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Description / Table of Contents: Abstract. In a controlled prospective randomized study, defibrillation by emergency medical technicians (EMTs) was compared with the current standard of care in Germany (basic life support by EMTs and defibrillation by emergency physicians only) in order to answer the following questions: 1. Does EMT defibrillation improve the survival rate and long-term prognosis of patients in ventricular fibrillation as compared to the current German standards in resuscitation (basic life support by EMTs and defibrillation by emergency physicians)? 2. Are the prerequisites for the use of semiautomatic defibrillators fulfilled in the emergency medical systems (EMS) of the participating centers? Methods. The study phase includes randomization of 121 adult patients with witnessed cardiac arrest and ventricular fibrillation (VF) as first ECG rhythm. Prior to the onset of the study, all EMTs of the participating EMS systems were retrained in basic life support (BLS) measures. In each center, randomly assessed EMT-Ds (EMTs trained in Defibrillation) were trained to use semiautomatic defibrillators. With the help of one-line tape recording, the time intervals during resuscitation and treatment steps were evaluated. Successfully resuscitated patients were followed up with the help of the Glascow Coma Scale and the Pittsburgh Cerebral and Overall Performance Categories. Results. From 1 February 1991 until 28 June 1992, 159 patients with VF were randomized. In 121 cases, collapse was witnessed. 25% (14/57) of the patients receiving defibrillation by EMT-Ds (study group=S) were discharged from the hospital alive. In the control group, 52 patients were defibrillated by emergency physicians, following BLS by EMTs [control group 1=C1; discharged: 29% (15/52)]. Fifty patients received BLS and advanced cardiac life support (ACLS) by the emergency physicians crews [control group 2=C2; discharged 18% (9/50)]. In the study group, the median time interval from collapse of the patient until initiation of BLS measures was 7.7 min, 7 min in C1 and 8 min in C2. ACLS measures were initiated significantly earlier (P〈0.05) in the control groups, as compared to the study group [S: 13 min, C1: 11 min; C2: 10.3 min]. Sixty-seven percent (30/45) of the study patients and 46% (36/76) of the control patients were defibrillated within 12 min. Study patients were defibrillated earlier (P〈0.05) (S: 9.9 min; C1: 12.2 min; C2: 12.75 min); return of spontaneous circulation (ROSC) was achieved earlier (P〈0.05) in the study group [S: 14 min; C1: 19 min; C2: 18.2 min] and the number of patients in the study group requiring no epinephrine during resuscitation was higher (P〈0.01) than in the control groups [S: 35.3% (12/34); C1: 10% (4/40); C2: 10.5% (4/38)]. Furthermore, the total amount of epinephrine [mean (±standard error)] administered in the study group [S: 2.35 (±0.49) mg; C1: 6.71 (±0.98) mg; C2: 7.71 (±1.31) mg] was significantly lower (P〈0.05). No significant differences in neurological long-term prognosis were found for the groups investigated. Conclusion. Neither the initial survival rate the number of patients discharged alive, nor the neurological long-term prognosis was significantly different for any of the groups investigated. Because of apparent differences in indirect prognostic parameters (time interval until ROSC, number of patients requiring no epinephrine) and because of the fact that the time interval to the first defibrillation was reduced by EMT defibrillation, EMT-Ds may perform defibrillation if: (a) they reach the patient before the emergency physician and (b) if they are trained intensively and supervised continuously. In order to increase the efficiency of defibrillation by EMT-Ds, far-reaching changes in our EMS are mandatory: (a) a reduction in the time interval from collapse until initiation of BCLS measures by intensifying layperson CPR training; (b) an increase in the number of emergency units equipped with semiautomatic defibrillators; (c) the consistent implementation of a tiered EMS.

Description / Table of Contents: Abstract 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 μg ml−1 min−1 and with a targeted concentration of 2 μg 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 (t1/2α =1.5±0.6 min; t1/2β=27±5 min; t1/2γ=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 (Table 3). The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance (Fig. 2). 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) (Fig. 3 and 4). 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 (Fig. 5). Conclusions. Eltanolone proved to be a potent hypnotic. With regard to haemodynamics and respiration it caused relatively modest reactions. The quantification of the concentration-effect relationship revealed a time lag between serum concentration and corresponding effect that seems to exceed the effect-hysteresis of thiopentone and propofol. This hysteresis restricts the control of the substance, if the effect has to be changed rapidly, and leads to a delayed recovery. Together with its possible proconvulsant properties and increased reports of urticaria this meanwhile led to the cessation of the clinical investigations with eltanolone.

Description / Table of Contents: Abstract Simulation has gained an important role in medical education and continuing education in the field of anaesthesia and emergency medicine. This article gives background information on how full-scale simulators are applied in medical education as well as in continuing education for advanced anesthesia and scientific applications. Acceptance of training seems enhanced by inclusion of the human factor aspect, since this has proven to be a major source for the development of critical situations in our specialty. Furthermore, drawbacks of the simulators available and the current training availability in Germany is described.

Description / Table of Contents: Abstract 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.

Description / Table of Contents: Abstract The need for better intravenous anaesthetic agents had 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 belonging to the group of opioids which has been released in Germany a few months ago. From the point of view of the intraoperative controllability this compound has reached the highest degree of 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 unspecific esterases occurring in blood and tissues. 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 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 with 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 soluable 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 socalled Target Controlled Infusions (TCI), there has been recently introduced the socalled 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.

