Epidural needle insertion : A large registry analysis.

BACKGROUND: Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. OBJECTIVE: This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. MATERIAL AND METHODS: A total of 14,503 epidural catheter insertions including lumbar (L1-L5; n = 5367), low thoracic (T7-T12, n = 8234) and upper thoracic (T1-T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). MAIN RESULTS: Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09-1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21-1.29], p < 0.001). In contrast, dural punctures occurred at significantly shallower depths (adjOR 0.73 [0.60-0.89], p = 0.002). Paraesthesia was unrelated to insertion depth. Body mass index and sex had no influence on paraesthesia, dural and vascular punctures. Thoracic epidural insertion was associated with a lower risk of vascular puncture than at lumbar sites (adjOR 0.39 [0.18-0.84], p = 0.02). CONCLUSION: Variation in midline insertion depth is an independent risk factor for epidural complications; however, variability precludes use of depth as a reliable guide to insertion in individual patients.

Obesity in regional anesthesia--a risk factor for peripheral catheter-related infections.

BACKGROUND: Obesity is believed to increase the risk of surgical site infections and possibly increase the risk of catheter-related infections in regional anesthesia. We, therefore, analyzed the influence of obesity on catheter-related infections defined within a national registry for regional anesthesia. METHODS: The German Network for Regional Anesthesia database with 25 participating clinical centers was analyzed between 2007 and 2012. Exactly, 28,249 cases (13,239 peripheral nerve and 15,010 neuraxial blocks) of patients ≥ 14 years were grouped in I: underweight (BMI 13.2-18.49 kg/m(2) , n = 597), II: normal weight (BMI 18.5-24.9 kg/m(2) , n = 9272), III: overweight (BMI 25.0-29.9 kg/m(2) , n = 10,632), and IV: obese (BMI 30.0-70.3 kg/m(2) , n = 7,744). The analysis focused on peripheral and neuraxial catheter-related infections. Differences between the groups were tested with non-parametric ANOVA and chi-square (P < 0.05). Binary logistic regression was used to compare obese, overweight, or underweight patients with normal weight patients. Odds ratios (OR and 95% confidence interval) were calculated and adjusted for potential confounders. RESULTS: Confounders with significant influence on the risk for catheter-related infections were gender, age, ASA score, diabetes, preoperative infection, multiple skin puncture, and prolonged catheter use. The incidence (normal weight: 2.1%, obese: 3.6%; P < 0.001) and the risk of peripheral catheter-related infection was increased in obese compared to normal weight patients [adjusted OR: 1.69 (1.25-2.28); P < 0.001]. In neuraxial sites, the incidence of catheter-related infections differed significantly between normal weight and obese patients (normal weight: 3.2%, obese: 2.3%; P = 0.01), whereas the risk was comparable [adjusted OR: 0.95 (0.71-1.28); P = 0.92]. CONCLUSION: This retrospective cohort study suggests that obesity is an independent risk factor for peripheral, but not neuraxial, catheter-related infections.

Technical note: gold marker implants and high-frequency jet ventilation for stereotactic, single-dose irradiation of liver tumors.

With reference to radiosurgery of the liver, we describe techniques designed to solve the methodological problem of striking targets subject to respiratory motion with the necessary precision. Implanting a gold marker in the vicinity of the liver tumor was the first step in ensuring the reproducibility of the isocenter's position. An 18-karat gold rod measuring 1.9 x 3 mm was implanted approximately 2 cm from the edge of the tumor as this was displayed in the spiral, thin-slice CT with contrast media. Both the implantation of the marker and the required, CT-controlled biopsy of the liver tumor can be achieved simultaneously with the same puncture needle. The efficiency of high-frequency jet ventilation (HFJV) in neutralizing the targeted organ's respiratory motion during stereotactic single-dose irradiation was evaluated. The procedure was carried out on ten patients without any complications. In the time between treatment planning and irradiation (3 days), no significant marker migration was observable. In all cases, the gold marker (volume: 7.5 mm(3)) was readily observable in the treatment beam using portal imaging. HFJV provided reliable immobilization. The liver motion in each anesthetized patient was limited to under 3.0 mm in all directions. Thus, the correct field settings and target reproducibility were able to be analyzed and documented during the irradiation. The combination of marker and HFJV enables the determination of stereotactic coordinates directly related to the liver itself and, in this way, stereotactic radiation treatment of liver tumors is freed from the uncertainties involved in orientation to bony landmarks, in respiratory motion, and in changes of position in the stereotactic body frame. The method is feasible and can improve the accuracy of stereotactic body radiation therapy.

[Total intravenous anesthesia with propofol and remifentanil. Results of a multicenter study of 6,161 patients]. / Total intravenöse Anästhesie mit Propofol und Remifentanil Ergebnisse einer multizentrischen Untersuchung an 6161 Patienten.

