpiratory). The interindividual variances amounted to between 10% and 40% of the variance of all patients. This corresponded to a standard deviation of about 6% (inspiratory) while the endexpiratory concentrations showed a standard deviation about 8% for the average values of every patient.

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

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

During the ZAK 1987 in Munich we performed a poll concerning monitoring during anaesthesia. 200 questionnaires could be evaluated. A majority of 2/3 rd monitored regularly blood pressure, ECG, FiO2, minute ventilation and ventilation pressure. These quantities were monitored independent of a presumably increasing anaesthesia risk associated with three clinical cases. Only blood pressure and ECG were considered as mandatory by a majority of 2/3 rd. Monitoring variables related more to the anaesthesia machine lide FiO2, minute ventilation, and ventilation pressure did not reach a 2/3 re majority. 78% detected at least once in their business life time a life threatening complication by monitoring devices earlier than by so called clinical signs. EEG and capnometer were the most frequent quoted monitors. Monitoring of neuromuscular blockade and intraoperative awareness was considered as a relevant problem only by 22%. 20% agreed to additional monitoring on the general ward while 2/3 rd disagreed.

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.

The principles of clinical pharmacokinetics of intravenous and inhalation anaesthesia and the correlation with pharmacodynamics are reviewed with special reference to the commonly used anaesthetic agents. Pharmacokinetics is regarded mainly as an aid towards optimization of dosage. Dosage rules based on pharmacokinetic principles, for repeated administration and infusion are outlined for the induction, maintenance and termination of anaesthesia. Interindividual variations and biological disposition are not taken into account. The kinetic processes common to intravenous and inhalation anaesthesia are presented in the form of a multiexponential function for constant concentrations.

The superposition principle of linear pharmacokinetics allows in a simple way simulation of blood levels and amounts of drug in other compartments for arbitrary dosage schemes provided the pharmacokinetic data are known. Assuming a 2-compartment model we compare for etomidate different dosage schemes as described in the literature with respect to the resulting course of blood levels or amounts of drug in different compartments. In conjunction with the reported clinical observations one can estimate minimal therapeutic blood levels and identify the compartment to which the site of action may be associated.

Dosing of drugs used in general anaesthetic practice is largely based on experience and trial-and-error. From the very beginning, anaesthesiological research has always attempted to supply a rational description of the rules governing the dose-response relationship. During the last few decades it became possible to identify pharmacokinetics as a main constituent of the relationship, since the rate of efficacy is primarily governed by the kinetics of the drug and the dose. On the other hand, the complete nonlinearity of the dose-response relationship can be demonstrated by means of a pharmacodynamic model. Control of anaesthesia by pharmacokinetic-dynamic models may be considered satisfactory as long as there is no pronounced scatter of the model parameters within a given population. Closed-loop feedback control is contrasted to feedforward control that attempts to monitor a given variable within a preset range by feeding back a measured signal to the drug delivery system. The present article reviews the experience and application of automatic feedback control systems used in anaesthesia. It was shown in all cases that adaptive, model-based feedback control is superior to non-adaptive methods. Pharmacokinetic and/or pharmacodynamic models were successfully applied to the servocontrol of volatile anaesthetics, intravenous hypnotics and neuromuscular blocking agents. Over and above these three applications, directly related to anaesthesia, the impact of feedback control on the regulation of blood pressure and blood glucose is reviewed.

Diazepam, flunitrazepam and midazolam have different pharmacokinetic properties, their biological halflives for instance, being 24 to 48 hours, 4,5 hours and 2,5 hours respectively. Moreover, the total plasma clearances calculated for these drugs resulted in 30 ml/min for diazepam, 250 ml/min for flunitrazepam and 450 ml/min for midazolam. On the other hand, all three drugs were found to have nearly the same volumes of distribution (V1: 25 l, VdSS: 80-100 l). A tissue binding of over 90% of the drugs applied can further be computed from their high plasmaprotein binding action and their volumes of distribution. Of the 3 benzodiazepines investigated, diazepam reveals extremely complex pharmacokinetic effects which vary the duration of pharmacological responses very widely; besides drug interaction, enzyme induction and -inhibition it gives rise to the active metabolite N-desmethyl-diazepam (biological halflife 50 to 120 hours). In this respect however, the metabolic products of flunitrazepam and midazolam seem to be of minor clinical importance only. The pharmacokinetics of flunitrazepam will be presented as an example to discuss several modes of dosage.