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BACKGROUND: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia. OBJECTIVE: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion. DESIGN: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study. SETTING: University Hospital, Germany from January 2012 to April 2012. PARTICIPANTS: Twenty-one healthy male volunteers. INTERVENTIONS: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 µg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min. MAIN OUTCOME MEASURES: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min. RESULTS: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P 

Background The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative. Objective To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone. Design Single-blinded, randomised trial. Setting University Hospital, Germany from December 2013 to April 2015. Participants Fifty adults undergoing cardiac surgery. Interventions Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study. Main outcome measures NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects. Results NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ± 6 min during TCI-PCA, compared with 19 ± 4 min during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46). Conclusion TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice. Trial registration EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.

Background Remimazolam (CNS 7056) is a new ultra–short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. Methods Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated. Results Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer’s Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer’s Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed. Conclusions Remimazolam was characterized by a pharmacokinetic–pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion. Methods Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index. Results EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma–effect equilibration times. Conclusions Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Objective Evaluate the accuracy and trending ability of the fourth-generation FloTrac/EV1000 (Edwards Lifesciences, Irvine, CA) system in patients with severe aortic valve stenosis by comparing FloTrac/EV1000-derived cardiac output (CCO-FT) with continuous thermodilution pulmonary artery catheter (CCO-PAC) measurements before and after surgical valve replacement. Design Prospective clinical study. Setting Anesthesia for cardiac surgery, operating room, single-center university hospital. Participants Twenty-five patients were included. After exclusion, 20 patients undergoing elective aortic valve replacement were analyzed. Interventions After induction of general anesthesia, CCO-FT and CCO-PAC values were recorded every 30 seconds before and after aortic valve replacement with a bioprosthesis under cardiopulmonary bypass (CPB). Measurements and Main Results Data were analyzed separately from skin incision to last suture and before and after CPB. Regression analyses, Bland-Altman analyses, and trending analyses (4-quadrant plot, polar plot) were performed. The percentage errors of the FloTrac/EV1000 were 69.7% and 59.3% before and after CPB, respectively. The concordance rates (CRs) and angular CRs of the FloTrac/EV1000 were 50.9% and 57.1%, and 48.7% and 61.9% before and after CPB, respectively. Conclusion This study revealed a low level of agreement and poor trending ability of the FloTrac/EV1000 system compared to continuous thermodilution pulmonary artery catheter in patients with severe aortic stenosis. Although there was a slight improvement after surgical valve replacement and CPB, the results were not within acceptable limits to replace CCO-PAC in this patient population.

Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery patients during postoperative analgesia. Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Data from twenty-one patients (aged 44–79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V1) = 8.1±2.2 L, steady-state volume of distribution (Vss) = 207±83 L, terminal elimination half-life (T1/2γ) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V1 = 5.5±0.8 L, Vss = 15.8±0.8 L, T1/2β = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate. The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine. Clinical Trials NCT02483221 (June 26, 2015).

Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients. Thirty-nine children aged 1–9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1–2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models. Data of 36 patients (age 1–9 years, weight 10–27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3–41.1) l/h, central volume of distribution 84.3 (70.3–91.4) l, intercompartmental clearance 82.8 (63.6–136.6) l/h, peripheral volume of distribution 114 (95–149) l, and terminal half-life 4.4 (3.6–5.3) h. Age did not show any influence on weight-adjusted parameters. Chinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians. ChiCTR-OPC-14005659.

Background Several anatomical factors, such as prognathism, sex, short thyromental distance and others are known to make direct laryngoscopy difficult. Objective We investigated the hypothesis that the anatomical position of the vocal cords in relation to the cervical vertebrae correlates with difficult laryngoscopy. Existing MRI was used to identify the position of the vocal cords relative to the cervical spine in patients with and without difficult laryngoscopy. Design Observational study with adaptive enrichment. Setting University hospital. Patients A total of 142 adult patients, 91 with easy (Cormack-Lehane class 1 or 2) and 51 with difficult (Cormack-Lehane class 3 or 4) laryngoscopy. Main outcome measures Position of the vocal cords relative to cervical vertebrae in patients with easy vs. difficult laryngoscopy. Results In patients with difficult laryngoscopy, we found a higher incidence of cranial position of the vocal cords in relation to the cervical spine compared with patients with easy laryngoscopy (P Conclusion Anaesthesiologists should take advantage of existing imaging of the cervical spine when assessing the patient's airway.

