Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial.

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol.

Pharmacodynamic response modelling of arterial blood pressure in adult volunteers during propofol anaesthesia.

BACKGROUND: Concentration effect relationships are commonly described with a direct response model as for example the sigmoid E(max) model with one effect compartment as site of action. In this study we investigated whether models with more than one effect site, or indirect response, or counter-regulatory response models may be more appropriate for modelling the propofol effect on arterial blood pressure. METHODS: Nine young healthy volunteers received propofol as target controlled infusion with predefined increasing and decreasing plasma target concentrations. Propofol concentrations were determined from arterial blood samples. Arterial blood pressure was measured invasively at radial artery site. Pharmacokinetic/-pharmacodynamic modelling was performed by population analysis with MONOLIX, testing different direct, indirect and counter-regulatory response models. RESULTS: Propofol plasma concentrations were well described by a three-compartment model. The propofol effect on arterial blood pressure was best described by a direct sigmoid E(max) model with two effect site compartments. CONCLUSIONS: Two effect sites were needed to describe the propofol effect on arterial blood pressure. This may reflect different pathways of arterial blood pressure response to propofol.

Influence of intensive care treatment on the protein binding of sufentanil and hydromorphone during pain therapy in postoperative cardiac surgery patients.

BACKGROUND: Our objective was to evaluate the effect of intensive care treatment on the protein binding of sufentanil and hydromorphone in cardiac surgery patients during postoperative analgesia using a target-controlled infusion (TCI) and patient-controlled analgesia (PCA). METHODS: Fifty adult patients were enrolled in this prospective randomized study; of which, 49 completed the study (age range 40-81 yr). Sufentanil was administered as an analgesic intraoperatively, and hydromorphone was dosed after operation with TCI and PCA until 8 a.m. on the first postoperative day. Arterial plasma samples were collected for drug and protein concentration measurements up to 24 h after cardiac surgery. Corresponding patient data were collected from the electronic patient data system. After explorative data analysis with principal component analysis, multivariate regression analysis and non-linear mixed effects modelling was used to study the effect of treatment on protein binding. RESULTS: Data of 35 patients were analysed. The median protein binding of sufentanil and hydromorphone was 88.4% (IQ range 85.7-90.5%) and 11.6% (IQ range 9.5-14.3%), respectively. Free fraction of sufentanil increased towards the end of the study period, whereas hydromorphone free fraction remained nearly constant. The total sufentanil concentration and volume balance were identified as significant covariates for the protein binding of sufentanil. For the protein binding of hydromorphone, no significant covariate effects were found. CONCLUSIONS: Sufentanil protein binding was significantly dependent on changes in the total drug concentration and volume balance addressing the importance of adequate dosing and fluid-guided therapy. Hydromorphone protein binding was nearly constant throughout the study period. CLINICAL TRIAL REGISTRATION: EudraCT 2011-003648-31 and ClinicalTrials.gov: NCT01490268.

High-dose remifentanil prevents development of thermal hyperalgesia in a neuropathic pain model.

BACKGROUND: Intraoperative nerve lesions can lead to chronic postoperative pain. There are conflicting data as to whether or not anaesthetics administered intraoperatively are beneficial. We investigated if remifentanil administered at the time of nerve injury was able to attenuate neuropathic hypersensitivity. METHODS: Rats were anaesthetized with isoflurane, endotracheally intubated, and a tail vein catheter was inserted. Rats received an i.v. infusion of either saline or low- or high-dose remifentanil (2 or 20 µg kg(-1) min(-1), respectively) for 20 min. During this time, rats received a spinal nerve L5 transection to induce neuropathic pain or a sham procedure. Behavioural tests to assess mechanical and cold allodynia and heat hyperalgesia were performed on postoperative days 1, 3, 7, 14, 21, and 28. RESULTS: Sham-operated animals exhibited no hypersensitivity regardless of the intraoperative remifentanil dose. In rats which received spinal nerve L5 transection, mechanical and cold allodynia developed with no significant differences between treatment groups. However, thermal hyperalgesia was reduced in rats given high-dose remifentanil: mean (standard deviation) area under the curve 426 (53) compared with 363 (34) and 342 (24) in saline or low-dose remifentanil treated rats, respectively (P<0.05). CONCLUSIONS: High-dose remifentanil administered at the time of transection of the spinal nerve at L5 prevents subsequent thermal hyperalgesia.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study.

BACKGROUND: Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS: We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS: Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS: Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.

BACKGROUND: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS: Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS: The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS: The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

[Dexmedetomidine. Pharmacokinetics and pharmacodynamics]. / Dexmedetomidin. Pharmakokinetik und Pharmakodynamik.

Dexmedetomidine is a highly selective, potent α2-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use.

Interaction of physostigmine and alfentanil in a human pain model.

