[Target-controlled infusion. Clinical relevance and special features when using pharmacokinetic models]. / "Target-controlled infusion". Klinische Relevanz und Besonderheiten im Umgang mit pharmakokinetischen Modellen.

Since its commercial introduction in 1996, target-controlled infusion (TCI) has become an established technique for administration of intravenous anaesthetics. Modern TCI systems, however, are characterized by an increasing number of additional options and features, such as the choice between different pharmacokinetic models and modes of application, which may confuse the less experienced user. This review describes the differences between pharmacokinetic models, modes of application and the effect of covariates as well as the consequences for dosing. The aim is to explicate for the user of modern TCI systems the underlying scientific concepts and the relevance for clinical practice.

[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.

[Mobile computing in anaesthesiology and intensive care medicine. The practical relevance of portable digital assistants]. / Mobile-Computing in Anästhesie und Intensivmedizin. Zur praktischen Relevanz von Portable digital assistants.

Portable digital assistants (PDAs) may be of value to the anaesthesiologist as development in medical care is moving towards "bedside computing". Many different portable computers are currently available and it is now possible for the physician to carry a mobile computer with him all the time. It is data base, reference book, patient tracking help, date planner, computer, book, magazine, calculator and much more in one mobile device. With the help of a PDA, information that is required for our work may be available at all times and everywhere at the point of care within seconds. In this overview the possibilities for the use of PDAs in anaesthesia and intensive care medicine are discussed. Developments in other countries, possibilities in use but also problems such as data security and network technology are evaluated.

Propofol sparing effect of remifentanil using closed-loop anaesthesia.

BACKGROUND: General anaesthesia is a balance between hypnosis and analgesia. We investigated whether an increase in remifentanil blood concentration would reduce the amount of propofol required to maintain a comparable level of anaesthesia in 60 patients undergoing ambulatory surgery. METHODS: Patients were allocated randomly to receive remifentanil to a target blood concentration of 2 ng ml(-1) (low), 4 ng ml(-1) (medium), or 8 ng ml(-1) (high), administered by target-controlled infusion (TCI). After equilibration, propofol TCI was commenced in closed-loop control, with auditory evoked potentials (AEPex) as the input signal, aiming for an AEPex of 35. This was to ensure a comparable and unbiased level of anaesthesia in all patients. RESULTS: We found a dose-dependent decrease in propofol requirements with increasing remifentanil concentrations. The mean (95% CI) propofol target blood concentration during adequate anaesthesia was 4.96 (3.85-6.01) micro g ml(-1) in the low, 3.46 (2.96-3.96) micro g ml(-1) in the medium, and 3.01 (2.20-3.38) micro g ml(-1) in the high group. There was no significant difference when recovery end points were achieved between the groups. Cardiovascular changes were moderate, but most pronounced in the high concentration group, with a decrease in heart rate of 21% compared with baseline. The mean calculated effect site propofol concentration at loss of consciousness was 2.08 (1.85-2.32) micro g ml(-1), and at recovery of consciousness was 1.85 (1.68-2.00) micro g ml(-1). CONCLUSIONS: This study confirms a synergistic interaction between remifentanil and propofol during surgery, whereas the contribution of remifentanil in the absence of stimulation seems limited. In addition, our results suggest that the propofol effect site concentration provides a guide to the value at which the patient recovers consciousness.

Delivery performance of commercial target-controlled infusion devices with Diprifusor module.