INTRODUCTION: The aim of this study was to investigate efficacy and tolerability of propofol, remifentanil and cisatracurium or mivacurium in routine anesthetic practice. PATIENTS AND METHODS: A total of 6,161 patients scheduled for abdominal or orthopedic surgery were included in this open multicenter phase IV study. Perioperative hemodynamics as well as induction, recovery and discharge times, anesthetics, frequency of PONV and side-effects were studied. RESULTS: Quality of induction and maintenance of anesthesia were evaluated by anesthesiologists to be good or very good in 88%. 86% of the patients assessed anesthesia as good or very good. Adverse events were reported for 28 patients (0.45%), with hypotension and bradycardia being most frequent. Recovery was evaluated by anesthesiologists to be good or very good in 88%, surgeons and nursing staff assessed the TIVA as good or very good in 90%. Most frequent postoperative complaints were pain (16.7%), nausea (6.1%), shivering (3.1%) and vomiting (0.7%). CONCLUSIONS: The study showed that total intravenous anesthesia using propofol, remifentanil and cisatracurium or mivacurium is safe, tolerable and effective and has a high degree of acceptance.

Testing and modelling the interaction of alfentanil and propofol on the EEG.

BACKGROUND AND OBJECTIVE: For total intravenous anaesthesia an opioid is often combined with a hypnotic. A supra-additive interaction has been reported for clinical signs such as loss of consciousness or loss of the eyelash reflex. This study investigated the type of interaction of alfentanil and propofol on the electroencephalogram. METHODS: Twenty patients scheduled for abdominal surgery were enrolled in the study. Anaesthesia was induced and maintained with alfentanil and propofol. Each patient received a target-controlled infusion of alfentanil. Three target concentrations of 150, 225 and 300 ng mL(-1) were applied to each patient in random order. Propofol was added to the alfentanil infusion by a feedback system. The set point was the range of 1.5-2.5 Hz median frequency of the electroencephalogram. Four arterial blood samples were taken within the last 20 min of each period. The mean drug concentrations were used to determine the type of interaction and an isobole was estimated by fitting Bernstein spline functions to the data. RESULTS: In 17 patients, all three alfentanil target concentrations could be administered. The test for supra-additivity as well as the isobole construction resulted in an additive type of interaction. The line of additivity cA/cA0 + cP/cP0 = 1 was best fitted for the values (standard deviation) cA0 = 1240 (51)ng mL(-1) and cP0 = 5.21 (0.36) microg mL(-1). CONCLUSIONS: The type of interaction between alfentanil and propofol on the electroencephalogram in the investigated dose range is additive. This gives the freedom and need to select the appropriate dosing ratio of alfentanil and propofol by other considerations.

Modelling the pharmacodynamic interaction between remifentanil and propofol by EEG-controlled dosing.

BACKGROUND AND OBJECTIVE: Knowledge of the pharmacodynamic interaction between remifentanil and propofol is important to permit optimal dosage strategies. We studied this pharmacodynamic interaction using the median power frequency of the processed electroencephalogram as a control parameter for feedback-controlled dosing of propofol. METHODS: Twenty-one patients were given total intravenous anaesthesia with remifentanil and propofol. During three target-controlled infusion regimens, the target concentrations of remifentanil (5, 10, 15 ng mL(-1)) and propofol dosing were automatically adjusted to keep the median power frequency in the range 2 +/- 0.5 Hz. In each patient and during each remifentanil target concentration, four arterial propofol/remifentanil concentration pairs were measured. The type of interaction was tested using the relative distance from the line of additivity and the isobole was modelled using Bernstein splines. RESULTS: The results from 13 patients were used for data analysis. The measured remifentanil concentrations during the three targets were (mean +/- SD): 3.6 +/- 0.9, 8.1 +/- 2.5 and 12.4 +/- 2.8 ng mL(-1). The corresponding propofol concentrations were 2.64 +/- 0.86, 2.13 +/- 0.58 and 2.09 +/- 0.58 microg mL(-1). The data were best described with an additive type of interaction and the isobole was estimated using: ((c)Remifentanil/64.2 ng mL(-1)) + ((c)Propofol/2.61 microg mL(-1)) = 1. CONCLUSIONS: Within the studied concentration range, remifentanil and propofol showed an additive type of pharmacodynamic interaction on the electroencephalogram.

[Recovery from anaesthesia and incidence and intensity of postoperative nausea and vomiting following a total intravenous anaesthesia (TIVA) with S-(+)-ketamine/propofol compared to alfentanil/propofol]. / Aufwachverhalten sowie Ubelkeit und Erbrechen nach einer totalen intravenösen Anästhesie mit S-(+)-Ketamin-Propofol Ein Vergleich mit Alfentanil-Propofol.