We recently developed a new population pharmacokinetic model for hydromorphone in patients including age and bodyweight as covariates. The aim of the present study was to evaluate prospectively the predictive performance of this new model during postoperative pain therapy. This was a prospective, single-blinded, randomized, single-center study with two parallel arms. Fifty patients aged 40–85 years undergoing cardiac surgery involving thoracotomy were enrolled. Hydromorphone was administered postoperatively on the intensive care unit as target controlled infusion (TCI) for patient controlled analgesia (TCI-PCA) using the new pharmacokinetic model, or as conventional patient controlled analgesia (PCA). Arterial blood samples were taken for measurement of the hydromorphone plasma concentration. The predictive performance of the pharmacokinetic model was assessed by the median performance error (MDPE), the median absolute performance error (MDAPE), wobble and divergence. For comparison, the performance indices were also determined for three older models from the literature. 903 plasma concentrations of 41 patients were analyzed. The mean values (95 % CI) of MDPE, MDAPE, wobble and divergence for the new pharmacokinetic model were 11.2 % (3.9 to 18.7 %), 28.5 % (23.9 to 33.0 %), 21.4 % (18.0 to 24.9 %) and −1.6 %/h (–2.3 to –0.8 %/h). When compared with older models from the literature, performance was better with less overshoot after bolus doses. The new pharmacokinetic model of hydromorphone showed a good precision and a better performance than older models. It is therefore suitable for TCI with hydromorphone during postoperative pain therapy. EudraCT 2013-002875-16, Clinical Trials NCT02035709.

Background Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone. Methods Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations. Results Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml). Conclusion TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

BackgroundSufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs.MethodsTwenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within ± 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements.ResultsData from 20 animals were analyzed. The cardiac outputs (means ± SD) were 2.9 ± 0.7, 5.4 ± 0.7, and 9.6 ± 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 μg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively.ConclusionsCardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected.

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.

Background Crohn's disease (CD) is a painful chronic inflammatory bowel disease. It primarily affects terminal ileum, but the involvement of large and small intestines or extraintestinal manifestations is very common. CD may go along with neurogenic inflammation, mediated by substance P and CGRP, which are also key players in pain transmission. This may in turn contribute to hyperalgesia and altered somatosensory function in CD. Methods One hundred and three (103) patients with CD and 80 healthy volunteers were enrolled. Patient characteristics and disease history were documented. We used quantitative sensory testing (QST) to investigate the somatosensory profile in patients and volunteers. We also calculated z-scores for the QST results of the patients with CD based on the data of our control group. A 2-step cluster analysis, using all QST data, was performed to find subgroups within patients and volunteers. Results Thresholds of warm detection, mechanical pain, and vibration detection did significantly differ between patients with CD and volunteers. Z-scores indicated a general trend of sensory loss in CD patients with a significant relationship between patients with a sensory loss for cold and warm detection. In the hyposensitive cluster of the CD cohort, patients were more frequently male, had a higher incidence of extraintestinal manifestations, and suffered longer from CD. Conclusions Our findings are consistent with the presence of a subclinical small fiber neuropathy. The group of CD patients with pronounced neuropathy findings were predominantly males, had a higher incidence of extraintestinal manifestations, and tended to have a longer history of disease duration.

ObjectivesPostictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population.MethodsThe study included 14 patients that underw

Objective Previous investigations reported a higher incidence of poor laryngoscopic views in pediatric patients undergoing cardiac surgery. The objective of this study was to analyze why children undergoing cardiac surgery have such an increased incidence of poor laryngoscopic views during anesthesia induction. Design This study was designed as a retrospective analysis. Setting This analysis was based on a single-center cohort of a university hospital. Participants One thousand one hundred seventy-seven general anesthesia procedures, including a direct laryngoscopic view over a period of 6 consecutive years, in pediatric patients undergoing cardiac surgery. Interventions Because of the retrospective character of this study, there were no study-related interventions. Measurements and Main Results Poor laryngoscopic views were defined as Cormack and Lehane (CML) grade III and IV. The overall incidence of poor laryngoscopic views was 3.5%. In patients younger than 1 year of age, the incidence of CML III or IV was significantly higher than in the older patients (5.6% v 1.7%). None of the patients with CML III/IV findings had Down syndrome; whereas in 9 of 41 patients with CML grade III/IV, a concomitant congenital syndrome like DiGeorge syndrome or CHARGE syndrome was found. Conclusions The general incidence of CML III/IV findings during the induction of anesthesia for pediatric cardiac surgery is more than twice as high as reported in unselected pediatric cohorts. In patients below 1 year of age and in male patients, difficult laryngoscopy is more frequent. Concomitant Down syndrome was not associated with difficult laryngoscopy.

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 Conclusions High-dose remifentanil administered at the time of transection of the spinal nerve at L5 prevents subsequent thermal hyperalgesia.

A method for a sensitive and specific analysis of hydromorphone total and unbound drug concentrations in human plasma was developed and validated. Sample preparation was preceded with an ultrafiltration step to separate the unbound drug from the protein bound fraction of hydromorphone. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with stable isotope-labeled hydromorphone that was used as internal standard. Chromatographic separation was performed by gradient elution with UPLC-like system and eluates were analyzed by tandem mass spectrometry equipped with an electrospray ionization source. Sample preparation was optimized for good recovery of hydromorphone and the results were consistent. Calibration curves demonstrated linearity in the concentration range of 78–5000 pg/ml for analysis of both total and unbound concentrations of hydromorphone. The limit of detection was 1 pg and the lower limit of quantification was 78 pg/ml for both total and unbound hydromorphone plasma drug concentrations. Intra- and interassay reproducibility and inaccuracy did not exceed 10%. Hydromorphone was on the average 14% bound to plasma proteins, supporting the previously published unreferenced statements that the protein binding of hydromorphone is low. Method was applied to a clinical trial in patients undergoing open heart surgery to generate a target controlled infusion model for the postoperative patient controlled analgesia with hydromorphone.

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.

There is controversy about combining opioids with different receptor affinities. We assessed the analgesic and antihyperalgesic effects of the μ-agonist fentanyl and the partial μ-agonist/κ-antagonist buprenorphine in a human pain model, when given alone or in combination.: Fifteen healthy male volunteers (22 to 35 y) were included in this randomized, double-blind, placebo-controlled, cross-over study. Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of secondary hyperalgesia. Pain intensities, measured on a numeric rating scale from 0 to 10, and the size of the hyperalgesic areas were assessed before, during, and after an intravenous infusion of 1.5 µg/kg fentanyl, 1.5 µg/kg buprenorphine, a combination of 0.75 µg/kg fentanyl and buprenorphine each, or saline 0.9%. Maximum effects of the treatments were compared by repeated measurement analysis of variance, and pharmacodynamic interaction models were fitted to the data.: Starting from a baseline value of numeric rating scale=6, the maximum reduction of pain intensity after correction for placebo effects was 43.9 ± 22.2% after fentanyl, 35.0 ± 23.0% after buprenorphine, and 39.4 ± 20.8% after the combination (mean ± SD, P=0.24). The maximum reduction of the hyperalgesic area was 38.3 ± 39.0% for fentanyl, 34.4 ± 32.7% for buprenorphine, and 30.0 ± 53.8% for the combination (mean ± SD, P=0.82). The time courses were best described by pharmacodynamic models assuming an additive interaction.: For the doses administered in this study, buprenorphine and fentanyl showed an additive interaction.