BACKGROUND AND OBJECTIVE: We measured the physical performance error of commercial syringe pumps incorporating the Diprifusor module to deliver propofol by target-controlled infusion in a laboratory experiment. METHODS: Three infusion devices (Graseby 3500; Fresenius Vial Master TCI; Alaris TIVA-TCI) were studied when infusing propofol at six different target concentrations (1, 1.5, 2, 3, 5, 8 microg mL(-1)) over 10 min. This procedure was repeated five times to average each target. Precision measurements were based on the volume delivered and a mean performance error was calculated. RESULTS: The mean performance error bandwidth for all pumps was from -2.07 to 4.22% with a 95% confidence interval always <4.5%. There was a higher variability at lower target concentrations associated with lower infusion rates. The Alaris TIVA-TCI pump showed the largest overall bias whereas the Fresenius Vial Master TCI pump had the smallest divergence and the lowest variation across all target concentrations. The Graseby 3500 pump had the smallest range in mean performance error with an acceptable variation (95% CI <2%). CONCLUSIONS: Despite the differences between the pumps, which may be related to the synchronization of the hardware components, the absolute inaccuracies in the physical performance were low and presumably negligible from a clinical point of view.

[The effect of anesthetics on control of respiration]. / Einfluss von Anästhetika auf die Atemkontrolle.

Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control. Perioperative respiratory depression remains a serious clinical problem in perioperative medicine. This review will give an overview of ventilatory control and discuss the most relevant responses, describe the effects of pain, anaesthetics and opioids on ventilatory control and their interaction. The current body of knowledge is put into perspective to identify patients at risk for perioperative respiratory depression.

[Target controlled infusion (TCI)--status and clinical perspectives]. / Target Controlled Infusion (TCI)--Stellenwert und klinische Perspektiven.

The technique of target controlled infusion (TCI) has influenced the development of intravenous anaesthesia substantially and opens the possibility of many new and exciting applications in peri-operative anaesthetic care. The launch of "Diprifusor" as the first commercially available TCI system for propofol was the cornerstone of a successful research period within the last decade, which evaluated the pharmacokinetic foundations of computer assisted intravenous drug delivery. We are now in a period where TCI technology is becoming a part of routine anaesthesia technique for the practitioner rather than a research tool for specialists and enthusiasts. This review gives an update on the rational pharmacokinetic basis of TCI development, the preliminary clinical experience with the new technique, the performance and accuracy of TCI devices and potential technical pitfalls in clinical routine. Besides clinical application in anaesthesia with "Diprifusor" TCI, target controlled systems are expected to play a significant role as research tools in the evaluation of drug interactions in anaesthesia and in the development of novel control techniques for the administration of sedative and analgesic drugs in the peri-operative period.

The performance of electroencephalogram bispectral index and auditory evoked potential index to predict loss of consciousness during propofol infusion.

UNLABELLED: The bispectral index (BIS) of the electroencephalogram and middle latency auditory evoked potentials are likely candidates to measure the level of unconsciousness and, thus, may improve the early recovery profile. We prospectively investigated the predictive performance of both measures to distinguish between the conscious and unconscious state. Twelve patients undergoing lower limb orthopedic surgery during regional anesthesia additionally received propofol by target-controlled infusion for sedation. The electroencephalogram BIS and the auditory evoked potential index (AEPi), a mathematical derivative of the morphology of the auditory evoked potential waveform, were recorded simultaneously in all patients during repeated transitions from consciousness to unconsciousness. Logistic regression procedures, receiver operating characteristic analysis, and sensitivity and specificity were used to compare predictive ability of both indices. In the logistic regression models, both the BIS and AEPi were significant predictors of unconsciousness (P < 0.0001). The area under the receiver operating characteristic curve for discrete descending index threshold values was apparently, but not significantly (P > 0.05), larger for the AEPi (0.968) than for the BIS (0.922), indicating a trend of better discriminatory performance. We conclude that both the BIS and AEPi are reliable means for monitoring the level of unconsciousness during propofol infusion. However, AEPi proved to offer more discriminatory power in the individual patient. IMPLICATIONS: Both the bispectral index of the electroencephalogram and the auditory evoked potentials index are good predictors of the level of sedation and unconsciousness during propofol infusion. However, the auditory evoked potentials index offers better discriminatory power in describing the transition from the conscious to the unconscious state in the individual patient.

Interaction modeling of propofol and sufentanil on loss of consciousness.

