[Target-controlled infusion (TCI) - a concept with a future?: state-of-the-art, treatment recommendations and a look into the future]. / "Target controlled infusion" (TCI) - ein Konzept mit Zukunft?: Standortbestimmung, Handlungsempfehlungen und Blick in die Zukunft.

Over the last 10 years the technique of target-controlled infusion (TCI) has substantially influenced the development and practice of intravenous anaesthesia. It opened the possibility of many new and exciting applications of perioperative anaesthetic care. More recent and current developments, such as open TCI (target-controlled infusion) and the availability of generic anaesthetic agents combined with modern infusion pumps, means that TCI can become a standard procedure in anaesthesia and is no longer just a research tool for specialists and enthusiasts. This review explains the fundamentals and applications of intravenous drug delivery by TCI and gives practice guidelines to successfully implement the technique into clinical practice. The aim is to provide a comprehensive reference based on clinically proven evidence.

Distributions of local oxygen saturation and its response to changes of mean arterial blood pressure in the cerebral cortex adjacent to arteriovenous malformations.

BACKGROUND AND PURPOSE: To test the hypothesis that neither "steal" as cortical ischemia caused by reduced perfusion pressure nor "breakthrough" on the grounds of loss of pressure autoregulation exist in brain tissue surrounding arteriovenous malformations (AVMs), we established patterns of cortical oxygen saturation (SO(2)) adjacent to AVMs and its behavior after alterations of mean arterial blood pressure. METHODS: With a microspectrophotometer, SO(2) was scanned in the cortex around AVMs of 44 patients before and after resection and in that of a non-AVM group (n=42) before transsylvian dissection. Autoregulation was evaluated by linear regression analysis after elevation of mean arterial blood pressure (5 microg/min IV noradrenaline). SO(2) values were calculated as medians, percentage of critical values (<25% SO(2)), and coefficients of variance (approximate heterogeneity of SO(2) distributions). All values are given as mean+/-SD. RESULTS: Forty patients with AVM had an uneventful postoperative course (group A). Four hyperemic complications ("breakthrough") occurred (group B). Autoregulation was tested intact in all groups at all times. Preoperative SO(2) distributions in groups A and C (non-AVMs) were identical. In group B, significantly (P<0.05) lower medians (group A, 52.9+/-16.3%; group B, 44.2+/-17.1%; group C, 51.9+/-11.5% SO(2)), more critical values (group A, 6.5+/-5.1%; group B, 14.7+/-11.1%; group C, 7.1+/-4.9%), and heterogeneous SO(2) distributions (group A, 20.2+/-12.7%; group B, 27.9+/-12.4%; group C, 26.8+/-10.9%) were seen. Increase of median values was significantly higher in group B (76.3+/-10.4% SO(2)) than in group A (65.9+/-13.4% SO(2)) after resection. CONCLUSIONS: Severely hypoxic areas are uncommon in the cortex adjacent to AVMs and occur predominantly in patients prone to hyperemic complications. Reduced perfusion pressure is compensated in most cases, and moderate hyperemia prevails after excision. Reperfusion into unprotected capillaries of severely hypoxic cortical areas results in "breakthrough," for which vasoparalysis appears not to be the underlying mechanism.

A rational approach to the control of sedation in intensive care unit patients based on closed-loop control.

Optimal control of long-term sedation during therapy in the intensive care unit is difficult to achieve in a number of patients when based on commonly used clinical sedation scores alone. We therefore used the median frequency of the EEG power spectrum as a quantitative measure for closed-loop administration of propofol in 21 artificially ventilated patients (nine trauma, 12 non-trauma). The EEG setpoint was correlated with a clinical sedation score and defined such, that mechanical ventilation was tolerated. The sedative therapy was given for 31 +/- 30 h. Non-trauma patients required sedation with an EEG median frequency between 2 and 3 Hz (propofol consumption: 1.4 +/- 0.8 mg kg-1 h-1) and sedation seemed to follow some circadian patterns, whereas trauma patients needed significantly deeper sedation (EEG median frequency: 1-2 Hz; propofol consumption: 2.6 +/- 0.8 mg kg-1 h-1). We conclude that the EEG closed-loop system could safely and reliably administer propofol to maintain a predetermined level of sedation for patients in intensive care unit over a protracted time.

[Analgo-sedation in intensive care: a quantitative, EEG-based trial with propofol 1% and 2%]. / Analgosedierung auf der Intensivstation. Eine quantitative, EEG-gestützte Untersuchung mit Propofol 1% und 2%.

OBJECTIVE: The primary aim of this study was to find out whether adequate long-term sedation (> or = 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 microgram/ml to 1.8 +/- 1.3 micrograms/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.

Steady-state properties of sodium channels from healthy and tumorous human brain.

This extensive bilayer study of unpurified human brain channels from non-diseased and tumorous human brain involves more than 300 lipid bilayer experiments. Single channel conductances and subconductances, single channel fractional open times, the voltage-dependence of tetrodotoxin (TTX) block and the steady-state activation behavior of four different human brain synaptosomal preparations have been examined. Reproducible values have been obtained for the molecular electrophysiological parameters and their standard deviations, providing a database for future comparisons involving disease or drug-related changes in molecular sodium channel functions. In comparison with sodium channels from other species and under other experimental conditions, the bilayer system proved to be a reliable experimental setting. Despite the very different histology of the tissue probes, there were no significant differences in any of the examined electrophysiological features.

Blocking effects of the anaesthetic etomidate on human brain sodium channels.

Sodium channels from human brain tissue were incorporated into voltage-clamped planar lipid bilayers in presence of batrachotoxin and exposed to increasing concentrations of the intravenous anaesthetic drug etomidate (0.03-1.02 mM). Etomidate interacted with the sodium-conducting pathway of the channel causing a concentration-dependent block of the time-averaged sodium conductance (computer fit of the concentration-response curve: half-maximal blocking concentration, EC50, 0.19 mM; maximal block, block(max), 38%). This block of sodium-conductance resulted from two distinct effects (I) major effect: reduction of the sodium-channel amplitude and (II) minor effect: reduction of the fractional channel open-time. These results were observed at concentrations above clinically-relevant serum concentrations (up to 0.01 mM), suggesting only a limited role for human brain sodium channels in the mechanism of action of etomidate during clinical anaesthesia.

Physiological steal around AVMs of the brain is not equivalent to cortical ischemia.

To challenge the concept of steal rendering the surrounding cortex ischemic, we examined patterns of nutritive capillary flow in the vicinity of AVMs. With a spectrophotometer (EMPHO, BGT) capillary O2 saturation (O2 satn.) was intraoperatively scanned around AVMs in n = 44 patients and in n = 42 controls. 130,000 O2 satn. values before AVM resection were calculated as medians, ratio of critical values (< 25% O2 satn.), coefficients of variance and compared via ANOVA (p < 0.05). n = 40 AVM patients had no postoperative complication (group A), while in n = 4 cases a hyperperfusion syndrome occurred (group B). Physiological variables were comparable among groups A, B and C (controls). Medians (A: 52.9+/-16.3, B: 44.2+/-17.1, C: 51.9+/-11.5% O2 satn.) and the ratio of critical values (A: 6.5+/-5.1, B: 14.7+/-11.1, C: 7.1+/-4.9 O2 satn.) were identical in groups A and C, but significantly different in group B, indicating exhausted compensation. Decreased flow heterogeneity in group A (A: 20.2+/-12.7, B: 27.9+/-12.4, C: 26.8+/-10.9 O2 satn.) kept median cortical perfusion identical to group C. These results confirm recent findings, that cerebrovascular adaption by capillary recruitment keeps CBF at normal levels in the majority of cases and that chronic noninfarctional cerebral hypoperfusion is eventually the equivalent of steal around AVMs. Only around AVMs predisposed to hemodynamic derangement some areas of local low flow anoxia may exist.

Molecular actions of droperidol on human CNS ion channels.

The molecular effects of droperidol (C22H22FN3O2) on single sodium channels from the human brain were investigated using the electrophysiological planar lipid-bilayer technique. Droperidol (0.05-0.8mM) induced a concentration dependent and voltage independent reduction in the time averaged single channel conductance by two mechanisms: a reduction in the fractional channel open time (major effect, approximately 90%) and a decrease in the channel amplitude (minor effect). The weighted computer fit of the concentration response for the combined effect curve yielded an EC50 of 0.68 mM droperidol and a maximal conductance block of 77%. These blocking effects of droperidol on CNS sodium channels occurred at a concentration range comparable with other specific anaesthetic compounds but far beyond clinical serum levels (up to 0.002 mM). Therefore in contrast with animal preparations (frog peripheral nerve, sodium channel) the human brain sodium channel is not a major target site for droperidol during clinical anaesthesia.

Pectin methylesterase regulates methanol and ethanol accumulation in ripening tomato (Lycopersicon esculentum) fruit.