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

Background Dexmedetomidine is a highly selective and potent α2-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.

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.

Summary Objective: Difficult laryngoscopy in pediatric patients undergoing anesthesia. Aim: This retrospective analysis was conducted to investigate incidence and predictors of difficult laryngoscopy in a large cohort of pediatric patients receiving general anesthesia with endotracheal intubation. Background: Young age and craniofacial dysmorphy are predictors for the difficult pediatric airway and difficult laryngoscopy. For difficult laryngoscopy, other general predictors are not yet described. Methods: Retrospectively, from a 5-year period, data from 11.219 general anesthesia procedures in pediatric patients with endotracheal intubation using age-adapted Macintosh blades in a single center (university hospital) were analyzed statistically. Results: The overall incidence of difficult laryngoscopy [Cormack and Lehane (CML) grade III and IV] was 1.35%. In patients younger than 1 year, the incidence of CML III or IV was significantly higher than in the older patients (4.7% vs 0.7%). ASA Physical Status III and IV, a higher Mallampati Score (III and IV) and a low BMI were all associated (P

A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of sufentanil total and unbound drug concentrations. Unbound drug was separated by an ultrafiltration step before sample preparation. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated sufentanil used as an internal standard. Separation was performed by gradient elution using UPLC-like system and analysed by MS/MS consisting of an electrospray ionization source. Calibration curves showed linearity in the concentration range of 5-2500 pg/ml for analysis of both total and unbound concentrations of sufentanil. The lower limit of quantification was 5 pg/ml for both total and unbound sufentanil plasma drug concentrations. Intra- and interassay precision and accuracy did not exceed 15%. Method was applied to pharmacokinetic study in patients undergoing coronary artery bypass grafting.

Background Propofol (Disoprivan, AstraZeneca AG, Zug, Switzerland) has long been considered to be nonanalgesic. However, accumulating evidence shows that propofol possesses modulatory action on pain processing and perception. In this study, the authors investigated the modulatory effects of propofol and a formulation similar to the solvent of propofol (10% Intralipid; Fresenius Kabi, Stans, Switzerland) on pain perception and central sensitization in healthy volunteers. Methods Fourteen healthy volunteers were included in this randomized, double-blind, placebo-controlled, crossover study. Intracutaneous electrical stimulation (48.8 +/- 25.8 mA) induced spontaneous acute pain (Numeric Rating Scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia were assessed regularly before, during, and after a 45-min target-controlled infusion (2 microg/ml) of propofol, the solvent 10% Intralipid, and saline. Results During administration, propofol significantly decreased pain scores and areas of hyperalgesia and allodynia compared with both 10% Intralipid and saline (placebo-corrected mean Numerical Rating Scale score reduction by propofol: 38 +/- 28%). This difference disappeared shortly after cessation of the infusion. Thereafter, no significant group differences were observed in the Numerical Rating Scale score and the areas of hyperalgesia or allodynia. However, there was a trend to reduced hyperalgesia and allodynia after propofol treatment. Pharmacodynamic modeling regarding the analgesic effect of propofol showed an EC50 (half-maximum effect site concentration) of 3.19 +/- 0.37 microg/ml. Ten percent Intralipid was free of pain-modulatory effects in the authors' experiments. Conclusions Propofol showed short-lasting analgesic properties during its administration, whereas the solvent-like formulation 10% Intralipid had no effect on pain perception.

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 µg kg −1 in 15 min), alfentanil (20 µg 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.

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) μg 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.

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.

For the quantification of propofol total and unbound drug concentrations a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. To separate unbound propofol an ultrafiltration step before sample preparation was performed. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated propofol as an internal standard. Separation was performed by gradient elution using UPLC-like system and analyzed by MS/MS consisting of an electrospray ionization source. To detect low and high concentration levels of propofol two calibration curves were identified and showed linearity within the range of 1-50ng/ml and 50-20000ng/ml. The lower limit of quantification was 1ng/ml. Intra- and interassay precision and accuracy did not exceed ±15%. The method was applied to a clinical study during intensive care treatment of patients after coronary artery bypass grafting.