STUDY OBJECTIVES: To examine the possible pharmacodynamic interaction of propofol and sufentanil with respect to the induction of loss of consciousness. DESIGN: Prospective, randomized, double-blinded study. SETTING: University hospital. PATIENTS: 30 female, ASA physical status I and II patients undergoing elective gynecologic surgery. INTERVENTIONS: Patients were allocated randomly to receive an individual combination of propofol (1, 2, 3, 4, 5, or 6 micrograms/ml) and sufentanil (0.1, 0.2, 0.3, 0.5, or 1.0 ng/ml) target blood concentrations using target-controlled infusions. MEASUREMENTS AND MAIN RESULTS: Study endpoint was loss of consciousness, which was tested by response to verbal commands and classified as responder or nonresponder, as assessed by the anesthetist, who was blinded to the drugs' target blood concentrations. Nonlinear association (interaction) of both drugs was accomplished with logistic regression analysis using the maximum likelihood method, based principally on the hypothesis of interaction: In [p/(1-p)] = beta 0 + beta 1 x Cprop + beta 2 x Csuf + beta 3 x Cprop x Csuf with a p-value < 0.05 for coefficient estimates considered significant. In the logistic regression model, sufentanil and propofol showed no supra-additive interaction regarding loss of consciousness (p = 0.5916). CONCLUSIONS: Our results give no evidence of additional hypnotic properties of sufentanil compared to the other fentanyl congeners, although logistic regression may be of limited value in modeling interaction of hypnotic-analgesic combinations.

Lack of rapid development of opioid tolerance during alfentanil and remifentanil infusions for postoperative pain.

UNLABELLED: Studies in animals and volunteers have suggested the development of acute tolerance to opioid analgesics. In this article, we present data from patients who regulated their own target-controlled infusions of alfentanil and remifentanil to provide analgesia in the immediate postoperative period. Fifty-one patients received alfentanil for 24 h after cardiac surgery, and 30 patients received remifentanil for 6 h after orthopedic surgery. Satisfactory analgesia, defined as a rating of < or =3 on an 11-point visual analog scale, was obtained by patients after each type of surgery. The target concentrations of the opioids required to produce postoperative analgesia and the cumulative opioid doses administered over the course of the clinical observation suggest there was no tolerance to the analgesic effects of the opioids. The requirements for both analgesic drugs in individual patients had a large variation (>200%). We conclude that our results may indicate an absence of tolerance to opioids in postoperative analgesia. Nonetheless, our data show that the postoperative requirement for these rapidly acting drugs is qualitatively similar to that for other opioids in that dosage escalation does not occur. IMPLICATIONS: The development of acute tolerance to opioid analgesics has been suggested based on experimental studies in animals and volunteers. Our report from patients who self-controlled their analgesic requirements by using target-controlled infusions of alfentanil and remifentanil for postoperative analgesia provides no evidence of tolerance to opioids.

Patient-maintained remifentanil target-controlled infusion for the transition to early postoperative analgesia.

We studied 30 male patients in the early postoperative period to assess the efficacy, safety and feasibility of a patient-demand, target-controlled infusion (TCI) of remifentanil. All patients received the same TCI-based propofol-remifentanil anaesthetic for elective orthopaedic surgery. At the end of surgery, infusion of remifentanil was reduced progressively until patients were breathing spontaneously. After extubation and transfer to the post-anaesthesia care unit, patients were given control of a hand-set and were able to increase the target remifentanil blood concentration by increments of 0.2 ng ml-1. If there were no demands, the TCI controller automatically reduced the target concentration. Pain scores, sedation level, ventilatory frequency, oxygen saturation and nausea were assessed. Mean time to onset of satisfactory analgesia (VAS < or = 3, out of 10) was 18.9 (95% confidence interval (Cl) 15.8-21.9) min at a mean target remifentanil concentration of 2.02 (Cl 1.87-2.16) ng ml-1. There were no episodes of hypoxaemia and the lowest ventilatory frequency was 9 bpm. Nausea occurred in 26.6% of patients and 10% vomited. The majority of patients were only slightly sedated. These results imply an effective tool without respiratory side effects in the early postoperative period after anaesthesia using remifentanil as the analgesic component.