BACKGROUND: Preclinical and clinical studies suggest an important role for cholinesterase inhibitors in pain therapy. The aim of this study was to examine the analgesic and antihyperalgesic properties of the cholinesterase inhibitor physostigmine and the opioid alfentanil, alone and in combination, in an experimental pain model in humans. METHODS: Twenty healthy volunteers were enrolled in this double-blind and placebo-controlled cross-over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities, measured on a numeric rating scale (NRS) from 0 to 10, and the extent of the hyperalgesic areas were assessed before, during, and 145 min after i.v. infusions of physostigmine (30 microg kg(-1) in 15 min), alfentanil (20 microg kg(-1) in 2 min), the combination of the same doses of both drugs, or saline 0.9%. The type of interaction was determined by fitting an interaction model to the data. RESULTS: Starting from a baseline value of NRS=6, the maximum reduction of pain intensity was 50.4 (sd 22.3) % after alfentanil, 35.4 (20.0) % after physostigmine, and 60.4 (17.1) % after the combination. The hyperalgesic areas were reduced by 53.8 (33.2) %, 47.0 (26.3) %, and 54.8 (33.2) %, respectively. The data were best described by a model assuming an infra-additive interaction for analgesic and antihyperalgesic effects. CONCLUSIONS: Physostigmine and alfentanil showed distinct effects on pain and hyperalgesia in a human pain model. The interaction of both drugs was found to be infra-additive.

[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.

Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children.

BACKGROUND: This study describes a pharmacodynamic model during general anaesthesia in children relating the bispectral index (BIS) response to the anaesthetic dosing of propofol, fentanyl, and remifentanil. METHODS: BIS, heart rate, mean arterial pressure, sedation scores, and anaesthetic protocols from 59 children aged 1-16 yr undergoing general surgery were considered for the study. Anaesthesia was performed with propofol, fentanyl, and remifentanil. A sigmoid model assuming additive interaction of propofol, fentanyl, and remifentanil was fitted to individual BIS as effect variable. The pharmacodynamic parameters were estimated by non-linear regression analysis. The ability of BIS to predict anaesthetic drug effect was quantified by the prediction probability Pk. RESULTS: BIS started at a baseline of 90 (9), decreased during induction to 30 (14) and remained at 57 (10) during anaesthesia. BIS predicted the anaesthetic drug effect with a Pk of 0.79 (0.08). The EC(50 Propofol) and the k(e0 Propofol) were 5.2 (2.7) microg ml(-1) and 0.60 (0.45) min(-1), respectively. The k(e0 Propofol) decreased from approximately 0.91 min(-1) at 1 yr to 0.15 min(-1) at 16 yr. The EC(50 Remifentanil), k(e0 Remifentanil), EC(50 Fentanyl), and the k(e0 Fentanyl) were 24.1 (13.0) ng ml(-1), 0.71 (0.32) min(-1), 8.6 (7.4) ng ml(-1), and 0.28 (0.46) min(-1), respectively. CONCLUSIONS: The effect equilibration half-time of propofol in children was age dependent. The pharmacodynamics of fentanyl and remifentanil in children were similar to those reported in adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in children older than 1 yr.

Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine.

OBJECTIVE: We investigated the pharmacokinetics of ketamine with special regard to enantiomer-specific differences. METHODS: Ten healthy young male volunteers (mean age, 28 +/- 4 years; mean weight, 79 +/- 11 kg) received racemic ketamine and S(+)-ketamine in a randomized double-blind crossover study. Drugs were administered by a computer-controlled device. Two infusion cycles with linearly increasing targets [slope, 0.1 microg x ml(-1) x min(-1) for S(+)-ketamine and 0.2 microg x ml(-1) x min(-1) for racemic ketamine] were administered. Concentrations of the ketamine enantiomers were determined from arterial blood, and pharmacokinetic parameters were estimated with a 2- and 3-compartment model. RESULTS: The total doses needed to reach defined end points were 271 +/- 80 mg and 409 +/- 75 mg for S(+)-ketamine and racemic ketamine, respectively (P <.05). S(+)-ketamine showed a significantly higher clearance (26.3 +/- 3.5 ml x kg(-1) x min(-1)) compared with racemic ketamine (14.8 +/- 1.7 ml x kg(-1) x min(-1); P <.05) and R(-)-ketamine (13.8 +/- 1.3 ml x kg(-1) x min(-1); P <.05). Furthermore, the clearance of the S (+)-ketamine was smaller in the racemate (18.5 +/- 0.7 ml x kg(-1) x min(-1); P <.05) than for the pure isomer. CONCLUSIONS: These results demonstrate that R(-)-ketamine inhibits the elimination of S(+)-ketamine.

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.

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.

The impact of intra-operative sufentanil dosing on post-operative pain, hyperalgesia and morphine consumption after cardiac surgery.

