Christian Jeleazcov

Precision and accuracy of a new device (CNAP™) 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.

Comparative Pharmacokinetics and Pharmacodynamics of the New Propofol Prodrug GPI 15715 and Propofol Emulsion: Retracted

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.

Sedation with GPI 15715, a water-soluble prodrug of propofol, using target-controlled infusion in volunteers.

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 Observers 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.

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

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.

Electroencephalogram Monitoring During Anesthesia with Propofol and Alfentanil: The Impact of Second Order Spectral Analysis

Bispectral analysis of the electroencephalogram (EEG) has been used for monitoring anesthesia. The estimation of bicoherence allows us to determine whether a given time series represents a linear random process in cases where the bicoherence is trivial, i.e., a mere constant independent of frequency. In this study, we investigated the proportion of EEG epochs with nontrivial bicoherence during surgical anesthesia with propofol and alfentanil as an indicator for the degree of nonlinearity in the EEG. We reanalyzed 90 h of EEG recorded from 20 patients undergoing abdominal surgery using the Hinich procedure, which provides a statistical test for the following hypothesis: the EEG is a linear random process. In approximately 90% of all artifact-free, stationary EEG epochs, the bicoherence was found to be zero or a mere constant. Under these conditions, the EEG can be considered as a linear random process. Our findings suggest that the spectral information in the frequency domain delivered by the EEG monitoring during anesthesia is largely contained in the power spectrum of the signal. This calls into question the benefit of EEG bispectral analysis for monitoring anesthesia effect.

Determination of total and unbound sufentanil in human plasma by ultrafiltration and LC-MS/MS: application to clinical pharmacokinetic study.

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.

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.

The discriminant power of simultaneous monitoring of spontaneous electroencephalogram and evoked potentials as a predictor of different clinical states of general anesthesia

Spontaneous or evoked electrical brain activity is increasingly used to monitor general anesthesia. Previous studies investigated the variables from spontaneous electroencephalogram (EEG), acoustic (AEP), or somatosensory evoked potentials (SSEP). But, by monitoring them separately, the available information from simultaneous gathering could be missed. We investigated whether the combination of simultaneous information from EEG, AEP, and SSEP shows a more discriminant power to differentiate between anesthesia states than from information derived from each measurement alone. Therefore, we assessed changes of 30 EEG, 21 SSEP, and 29 AEP variables recorded from 59 patients during four clinical states of general anesthesia: “awake,” “light anesthesia,” “surgical anesthesia,” and “deep surgical anesthesia.” The single and combined discriminant powers of EEG, AEP, and SSEP variables as predictors of these states were investigated by discriminant analysis. EEG variables showed a higher discriminant power than AEP or SSEP variables: 85%, 46%, and 32% correctly classified cases, respectively. The frequency of correctly classified cases increased to 90% and 91% with information from EEG + AEP and EEG + AEP + SSEP, respectively. Thus, future anesthesia monitoring should consider combined information simultaneously distributed on different electrophysiological measurements, rather than single variables or their combination from EEG or AEP or SSEP.

Prazision von target-controlled infusion (TCI) mit zwei unterschiedlichen Propofolformulierungen

ZusammenfassungHintergrund„Target controlled infusion“ (TCI) von Propofol war zunächst nur mit kodierten Fertigspritzen für das System Disoprifusor® möglich. Neuere TCI-Systeme erlauben den Einsatz beliebiger Propofolformulierungen. Wir haben die Präzision einer TCI sowie die Pharmakokinetik für zwei unterschiedliche Propofolformulierungen untersucht.Material und MethodenZehn Probanden erhielten Disoprivan® 1% und Propofol 1% MCT Fresenius® als TCI unter Verwendung des Disoprifusor®-Modells. Der Vorhersagefehler der TCI wurde aus gemessenen arteriellen Konzentrationen bestimmt und die Pharmakokinetik mit einem Drei-Kompartiment-Modell analysiert.ErgebnisseDer mittlere Fehler und der mittlere absolute Fehler waren -1,4% und 23,3% für Disoprivan® 1% sowie -5,9% und 17,8% für Propofol 1% MCT Fresenius®. Die beiden Propofolformulierungen zeigten gleiche Pharmakokinetik mit einem kleineren Verteilungsvolumen als zur TCI-Steuerung verwendet.SchlussfolgerungenDas Disoprifusor®-Modell kann auch mit Propofol 1% MCT Fresenius® verwendet werden. Das große Verteilungsvolumen dieses Modells kann zu einem Überschießen der Konzentration führen.AbstractBackgroundTarget-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 methodsA 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.ResultsThe 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.ConclusionsThe 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.