Clinical utility of EEG parameters to predict loss of consciousness and response to skin incision during total intravenous anaesthesia.

We studied 30 female patients undergoing elective surgery, to assess the reliability of electroencephalogram spectral edge frequency and median frequency to predict loss of consciousness and movement in response to skin incision during total intravenous anaesthesia. Each patient received a different combination of propofol (1, 2, 3, 4, 5 or 6 micrograms.ml-1) and sufentanil (0.1, 0.2, 0.3, 0.5 or 1.0 ng.ml-1) target concentrations for induction of anaesthesia using target controlled infusions, assigned randomly. In a logistic regression model, spectral edge frequency was a significant determinant of both loss of consciousness (p = 0.0006) and movement to skin incision (p = 0.0044), whereas for median frequency no significant prediction model could be established. The probabilities of 50% and 95% no response for spectral edge frequency were 13.4 Hz and 6.8 Hz, respectively. The variability of the data limited the predictive value, so that spectral edge frequency was a poor predictor and median frequency was no predictor of response in the individual patient during total intravenous propofol/sufentanil anaesthesia.

[The effect of total intravenous anesthesia with propofol, alfentanil and vecuronium (TIVA) on bronchial mucosal transport]. / Effekt einer total intravenösen Anästhesie mit Propofol, Alfentanil und Vecuronium (TIVA) auf den bronchialen Schleimtransport.

PURPOSE: The mucociliary escalator of the lung is an important protective transport system by means of which inhaled particles and microorganisms are removed from the tracheobronchial system. In the present prospective study the effect of total intravenous anaesthesia with propofol, alfentanil, vecuronium, and oxygen-air ventilation on bronchial mucus transport velocity (BTV) was investigated. METHOD: 10 patients undergoing major abdominal surgery were included in the study. In all patients anaesthesia was induced and maintained with propofol, alfentanil, and vecuronium. Ventilation was assisted with a mixture of air and oxygen (FiO2:0.35). The BTV was measured preoperatively in the conscious patients one day before surgery while they received local anaesthesia with 10 ml of 1 percent lidocaine and after the end of the operation during intubation anaesthesia. BTV was determined with a small volume of albumin microspheres labelled with technetium -99m, which was deposited on the dorsal surface at the lower ends of the right and left main bronches via a catheter placed in the inner channel of a fibre-optic bronchoscope [7]. The study was approved by the ethics committee of our hospital. RESULTS: The administered dose of propofol was 3.0 g (1.8-5.5), of alfentanil 26 mg (20-50), and of vecuronium 20 mg (16-34) (median with range). The duration of mechanical ventilation up to the time of measurement was 5 h (3.0-9.5). TIVA produced a decrease of BTV in the right (9.7 vs 4.9 mm/min) and left main bronchus (11.3 mm/min vs 5.3 mm/min). CONCLUSIONS: Total intravenous anaesthesia with propofol, alfentanil, and vecuronium depressed mucociliary flow in patients with healthy lungs. The period for recovery of mucociliary clearance and the possible disadvantage in patients with increased pulmonary risk (e.g. patients with chronic bronchitis and abdominal surgery) should be clarified in further studies.

Recovery from opioid anesthesia: the clinical implication of context-sensitive half-times.