BACKGROUND: Opioids contribute to postoperative nausea and vomiting (PONV). An intraoperative analgesia with S-(+)-ketamine will make opioid administration dispensable and may reduce postoperative analgesic requirements. The aim of the study was to record the incidence and intensity of PONV following a total intravenous anesthesia (TIVA) with S-(+)-ketamine/propofol (K/P) or alfentanil/propofol (A/P) as well as recovery from anaesthesia. PATIENTS AND METHODS: A total of 145 patients received a TIVA with K/P or A/P. Recovery time,PONV, intensity of pain and overall acceptance of the delivered anaesthesia were recorded. RESULTS: Recovery times were prolonged in the K/P group. Both groups had a comparable incidence of PONV (26% and 22% for K/P vs A/P, respectively), the intensity was low in both groups with a VAS of <6/100 mm at all times. The intensity of postoperative pain and analgesic requirement did not differ. Overall acceptance of the delivered anaesthesia was lower in the K/P group. Unpleasant dreams were not more common in the K/P group. CONCLUSIONS: A TIVA with K/P did not reduce PONV when compared to A/P, but prolonged recovery.

Does etomidate increase postoperative nausea? A double-blind controlled comparison of etomidate in lipid emulsion with propofol for balanced anaesthesia.

In a double-blind randomized study, the incidence and severity of postoperative nausea and vomiting was investigated with a new formulation of etomidate (Etomidate-(R)Lipuro, B. Braun Melsungen AG, Germany) compared with propofol for induction of a balanced anaesthesia with isoflurane/fentanyl in air. The incidence and intensity of nausea was examined by use of a visual analogue scale (VAS; 0-100 mm) at 1, 2, between 6 and 8, and 24 h postoperatively. One-hundred-and-sixty-four patients undergoing orthopedic procedures were studied. For etomidate vs. propofol, 14.6% vs. 14.2% male and 26.8% vs. 27.5% female patients were nauseated during the first two postoperative hours. The median rating for nausea remained below 5 mm at any time in both groups, i.e. the intensity of nausea was very low. The incidence of vomiting was higher in women receiving etomidate (26.8% vs. 10%). We conclude that etomidate does not increase nausea during the early postoperative period.

[Pharmacokinetic-pharmacodynamic modeling in phase II of drug development. A comparative study with young and old volunteers with benzdiazepine as an example]. / Pharmakokinetisch-pharmakodynamische Modellbildung in der frühen Phase II der Arzneimittelentwicklung. Eine vergleichende Untersuchung bei jungen und alten Probanden am Beispiel eines Benzodiazepins.

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.

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.

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.

Pharmacokinetic-pharmacodynamic modeling of the new steroid hypnotic eltanolone in healthy volunteers.

BACKGROUND: In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers. METHODS: Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model. RESULTS: The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening. CONCLUSIONS: Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

[New intravenous anesthetics. Remifentanil, S(+)-ketamine, eltanolone and target controlled infusion]. / Neue intravenöse Anästhetika. Remifentanil, S(+)-Ketamin, Eltanolon und 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.

[Concentration-effect relationship, hemodynamics and respiration after infusion of the steroid anesthetic eltanolone in healthy subjects]. / Konzentrations-wirkungsbeziehung, Hämodynamik und Respiration nach Infusion des Steroid-anästhetikums Eltanolon bei gesunden Probanden.

UNLABELLED: During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic eltanolone (pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of eltanolone after arterial blood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects. MATERIAL AND METHODS: Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075 microgram ml-1 min-1 and with a targeted concentration of 2 micrograms ml-1. During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysed with NONMEM by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO2 was analysed every 6 min. RESULTS: The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l min-1), small volumes of distribution (Vc = 7.7 +/- 3.4 l; Vdss = 92 +/- 22 l and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15 min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7 +/- 1.3 min (mean +/- SD), reaction to verbal contact was lost after 10.4 +/- 1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9 +/- 2.8. During recovery, the corneal reflex reappeared 9.4 +/- 2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2 +/- 4.3 min and full orientation was regained after 34.7 +/- 6.2 min. During the second cycle all signs disappeared faster and were regained later. The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance. The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P < 0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about 24% (P < 0.05). Oxygen saturation remained stable with values between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO2 analyses was 41 mmHg with a range of 25-60 mmHg. The only serious undesirable effect was a seizure during awakening in one volunteer which coincided with polyspike waves in his raw-EEG recordings. (ABSTRACT TR

[RO 48-6791--a short acting benzodiazepine. Pharmacokinetics and pharmacodynamics in young and old subjects in comparison to midazolam]. / Ro 48-6791--ein kurzwirksames Benzodiazepin. Untersuchungen zur Pharmakokinetik und Pharmakodynamik bei jungen und älteren Probanden im Vergleich mit 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.