International audience; Background: Concentration effect relationships are commonly described with a direct response model as for example the sigmoid Emax 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 Emax 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.

We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive. Perspective Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.

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) μg ml−1 at the beginning to 5.8 (3.8) μg ml−1 at 90 min [mean ( sd ), P Conclusions The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

BACKGROUND GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion. METHODS In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 microg/ml. Subsequently, the targets were reduced to 3 microg/ml and 1.5 microg/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data. RESULTS Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 microg/ml for GPI 15715 and 3.0 +/- 0.7 microg/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect. CONCLUSIONS Compared with propofol emulsion, propofol from GPI 15715 showed different pharmacokinetics and pharmacodynamics, particularly a higher potency with respect to concentration. These differences may indicate an influence of the formulation.

Aims We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. Methods Nine young (24–28 years) and nine elderly (67–81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml−1 min−1 for midazolam, 3 and 1.5 ng ml−1 min−1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum. Results The concentration–effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3–91.6%) and 37% (5.3–69.5%); Ro 48-6791, 22% (−2.8% to 44.6%) and 43% (3.4–82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results. Conclusion Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

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

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 μg · ml−1 · min−1 for S(+)-ketamine and 0.2 μg · ml−1 · 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 · kg−1 · min−1) compared with racemic ketamine (14.8 ±1.7 ml · kg−1 · min−1; P < .05) and R(−)-ketamine (13.8 ±1.3 ml · kg−1 · min−1; P < .05). Furthermore, the clearance of the S(+)-ketamine was smaller in the racemate (18.5 ±0.7 ml · kg−1 · min−1; P < .05) than for the pure isomer. Conclusions These results demonstrate that R(−)-ketamine inhibits the elimination of S(+)-ketamine. Clinical Pharmacology & Therapeutics (2001) 70, 431–438; doi: 10.1016/S0009-9236(01)06321-4

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.

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.

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.

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

Seit April 1997 ist in Deutschland ein TCI-System fur Propofol (Disoprifusor-TCI®) kommerziell erhaltlich. Wir haben Pradiktivitat und Prazision dieses Systems untersucht und mit dem Bias, der Prazision, dem Propofolverbrauch und dem Blutspiegelverlauf einer manuell gesteuerten Infusion verglichen. Methode: 21 Patienten erhielten randomisiert eine intravenose Anasthesie mit Propofol entweder als manuell gesteuerte Infusion oder als TCI. Blutplasmaspiegel wurden mittels HPLC bestimmt. Ergebnisse: Fur das untersuchte TCI-System ergab sich eine Prazision von 27,5% und ein Bias von 6,7%. In der manuellen Gruppe betrug der Bias 44,2% und die Prazision 50%. Die durchschnittlich infundierte Propofolmenge (9,0 ± 1,2 vs. 6,6 ± 1,2 mg/kg/h, p

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±91ml min -1 for midazolam (mean ± SD; P

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 NON-MEM® 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 pCO 2 was analysed every 6 min. Results. The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75±0.221 min -1 ), small volumes of distribution (Vc=7.7 ± 3.4 I; Vdss=92 ± 22 1) and relatively short half-lives (t 1 / 2α = 1.5±0.6 min; t 1/2β =27±5 min; t 1/2γ =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