We provide genetic evidence that the production of methanol in tomato fruit is regulated by pectin methylesterase (PME, EC 3.1.1.11), an enzyme that catalyzes demethoxylation of pectins. The role of PME in methanol production in tomato fruit was examined by relating the tissue methanol content to the PME enzymatic activity in wild-type Rutgers and isogenic PME antisense fruits with lowered PME activity. In the wild-type, fruit development and ripening were accompanied by an increase in the abundance of PME protein and activity and a corresponding ripening-related increase in methanol content. In the PME antisense pericarp, the level of methanol was greatly reduced in unripe fruit, and diminished methanol content persisted throughout the ripening process. The close correlation between PME activity and levels of methanol in fruit tissues from wild-type and a PME antisense mutant indicates that PME is the primary biosynthetic pathway for methanol production in tomato fruit. Interestingly, ethanol levels that were low and unchanged during ripening of wild-type tomatoes increased progressively with the ripening of PME antisense fruit. In vitro studies indicate that methanol is a competitive inhibitor of the tomato alcohol dehydrogenase (ADH, EC 1.1.1.1) activity suggesting that ADH-catalyzed production of ethanol may be arrested by methanol accumulation in the wild-type but not in the PME mutant where methanol levels remain low.

No evidence for specific opioid effects on batrachotoxin-modified sodium channels from human brain synaptosomes.

Human central nervous system (CNS) sodium channels modified by batrachotoxin and incorporated inter voltage-clamped lipid bilayers, were exposed to various concentrations of the opioid alfentanil (0.2-8.0 mM). Alfentanil caused a concentration-dependent and membrane potential independent reduction of the single channel amplitude and the fractional channel open-time. The weighted computer fit of the dose-response curve yielded a maximal conductance block of 50% with an EC50 of 1.3 mM. These effects occurred at levels beyond clinically relevant human serum/brain levels (0.003 mM) but within the predicted concentration range using the Meyer-Overton (lipid solubility/anaesthetic potency) correlation. Thus, human CNS sodium channels are probably not a main target site for the clinical effects of alfentanil but they provide a model system to estimate the proportion of the lipophilic interactions contributing to its overall effect.

Pharmacokinetics and pharmacodynamics of propofol/alfentanil infusions for sedation in ICU patients.

OBJECTIVE: Population pharmacokinetic analysis and pharmacodynamic profile of propofol/alfentanil infusions for sedation and analgesia of intensive care unit patients for up to 24 h. DESIGN: Institutional Review Board-approved prospective clinical trial. SETTING: The ten-bed intensive care unit of an university hospital. PATIENTS: 18 consecutive patients (ten men/eight women; age: 17-73 years, mean 51.6 +/- 16.7 years, SD; body weight: 60-110 kg, mean 82.9 +/- 11.2 kg, SD) requiring mechanical ventilation and prolonged sedation/analgesia after major surgery or trauma. INTERVENTIONS: Plasma propofol and alfentanil concentrations were measured at regular intervals during the long-term drug infusion using a high-performance liquid chromatography (propofol) and radioimmunoassay (alfentanil) analysis. The depth of sedation was controlled by monitoring a two-lead online EEG. Thus, drug application was computer controlled via a closed-loop EEG median-frequency feedback system. RESULTS: ICU long-term infusion population pharmacokinetics (open three-compartment model) revealed for propofol: central compartment distribution volume (V1): 31.2 +/- 5.3 l; steady-state distribution volume (Vdss): 499 +/- 173 l; total clearance (Cltot): 1001- +/- 150 ml/min; redistribution half-life (t1/2 gamma): 90 +/- 23 min; elimination half-life (t1/2 beta): 558 +/- 218 minutes. For alfentanil: V1: 31.9 +/- 10.1 l; Vdss: 124 +/- 41 l; Cltot: 345 +/- 70 ml/min; t1/2 gamma: 36 +/- 15 min; t1/2 beta: 275 +/- 94 min, respectively. CONCLUSIONS: The population pharmacokinetic analysis of propofol/alfentanil for ICU sedation therapy revealed increased volumes of drug distribution and decreased elimination characteristics as compared to pharmacokinetic data from short-term infusions in surgical patients. This can be attributed in part to altered distribution/redistribution processes and/or drug elimination under the condition of ICU therapy. No significant drug accumulation was observed. For future long-term sedation and analgesia of ICU patients with propofol/alfentanil, this altered pharmacokinetic behaviour should be taken into consideration to allow a more individualized and safer dosing of this drug combination.

[Do general anesthetics act on specific receptors?]. / Greifen Allgemeinanästhetika an spezifischen Rezeptoren an?

First of all, the meanings of the terms anaesthesia, anaesthetic and receptor are defined. Examples of anaesthetic actions in model systems are then described and compared with clinical actions of anaesthetics. When anaesthetics achieve a certain membrane concentration, they begin to influence membrane protein function in a nonspecific manner. If the anaesthetic drug possesses polar functional groups in addition to lipophilic ones, it may selectively affect membrane proteins and interact with them specifically. The absolute lipophilicity of a drug does not necessarily determine whether or not a drug is a suitable anaesthetic. Rather, it is important that the drug does not show undesirable side effects when it achieves a critical membrane concentration at which lipophilic interactions occur. There are examples of specific interactions of general anaesthetics with receptors as well as examples of nonspecific effects on membranes. Whether these interactions are important for anaesthesia remains to be seen.

