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H Schwilden

Publications and source records attributed to H Schwilden.

At least 37 records · Page 2Linked to original sources
PubMed1999

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.

Adult↗
PubMed1999

[Pharmacokinetic-pharmacodynamic modeling in phase II of drug development. A comparative study with young and old volunteers with benzdiazepine as an example].

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.

Adolescent↗
PubMed1999

Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil.

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.

Adult↗
PubMed1999

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.

Algorithms↗
PubMed1998

[Predictability and precision of "target-controlled infusion" (TCI) of propofol with the "Disoprifusor TCI" system].

UNLABELLED: 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. METHODS: 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. RESULTS: 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 was < or = 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, p < 0.005). CONCLUSIONS: 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.

Abdomen↗
PubMed1997

Pharmacokinetic-pharmacodynamic modelling of the EEG effects of Ro 48-6791, a new short-acting benzodiazepine, in young and elderly subjects.

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.

Adult↗
PubMed1997

[Anesthesiology].

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.

Anesthesia↗
PubMed1996

[The interaction of nitrous oxide and enflurane on the EEG median of 2-3 Hz is additive, but weaker than at 1.0 MAC].

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

Adult↗
PubMed1996

[New intravenous anesthetics. Remifentanil, S(+)-ketamine, eltanolone and target controlled infusion].

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.

Anesthesia, Intravenous↗
PubMed1996

[RO 48-6791--a short acting benzodiazepine. Pharmacokinetics and pharmacodynamics in young and old subjects in comparison to midazolam].

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

Adjuvants, Anesthesia↗
PubMed1996

Interaction of isoflurane and nitrous oxide combinations similar for median electroencephalographic frequency and clinical anesthesia.

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

Adult↗
PubMed1995

[Clinical potency of nitrous oxide--is MAC the gold standard?].

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.

Anesthesia, General↗
PubMed1995

[Intravenous anesthesia with inhalation anesthetics].

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.

Anesthesia, Intravenous↗
PubMed1993

Pharmacokinetic model identification and parameter estimation as an ill-posed problem.

For model identification and parameter estimation in the framework of linear pharmacokinetics it is most often assumed that the disposition function is a finite sum of exponential functions with time constants lambda i and associated coefficients Ci. Least-square fitting procedures are used to estimate the coefficients Ci and the corresponding discrete locations lambda i on the lambda-axes. This work presents an alternative approach. It does not assume that the non-zero coefficients are located at sharply defined values of lambda, but that they are represented by a continuous function h(lambda), the spectrum of the disposition function. This turns the non-linear least-square problem into a linear problem, which is known to be as so-called "ill-posed". Regularization methods have been developed in recent years as suitable tools for the treatment of such ill-posed problems. Application of Tikhonov regularization to the case of the bolus kinetics of propofol in 8 volunteers is demonstrated. In 7 of the 8 cases a spectrum with 4 to 5 peaks was found, and in one volunteer there were only 2 peaks. All spectra with more than 2 peaks showed negative values of h(lambda). The method used is described and the results are compared with those of conventional compartment analysis.

Humans↗
PubMed1993

Closed-loop feedback controlled administration of alfentanil during alfentanil-nitrous oxide anaesthesia.

We have studied the automatic administration of alfentanil during alfentanil-nitrous oxide anaesthesia in 11 patients using a closed-loop feedback control system based on EEG analysis. We chose a median EEG frequency of 2-4 Hz as the EEG set point. The slope of the asymptote to the cumulative dose requirement was used to define an effective therapeutic infusion of alfentanil. Median EEG frequency (mean (SD)) during the feedback period was 3.03 (0.45) Hz. The average effective therapeutic infusion of alfentanil was 0.140 (0.032) mg min-1. We conclude that EEG feedback control may be useful in assessing and defining the dose requirements of alfentanil.

Adult↗