BACKGROUND: There is an ongoing debate whether opioids when used for intra-operative analgesia may enhance post-operative pain. We studied the effect of two different intra-operative dosings of sufentanil on post-operative morphine consumption, pain and hyperalgesia after cardiac anaesthesia. METHODS: Forty-two male patients (age: 48-74 years) undergoing first-time coronary artery bypass graft surgery were randomized to one of two groups receiving total intravenous anaesthesia with propofol and a target controlled infusion of sufentanil with a target of 0.4 ng/mL (group SL, n = 20) or 0.8 ng/mL (group SH, n = 22) plasma concentration. Post-operative morphine requirement in the first 48 h was assessed using patient-controlled analgesia (PCA). Pain rating during deep inspiration, and the extent of primary and secondary hyperalgesia near the sternotomy wound were assessed. RESULTS: The post-operative morphine requirements in the first 48 h were 0.68 ± 0.21 mg/kg in group SL and 0.96 ± 0.44 mg/kg in group SH (p < 0.05). In group SL, pain during deep inspiration was significantly lower on the first post-operative day (p < 0.05). Primary hyperalgesia had its maximum on the second and third post-operative day, without a difference between the two groups. The extent of secondary mechanical pinprick hyperalgesia was not different between the groups. DISCUSSION: Intra-operative dosing of sufentanil significantly influenced post-operative morphine consumption, pain and hyperalgesia. For cardiac anaesthesia in combination with propofol, a sufentanil target concentration of 0.4 ng/mL may be preferable.

Teletherapeutic drug administration by long distance closed-loop control of propofol.

BACKGROUND: The objective of this pilot study was to investigate the feasibility of an EEG-controlled closed-loop administration of propofol over a long distance of about 200 km. METHODS: We performed a teletherapeutic propofol infusion during total intravenous anaesthesia with propofol in 11 patients undergoing general surgery. The teletherapeutic system consisted of a computer at the patient site in Munich and a computer at the control site in Erlangen, which were connected via the internet through a virtual private network. The patient's EEG signal was sent to the control site computer, where the median frequency (MEF) of the EEG power spectrum was calculated. The propofol infusion, determined by a model-based adaptive feedback algorithm to maintain a MEF of 1.5 to 2 Hz, was sent to the patient site computer connected to the infusion pump. The quality of the control was assessed by the performance error defined as the percentage deviation of the measured MEF from the set point and the necessity of interventions by the anaesthetist at the patient site. RESULTS: During closed-loop administration of propofol [83 (52) min] the median performance error of the system was - 4.6 (4.4)% and the median absolute performance error was 18.8 (5.7)%. From a total number of 10 905 transmitted EEG epochs, there were five epochs with transmission errors, without further consequences for drug control. In one patient, teletherapy was stopped because the internet connection was interrupted. CONCLUSIONS: Teletherapeutic drug administration could be realized over a longer distance. Further studies have to investigate the practicability and safety of teletherapeutic drug control in anaesthesia.

[Pharmacodynamics of two different propofol formulations]. / Pharmakodynamik zweier unterschiedlicher Propofolformulierungen.

BACKGROUND: Propofol is nowadays available in various lipid formulations. We compared two different propofol formulations with respect to pharmacodynamics, using the EEG and clinical signs. MATERIALS AND METHODS: Ten volunteers received Diprivan 1% and Propofol 1% MCT Fresenius as a computer controlled infusion with increasing propofol target concentrations. A sigmoid E(max) model with effect compartment was estimated for the median frequency of the EEG power spectrum, based on measured arterial propofol plasma concentrations. Clinical pharmacodynamics were assessed by reaction on acoustic stimuli, eyelid reflex and corneal reflex. RESULTS: The drugs did not differ in pharmacodynamics with respect to EEG (EC(50) 2.1+/-0.6 for Diprivan and 2.1+/-0.5 microg/ml for Propofol Fresenius) and clinical signs. The pharmacodynamic model was characterized by a steep concentration effect relationship and a distinct hysteresis between propofol plasma concentration and effect (k(e0) 0.12+/-0.04 and 0.12+/-0.5 min(-1)). CONCLUSIONS: The investigated lipid formulations have no influence on the pharmacodynamics of propofol.

Development of acute tolerance to the EEG effect of propofol in rats.

BACKGROUND: A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect. METHODS: Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC. RESULTS: The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) microg ml(-1) at the beginning to 5.8 (3.8) microg ml(-1) at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg(-1) min(-1). The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg. CONCLUSIONS: The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

Population pharmacokinetics of propofol: a multicenter study.

BACKGROUND: Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. METHODS: The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. RESULTS: The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). CONCLUSIONS: Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects.

BACKGROUND AND OBJECTIVE: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance. METHODS: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect. RESULTS: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment. CONCLUSIONS: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.