[Interactions of intravenous anesthetics with human CNS ion channels. Electrophysiologic studies with a new type of voltage clamp technique]. / Interaktionen intravenöser Anästhetika mit menschlichen ZNS-Lonenkanälen. Elektrophysiologische Untersuchungen mit einer neuartigen Voltage-Clamp-Technik.

UNLABELLED: Despite a widespread approach to explain the molecular mechanisms of anaesthetic agents, the complex state of "general anaesthesia" is still not completely understood. Voltage-activated sodium channels from human brain cortex served as a model membrane protein to investigate anaesthetic drug-protein interactions using a novel electrophysiological voltage-clamp technique. Sodium channels are already well-characterized important integral membrane proteins responsible for the generation of the fast-propagated action potential and thus are vital components for neuronal signal integration and cell communication. In order to elucidate the molecular interactions of intravenous anaesthetics with single human brain sodium channels, representative compounds of four different clinical intravenous anaesthetic groups were used to correlate different types of clinical anaesthesia with differential anaesthetic effects on the molecular level. METHODS. Single sodium channels from human brain cortex were incorporated into artificial phospholipid bilayers and studied under our standard experimental conditions (Electrolyte solution: 500 mM NaCl, 10 mM HEPES, pH 7.4, Temp. 22-25 degrees C) with an electrophysiological voltage-clamp technique. In the presence of a channel activator (1 microM batrachotoxin) single-channel characteristics (fractional open time, single-channel conductance and amplitude, steady-state activation behaviour) were characterized for control conditions and in the presence of various doses of four different anaesthetic agents (pentobarbital, propofol, ketamine, midazolam). RESULTS. During control measurements the investigated human brain sodium channels showed stable and reproducible characteristics on the range expected for batrachotoxin-modified sodium channels in bilayers. After completion of the control measurement the effects of the four different general anaesthetics pentobarbital, propofol, ketamine and midazolam were investigated on the same control sodium channels. All four substances demonstrated a blocking effect of sodium channel conductance (pentobarbital: K50: concentration for 50% block of the maximal conductance block: 0.69 mM; blockmax: maximal conductance block (%): 100%; propofol: K50: 0.02 mM, blockmax: 28%; ketamine: K50: 1.1 mM, blockmax: 71%; midazolam: K50: 0.52 mM, blockmax: 100%). Furthermore, a destabilization of the steady-state activation process could be demonstrated. These effects were dose dependent, but only pentobarbital and propofol demonstrated these effects at or near clinically relevant serum concentrations. DISCUSSION: At the clinical level, "general anaesthesia" is a highly complex phenomenon. Similarly, anaesthetics may demonstrate a multimechanistic mode of action also at the molecular level. In this study all four investigated anaesthetic compounds interacted with at least two primary sodium channel functions, leading to a voltage-independent reduction of the fractional channel open time and an interaction with the steady-state activation behaviour, respectively. The effects of pentobarbital and propofol were detectable at concentrations within the range of serum concentrations achieved during clinical anaesthesia, whereas ketamine and midazolam demonstrated qualitatively similar effects exceeding this range 10- to 50-fold. Thus, the human brain sodium channel might serve as a molecular target only for pentobarbital and propofol. This suggests that different types of clinical anaesthesia may correlate with differential actions of anaesthetics on the molecular level.

Efficacy of methylprednisolone administration in a case of continuous abnormal muscle activity syndrome.

We report a 20-year-old woman with continuous abnormal muscle activity syndrome in which pharmacological blockade of different sites of the motor unit demonstrates a peripheral nerve origin for the abnormal muscle activity. The case showed no markers of autoimmune disease. A rapid recovery after high dose i.v. methylprednisolone was observed supporting the hypothesis of an autoimmune pathogenesis.

[Progressive hereditary dystonia with diurnal fluctuations: report of 2 cases]. / Distonía hereditaria progresiva con fluctuaciones diurnas: descripción de dos casos.

We report two patients with diurnally fluctuating hereditary progressive dystonia, that presented with dystonic movements and parkinsonian symptoms with marked diurnal fluctuations. There was a significant and maintained improvement of symptoms with small doses of L-Dopa. The pathogenesis of this disease could be a functional alteration of basal ganglia in the dopaminergic striatonigral region. The diurnal fluctuation of symptoms would be related to the circadian variation of tyrosine hydroxylase function.