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.

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.

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.

Precision and accuracy of a new device (CNAPTM) for continuous non-invasive arterial pressure monitoring: assessment during general anaesthesia.

BACKGROUND: Continuous non-invasive arterial pressure measured with CNAP (CNAP) has been shown to be superior to intermittent oscillometric measurements during procedural sedation and spinal anaesthesia. We assessed the performance of CNAP during general anaesthesia by analysis of agreement with invasive measurements of arterial pressure (AP). METHODS: Eighty-eight patients undergoing elective abdominal surgery, cardio-, or neurosurgery were included in the study. Systolic, diastolic, and mean AP measured by an intra-arterial catheter in the radial artery (IAP) were compared with those obtained by CNAP from the same arm. Data were analysed to determine the precision (i.e. measurement error) and accuracy (i.e. systematic error) of beat-to-beat CNAP values with respect to IAP. Also, we compared the frequency of fast changes in AP (FCAP) and hypotension (IOH) by both methods. RESULTS: CNAP precision of 4.5, 3.1, and 3.2 mm Hg (systolic, diastolic, and mean AP, respectively) was not significantly different from IAP precision, and CNAP accuracy was +6.7, -5.6, and -1.6 mm Hg. The frequency of AP pairs having a difference within the calculated limits of agreement was 81%, 64%, and 76% for systolic, diastolic, and mean AP, respectively. The calculated limits of agreement were +/-17.6, +/-11.4, and +/-12.0 mm, Hg, respectively. CNAP and IAP detected simultaneously to 82.1% FCAP and to 84.6% IOH. CONCLUSIONS: CNAP provides real-time estimates of arterial pressure comparable with those generated by an invasive intra-arterial catheter system during general anaesthesia.

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.

EEG variables as measures of arousal during propofol anaesthesia for general surgery in children: rational selection and age dependence.

BACKGROUND: Clinical benefits of measuring processed EEG during anaesthesia in adults, such as improved recovery and reduced risk of awareness, may also be valid in children. This study evaluated a rational selection of EEG variables as measures of arousal during surgical anaesthesia in children. METHODS: Sixty children undergoing surgical anaesthesia with propofol and remifentanil were enrolled. The performance of 33 single EEG variables and bispectral index (BIS) was assessed by simultaneous analysis of prediction probability (Pk) of Children's Hospital of Wisconsin Sedation Scores and their signal-to-noise ratio (SNR). Variables performing best in Pk and SNR analysis were selected as potential measures of arousal. Their performance was investigated in five age groups, 0-1, 1-2, 2-5, 5-8, and 8-13 yr. RESULTS: Single EEG variables such as relative power from frequency bands 13-20 and 20-26 Hz, SEF95, and approximate entropy performed best with Pk>0.59 and SNR>5.50. The Pk and SNR of BIS were 0.71 and 15.76, respectively. Their performance was significantly better in children aged 1-13 yr than in 0-1 yr. CONCLUSIONS: BIS may provide a measure of arousal during propofol anaesthesia in children, but its accuracy is less in infants younger than 12 months. Single EEG variables such as high-frequency components of EEG, SEF95, and approximate entropy may be of limited value to detect arousal in the individual paediatric patient.

[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.

[Accuracy of target-controlled infusion (TCI) with 2 different propofol formulations]. / Präzision von "target-controlled infusion" (TCI) mit zwei unterschiedlichen Propofolformulierungen.

BACKGROUND: Target-controlled infusion (TCI) of propofol was initially realized as a device for prefilled syringes (Diprifusor). New TCI systems can be used with any propofol formulation. We compared two different propofol formulations with respect to accuracy of TCI and pharmacokinetics. MATERIALS AND METHODS: A total of 10 volunteers received Diprivan 1% and Propofol 1% MCT Fresenius as TCI using the pharmacokinetic model of the Diprifusor. The prediction error was determined from measured arterial concentrations. A three-compartment model was fitted to the concentration data. RESULTS: The median prediction error and the median absolute prediction error were -1.4% and 23.3% for Diprivan, and -5.9% and 17.8% for Propofol Fresenius. The drugs did not differ in pharmacokinetics but showed a smaller central volume of distribution than used for infusion control. CONCLUSIONS: The pharmacokinetic model of Diprifusor can also be used for TCI of Propofol Fresenius. The large volume of distribution in this model may cause an overshoot in concentration.

Automated EEG preprocessing during anaesthesia: new aspects using artificial neural networks.

The computer-aided detection of artefacts became an essential task with increasing automation of quantitative electroencephalogram (EEG) analysis during anaesthesiological applications. The different algorithms published so far required individual manual adjustment or have been based on limited decision criteria. In this study, we developed an artificial neural networks-(ANN-)aided method for automated detection of artefacts and EEG suppression periods. 72 hr EEG recorded before, during and after anaesthesia with propofol have been evaluated. Selected parameterized patterns of 0.25 s length were used to train the ANN (22 input, 8 hidden and 4 output neurons) with error back propagation. The detection performance of the ANN-aided method was tested with processing epochs between 1 to10 s. Related to examiner EEG evaluation, the average detection performance of the method was 72% sensitivity and 80% specificity for artefacts and 90% sensitivity and 92% specificity for EEG suppression. The improvement in signal-to-noise ratio with automated artefact processing was 1.39 times for the spectral edge frequency 95 (SEF95) and 1.89 times for the approximate entropy (ApEn). We conclude that ANN-aided preprocessing provide an useful tool for automated EEG evaluation in anaesthesiological applications.

Functional changes of ventricular late potentials by provocation with increase of heart rate. Evaluation during atrial pacing.

BACKGROUND: Standard methods fail to reveal late potentials in 20 to 30% of patients with ventricular arrhythmias after myocardial infarction. However, these patients may develop transient delayed ventricular activation during increases in heart rate. METHODS AND RESULTS: Atrial pacing was performed, at the rates of 100 min-1 and 120 min-1, in 50 patients after myocardial infarction. Twenty-six patients had a history of documented, sustained ventricular tachycardia, 12 had a history of ventricular fibrillation and 12 no history of ventricular arrhythmias. The low-noise surface electrocardiogram was analysed before and during atrial pacing in the time and frequency domains. Fifteen of 26 patients with ventricular tachycardia, four of 12 with ventricular fibrillation and three of 12 without ventricular arrhythmias experienced late potentials during sinus rhythm. Atrial pacing led to a shift of 26 +/- 15 ms of preexistent late potentials into the ST segment, this being greater in patients with anterior infarctions and to an increase in magnitude in patients with inferior infarctions. In patients without late potentials during sinus rhythm, atrial pacing provoked late potentials in eight of 11 patients with ventricular tachycardia, in four of eight patients with ventricular fibrillation and in one of nine patients without ventricular arrhythmias. Low amplitude signals (LAS) were increased in patients after inferior and filtered QRS in patients after anterior infarction. In 10 patients without cardiac disease no late potentials were detectable in the time and frequency domain either at rest or during increased heart rate. CONCLUSIONS: Increase in heart rate may unmask late potentials in patients prone to malignant ventricular arrhythmias. Therefore, functional late potential analysis with non-invasive clinical stress tests, i.e. exercise tests, should be performed only with an adequate rate response. This might identify patients at risk of malignant ventricular arrhythmias otherwise not identified with conventional late potential analysis.