Objective To determine safety and efficacy of the water-soluble prodrug fospropofol for anesthesia in cardiac surgery and to compare the pharmacodynamic profiles of fospropofol and propofol. Design Pilot study and a prospective, phase I, open-label, single-center, randomized clinical trial. Setting University hospital; single institution. Participants Sixteen patients undergoing elective first-time coronary artery bypass surgery. Interventions Patients were randomized to receive total intravenous anesthesia with fospropofol (n = 8) or propofol (n = 8) combined with alfentanil as total intravenous anesthesia. Bispectral index, arterial blood pressure, and heart rate were recorded continuously, and pulmonary artery catheter measurements were obtained. Plasma concentrations of formate, phosphate, and Ca2+ were monitored closely. Safety and tolerability were assessed by adverse events, neurologic examinations, clinical laboratory tests, and vital signs. Measurements and Main Results The total doses of fospropofol and propofol during anesthesia were 11.3±2.5 and 4.4±1.0 mg/kg/h, respectively. According to the achieved bispectral index (BIS) values, fospropofol was as effective as propofol in providing general anesthesia and sedation. There were no clinical signs of formate toxicity in the fospropofol group. The only treatment-related adverse event after administration of fospropofol was a transient burning sensation in the perineal and perianal region during induction of sedation or anesthesia. Conclusions Fospropofol could be used to provide general anesthesia in patients undergoing coronary artery bypass graft surgery. Further larger studies are needed to prove the safety of fospropofol when given to provide general anesthesia for major cardiac surgical procedures.

Topical application of lidocaine is an effective approach for treatment of post-herpetic neuralgia and other painful neuropathies. Lidocaine inhibits voltage-gated Na(+) channels and it most likely reduces excitability of cutaneous sensory neurons which can be hyperexcitable or spontaneously active in states of neuropathic pain. However, lidocaine and other local anesthetics also exert a pronounced neurotoxicity and they activate the irritant receptors TRPV1 and TRPA1. In this randomized and double-blinded study, we explored the ability of lidocaine patches (5%) to alter sensory function and epidermal nerve fiber density in skin of healthy volunteers. As assessed by quantitative sensory testing, significantly elevated thresholds for touch, pin prick pain and mechanically induced wind-up were observed in skin treated with lidocaine patches. These effects reversed to baseline values within 2days after termination of the treatment. Pressure pain and thresholds for heat and cold-induced pain were not affected by the lidocaine patch. A moderate but significant decrease in epidermal nerve fiber density was observed in skin blister roofs obtained after 42days of treatment with lidocaine patches. The placebo patch did not induce any changes in sensory thresholds or nerve fiber density. In conclusion, lidocaine patches seem to have differential effects on sensory modalities in healthy skin. A degeneration of epidermal nerve fibers has previously been demonstrated for patches containing the TRPV1-agonist capsaicin and our findings suggest that this effect might also be relevant for lidocaine patches. These data warrant further studies on molecular mechanisms mediating a relief of neuropathic pain by topical lidocaine.

Background Studies with nondepolarizing neuromuscular blocking agents showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy. The objective of this study was to investigate if these alterations depend on disease progression. Methods The authors studied 11 children (6-9 yr) with moderate Duchenne muscular dystrophy, 11 adolescents (12-16 yr) with advanced Duchenne muscular dystrophy, and 2 age-matched control groups of 8 patients each (5-9 and 10-17 yr). Anesthesia was performed with propofol and remifentanil. Patients received a single intravenous dose of 0.2 mg/kg mivacurium. Neuromuscular transmission was monitored by acceleromyography. The time course of neuromuscular blockade was characterized by the onset time and the times to different levels of recovery. Results Onset and duration of neuromuscular blockade were significantly prolonged in adolescent Duchenne muscular dystrophy patients (onset time, 4.0 min; recovery index, 12.3 min; median), as compared with Duchenne muscular dystrophy children (onset time, 2.3 min; recovery index, 6.8 min), and also as compared with young controls (onset time, 2.0 min; recovery index, 4.4 min) and adolescent controls (onset time, 2.5 min; recovery index, 4.8 min). Within the Duchenne muscular dystrophy patients, onset time and recovery index increased significantly with age. In the control group, age had no effect. Conclusions The neuromuscular blocking effects of mivacurium showed a significant age dependency in Duchenne muscular dystrophy patients, which was most probably caused by the progression of the disease.