Description / Table of Contents: Abstract 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 ≤ 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 kilogramm body weight and hour was signifikant 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.

Description / Table of Contents: Abstract Objective: The primary aim of this study was to find out whether adequate long-term sedation (≥72 h) can be achieved in critically ill patients with an EEG median frequency controlled closed-loop system for the application of propofol 1% and 2%. Moreover, we investigated the pharmacokinetics and pharmacodynamics of propofol with respect to possible tolerance and compared the quality of sedation of both propofol formulations and their lipid load. Patients and methods: After institutional approval and written consent, 16 ASA II-IV patients were included in this study. Main inclusion criterion was the necessity for prolonged sedation/analgesia for at least 72 h. Sedation was induced and maintained using continuous infusion of propofol 1% (n=7) or 2% (n=9). Analgesia was maintained with continuous infusion of alfentanil. The EEG was recorded from four leads (Fp1,2 and C3,4) and the EEG median frequency was obtained from the power spectrum (0.5–32 Hz). Propofol was administered computer-controlled with a median frequency setpoint depending on the depth of sedation which was assessed clinically using a modified Ramsay score. Alfentanil was applied as TCI. Arterial plasma concentrations were measured by HPLC (propofol) and RIA (alfentanil). Pharmacokinetics of propofol and alfentanil were derived using a three compartment model. Results: All patients were successfully sedated for 77±9 h. The median EEG frequency during sedation was stable at 1.5±0.2 Hz. The sedation score increased from 1 in the first 12 h to values between 2 and 3 for the remaining sedation period. At the same time, propofol plasma concentrations increased from 0.7±0.3 µg/ml to 1.8±1.3 µg/ml. The patients required an average of 2.5 mg/kg/h propofol and 0.030 mg/kg/h alfentanil. Pharmacokinetics of propofol 2% showed an increased volume of distribution when compared to propofol 1%. Alfentanil clearance was found to be reduced with four patients having extremely small clearance values (33±3 ml/min). Triglyceride values increased up to 4.5±1.2 mmol/l for patients receiving propofol 1% and remained within normal range for propofol 2%. Conclusions: The EEG median frequency can be used for closed-loop control of propofol even for long-term sedation in critically ill patients. EEG median frequencies were similarly low as in deeply anaesthetised patients. No differences in quality of sedation were seen between the two propofol formulations, but propofol 2% seems to be advantageous due to lower lipid load and triglyceride values. Increasing concentrations of propofol at unchanged sedation scores and EEG median frequencies may indicate development of tolerance.

Description / Table of Contents: Abstract For cardio-pulmonary resuscitation there are standardized treatment concepts, but there have been few prospective investigations examining the efficacy of prehospital advanced trauma life support and its effect on the outcome in patients with severe head injury and multiple trauma treated within the German emergency system. The results of this study underline the importance of intensive prehospital treatment and highlight some problems that should be taken into account in future in the training of emergency physicians. Methods. A total of 179 patients with cerebral trauma were investigated. Data obtained included demographic and logistic data of the patients and the emergency physicians, diagnoses and treatment at the scene of the accident and state of the patient on admission in each case. Having divided the patients into three groups by severity of the trauma, we distinguished between sufficient and insufficient treatment and assessed infusion therapy, ventilatory support, positioning and immobilization, and analgesic and sedative therapy. For statistical analysis of the data we used χ2-test and Fisher's exact test. P〈0.05 was considered significant. Results. There were 102 patients who had sustained a cerebral trauma without other life-threatening lesions (score 1), 40 with multiple trauma (score 2) and 37 with multiple trauma (score 3). On average 2.4 IV lines were established and the patients received 1186±765 cc of crystalloid in addition to 801±411 cc of colloid fluids. In all groups, patients who received adequate infusion therapy had a better outcome; even in the group with score 1 significantly fewer had a fatal outcome. In all, 167 (93%) patients had endotracheal tubes placed, and in 150 cases (84%) ventilatory therapy was considered sufficient. The proportion of score 1 patients with sufficient ventilatory support who had a fatal outcome was significantly lower than that in the group with insufficient treatment. In patients with multiple trauma we could not separate the benefits of sufficient respiratory therapy and infusion therapy. In only 54% of the cases a vacuum mattress was used and in only 41% the patients were positioned with the upper part of the body elevated by 30°. These were 28 patients (16%) who received neither analgesics nor sedatives. Regardless of the quality of prehospital treatment of isolated head injury, a Glasgow Coma Scale (GCS) score lower than 5 involved a very high mortality and all patients with a GCS score of 9 or more survived. In the group with GCS scores between 5 and 8, however, significantly more of the patients who received adequate treatment survived (82.5% vs 40%). Conclusions. The present study confirms that sufficient advanced trauma life support can improve the outcome of trauma victims with cerebral trauma. Adequate infusion and respiratory therapy reduce the mortality among such patients significantly. In patients with multiple trauma a clear positive effect of generous infusion therapy also is evident. The clearest effect of sufficient prehospital treatment is seen in patients with isolated cerebral trauma and a GCS score between 5 and 8. These results demonstrate the importance of advanced trauma life support and show emphatically that the so-called scoop-and-run strategy should be abandoned when resources are available for extended preclinical emergency treatment. On the other hand, we detected some problem areas in the prehospital treatment of trauma victims, such as positioning, immobilization and drug therapy with analgesics and sedatives. These findings allow us to pinpoint specific points that should be stressed in the training of emergency physicians and paramedics.