EEG analysis and pharmacodynamic modelling after intravenous bolus injection of eltanolone (pregnanolone).

An intravenous bolus dose of 0.75 mg Kg-1 eltanolone emulsion was administered to 18 unpremedicated ASA I or II patients. In addition to clinical observation and haemodynamic monitoring, EEG power spectrum and median frequency were recorded. Venous blood was collected to establish a concentration-effect relation using the median frequency as a pharmacodynamic parameter for hypnotic effect, and with analysis of data with the sigmoidal Emax model. Emax was determined as the maximal decrease of the median frequency caused by the CNS depressant effect of eltanolone. The results of seven of 15 patients with complete serum and EEG analysis could be described by a sigmoidal curve. The calculated IC50, the serum concentration producing 50% inhibition of Emax, was 0.57 micrograms mL-1. Median frequency occasionally decreased independently of eltanolone serum concentration in seven patients because interference by natural sleep was not prevented before induction or during awakening by setting continuous stimulations. In relation to the peak serum concentration, the decrease in median frequency occurred late in one patient. Nevertheless, the present study provides a preliminary estimation of the IC50 of eltanolone. From the clinical point of view, eltanolone showed satisfactory induction characteristics which warrant further evaluation.

Changes in the EEG power spectrum after midazolam anaesthesia combined with racemic or S- (+) ketamine.

Changes in the EEG power spectrum were studied in 50 patients (ASA status I or II), receiving either 2 mg.kg-1 of racemic ketamine or 1 mg.kg-1 of S-(+) ketamine in a randomized and double-blind manner after prior administration of 0.1 mg.kg-1 of midazolam. The patients receiving intramuscular premedication with midazolam about 45 minutes prior to induction of anaesthesia showed, in a deliberately quiet environment and mostly in the early morning, a delta dominated EEG (56% delta power) with a reduced alpha peak (17% alpha power) and an average median of 4 Hz as the baseline findings of the EEG power spectrum. The intravenous administration of midazolam led to activation of the lower beta range (13-18 Hz) and the subsequent injection of ketamine caused an increase in activity in the fast beta range (21-30 Hz), both being accompanied by a reduction of delta power from 56% to 40%. Correspondingly, an increase in the median frequency was noted. Causing nearly the same changes in EEG, S-(+) ketamine was confirmed to be twice as potent as racemic ketamine.

Increased fMet-Leu-Phe receptor expression and altered superoxide production of neutrophil granulocytes in septic and posttraumatic patients.

Activation of neutrophils by various inflammatory stimuli has been shown to play a pivotal role in septic and posttraumatic tissue injury. To further elucidate the mechanisms modulating the oxidative metabolism, we assessed superoxide production induced by N-formylmethionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate and the expression of FMLP receptors of human neutrophils on several days during sepsis and after trauma. Neutrophils of septic patients isolated on days 0-4 after the diagnosis of sepsis showed a significant, more than twofold increase in specific binding of [3H]FMLP at 1, 120, and 240 nM. Scatchard plot analyses revealed that this increase in specific binding was due to an increase in the number of low- and high-affinity FMLP receptors with no changes in receptor affinity. On days 5-10 after the onset of sepsis the up-regulation of FMLP receptors on circulating neutrophils was followed by receptor down-regulation. Likewise, neutrophils from patients with trauma that was not complicated by sepsis bound significantly more [3H]FMLP than neutrophils from volunteers. However, the increase in FMLP receptors was less than that in septic neutrophils and returned earlier to normal. In accordance with the up-regulation of FMLP receptors, neutrophils obtained from patients with sepsis or after trauma on days 1-4 and days 1-2, respectively, produced significantly more superoxide anion upon stimulation with FMLP. However, after stimulation with phorbol myristate acetate, a receptor-independent activator of protein kinase C, these cells released less superoxide anion than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method.

In a randomized, double-blind study, we have examined the stereoselective disposition and pharmacodynamic characteristics of ketamine in surgical patients after i.v. administration of S(+)-ketamine 1 mg/kg body weight (25 patients) or racemic ketamine 2 mg/kg body weight (25 patients). S(+)-Ketamine was not inverted to R(-)-ketamine. After racemate administration we observed statistically significant (P < 0.01) smaller clearance and volume of distribution for R(-)-ketamine compared with S(+)-ketamine. In contrast, the pharmacokinetic variables of S(+)-ketamine were not significantly different between treatment groups. Systolic and diastolic arterial pressure and heart rate increased significantly (P < 0.005) in both groups. At 1, 3 and 15 min after S(+)-ketamine administration, significantly greater increase in systolic and diastolic pressures were observed compared with the racemate group. There was no correlation between the changes in haemodynamic variables and plasma catecholamine concentrations, which remained unaffected after administration of the medications.