UNLABELLED: The context-sensitive half-time, the time required for a 50% decrease in drug concentration, has been proposed to predict the speed of recovery after infusions of i.v. anesthetics. We studied 40 patients to compare the clinical recovery characteristics of alfentanil and sufentanil. Patients were randomly allocated to receive either sufentanil/propofol (Group 1) or alfentanil/propofol (Group 2) total i.v. anesthesia by target-controlled infusions (TCI), assuming an equipotency ratio of 500:1. After discontinuation, times to tracheal extubation and to discharge from the postanesthesia care unit were measured, as were drug concentrations up to 24 h. The TCI bias was -17.1% for sufentanil and -16.9% for alfentanil. We found no difference in mean extubation times between the groups (48.7 min in Group 1 versus 46.4 min in Group 2), whereas discharge criteria were fulfilled significantly (P = 0.039) earlier after alfentanil (99.5 min) compared with sufentanil (131.3 min). The relative decrement values to tracheal extubation were 62.1% for sufentanil and 48.0% for alfentanil, compared with 75.7% and 65.0% for discharge, respectively. Based on a difference in propofol requirements, we suggest an actual sufentanil to alfentanil equipotency ratio of 1:300. We conclude that the decay in pharmacodynamic effect is not only the result of pharmacokinetics. IMPLICATIONS: Computer simulations may help to anticipate the clinical behavior of anesthetic drugs. In a clinical setting, we tested whether the recovery characteristics after i.v. anesthesia could be explained by a pharmaco-kinetic value, which describes the decline of drug concentrations in the body. This was not fully achieved.

Perioperative respiratory events in smokers and nonsmokers undergoing general anaesthesia.

BACKGROUND: The prevalence of respiratory diseases in smokers and nonsmokers and the incidence of perioperative respiratory events (PREs) were investigated for patients undergoing general anaesthesia. The aim was to quantify well-known problems and to identify possible new associations between smoking and PREs. METHODS: From July 1992 to December 1994, risk factors, demographic data, and PREs were documented by an automatically readable anaesthetic record (ARAR). PREs were used as defined by the German Society of Anaesthesiology and Intensive Care. RESULTS: Of 26961 subsequent anaesthesias in adults, 7122 (26.4%) were performed in smokers with a prevalence of chronic bronchitis of 23.3% (4.8% in nonsmokers). 1573 PREs occurred in 1397 (5.2%) of all anaesthetics. 459 events concerned intubation problems and problems in technical airway management. 1114 specific respiratory events (SPREs) like re-intubation, laryngospasm, bronchospasm, aspiration, hypoventilation/hypoxaemia and others had a total incidence of 5.5% in smokers and 3.1% in nonsmokers. The relative risk (RR) of SPREs was 1.8 in all smokers, 2.3 in young (16-39 years) smokers, and 6.3 in obese young smokers. The RR of perioperative bronchospasm was 25.7 in young smokers with chronic bronchitis. CONCLUSION: The impact of smoking on perioperative respiratory problems should make anaesthetists take this widespread preoperative condition seriously, particularly in young adults. The presented method of incident reporting (based on a national classification) could contribute to future research in anaesthetic epidemiology.

The role of ascorbic acid and xylitol in etomidate-induced adrenocortical suppression in humans.

Etomidate-induced suppression of cortisol biosynthesis is a result of a blockade of 11-beta-hydroxylation in the adrenal gland, mediated by the imidazol radical of etomidate. Since the generation of steroids requires reductive and energy rich equivalents, the present study examined whether supplementation with ascorbic acid or xylitol, a major source of NADPH, could attenuate adrenal suppression by etomidate in human subjects by promoting the turnover rate of 11-beta-hydroxylase. During continuous etomidate/alfentanil anaesthesia for pelviscopic surgery 30 female patients received either Ringer's lactate, xylitol (0.25 g kg-1 h-1) or ascorbic acid (0.5 g h-1) intravenously (i.v.). The plasma concentrations of cortisol, aldosterone and dehydroepiandrosterone (DHEA) were recorded for 5 h after end of surgery and a stimulation with synthetic ACTH was performed. The results showed no evidence of a clinically relevant attenuating effect of ascorbic acid or xylitol on etomidate-induced adrenocortical suppression. However, the observed suppression of cortisol levels was not enough to allow an attenuating affect to be measured.