J. Fechner

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.

Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers.

BACKGROUND GPI 15715 (AQUAVAN injection) is a new water-soluble prodrug which is hydrolyzed to release propofol. The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715. METHODS Three groups of three healthy male volunteers (aged 19-35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h. Pharmacokinetics were analyzed with compartment models. Pharmacodynamics were assessed by clinical signs. RESULTS GPI 15715 was well tolerated without pain on injection. Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion. Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg. After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 +/- 0.6 microg/ml. A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml. kg-1 min-1; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data. The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%. There were no significant laboratory abnormalities. CONCLUSIONS Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose. Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.

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.

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rates

Background and objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan® injection), a new water-soluble prodrug metabolized to propofol by hydrolysis. Methods: Nine adult male Sprague-Dawley rats (398 ± 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum. Results: A maximum propofol concentration of 7.1 ± 1.7 μg mL−1 was reached 3.7 ± 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 ± 0.2 and 23.9 ± 9.9 min), an elimination rate constant of 0.18 ± 0.01 min−1 and a central volume of distribution of 0.25 ± 0.02 L kg−1. For propofol, the half-life was 1.9 ± 0.1 and 45 ± 7 min, the elimination rate constant was 0.15 ± 0.02 min−1 and the central volume of distribution was 2.3 ± 0.6 L kg−1. The maximum effect on the electroencephalogram (EEG) - EEG suppression for >4 s - occurred 6.5 ± 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 ± 7.9 Hz, EC50 = 2.6 ± 0.8 μg mL−1, ke0 = 0.35 ± 0.04 min−1). Conclusions: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

Prädiktivität und Präzision einer „target-controlled infusion” (TCI) von Propofol mit dem System „Disoprifusor TCI®”

ZusammenfassungSeit April 1997 ist in Deutschland ein TCI-System für Propofol (Disoprifusor-TCI®) kommerziell erhältlich. Wir haben Prädiktivität und Präzision dieses Systems untersucht und mit dem Bias, der Präzision, dem Propofolverbrauch und dem Blutspiegelverlauf einer manuell gesteuerten Infusion verglichen. Methode: 21 Patienten erhielten randomisiert eine intravenöse Anästhesie mit Propofol entweder als manuell gesteuerte Infusion oder als TCI. Blutplasmaspiegel wurden mittels HPLC bestimmt. Ergebnisse: Für das untersuchte TCI-System ergab sich eine Präzision von 27,5% und ein Bias von 6,7%. In der manuellen Gruppe betrug der Bias 44,2% und die Präzision 50%. Die durchschnittlich infundierte Propofolmenge (9,0 ± 1,2 vs. 6,6 ± 1,2 mg/kg/h, p < 0,005) und die mittlere Propofolplasmakonzentration (3,7 ± 0,5 vs. 3,0 ± 0,5 µg/ml, p < 0,05) waren in der TCI-Gruppe signifikant höher. Schlußfolgerung: Die in dieser Studie ermittelte Präzision und der Bias des untersuchten TCI-Systems ist nur unwesentlich größer als die Variabilität der pharmakokinetischen Parameter selbst, und kann somit als akzeptabel angesehen werden.AbstractIn Germany a TCI-system for propofol (Disoprifusor-TCI®) has been commercially available since spring 1997. We investigated the prediction error and precision of this TCI system as part of a multicentre study. Bias, precision, blood concentrations and dosage of propofol were compared with patients receiving propofol via a manually controlled infusion device. Methods: After approval by the local Ethics Committee and written informed consent, 21 patients of ASA-classification I to III scheduled for major abdominal surgery received either a target controlled infusion (group T, Disoprifusor-TCI®) or a manually controlled infusion (group M) of propofol. The propofol plasma concentrations were measured by HPLC. The prediction error for each measurement, the median prediction error (MDPE) or bias, the median absolute prediction error (MDAPE) or precision and the divergence (change of the prediction error over infusion time) were calculated for both groups. Results: For all patients in group T (n = 12) the bias of the TCI system was 6.7% and the precision 27.5%. For 70% of all measured plasma concentrations the absolute prediction error was ≤ 37%. The divergence was −5.4% per hour. For all patients in group M (n = 9) the bias was 44.2% and the precision 50%. The mean amount of propofol infused per kilogramm body weight and hour was signifikant higher in T (9.0 ± 1.2 mg/kg/h) than in M (6.6 ± 1.2 mg/kg/h, p < 0.005). Conclusions: With a precision of 27.5% the investigated TCI system (Diprifusor-TCI®) showed an acceptable inaccuracy, as for TCI-systems a median prediction error of ± 30% has to be expected due to the inherent variability of pharmacokinetic parameters. Further studies will be necessary to find out whether the investigated TCI system for propofol may offer substantial advantages.

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.

Propofol/Remifentanil versus Sevofluran/Remifentanil zur Anästhesie bei Unterbaucheingriffen im Säuglings-, Kindes- und Jugendalter

ZusammenfassungFragestellung. Ziel dieser Studie war der Vergleich einer totalen intravenösen Anästhesie (TIVA) mit Propofol und Remifentanil (P/R-Gruppe) mit einer balancierten Anästhesie (BA) mit Sevofluran und Remifentanil (S/R-Gruppe) bei Säuglingen und Kindern. Patienten und Methodik. 120 Patienten (Alter: 6 Monate bis 16 Jahre), die sich einem elektiven Unterbaucheingriff unterziehen mussten, wurden entweder mit Propofol (5–10 mg/kg/h) und Remifentanil (0,125–1,0 μg/kg/min) oder mit Sevofluran (1,0–1,5 MAC) und Remifentanil (0,125–1,0 μg/kg/min) anästhesiert. Dabei wurden Einleitungs- sowie Aufwach- und Verlegungszeiten, hämodynamische Parameter, postoperative Schmerzintensität und Wohlbefinden (Objective Pain Discomfort Scale), die postoperative Wachheit (Steward Post-Anaesthetic Recovery Score) und PONV verglichen. Ergebnisse. Es ergaben sich signifikant kürzere Aufwach- (9,0 vs. 11,6 min), Extubations- (11,8 vs. 15,0 min) und Verlegungszeiten (17,2 vs. 20,8 min) sowie kürzere Zeiten bis zum Erreichen eines Steward Post-Anaesthetic Recovery Score >3/4 (15,2 vs. 21,4 min) in der P/R-Gruppe. Postoperatives Wohlbefinden, PONV, Schmerzintensität, Analgetikabedarf und die Dauer bis zur Verlegung auf Normalstation waren vergleichbar. Schlussfolgerung. Die TIVA mit Propofol und Remifentanil stellt bei Säuglingen, Kindern und Jugendlichen hinsichtlich der untersuchten Parameter ein gleichwertiges Anästhesieverfahren zur BA dar, wobei es unter den verwendeten Dosierungen in der TIVA-Gruppe zu signifikant kürzeren Aufwachzeiten kam.SummaryIntroduction. The aim of this study was to compare total intravenous anaesthesia (TIVA) using propofol and remifentanil (P/R-group) and balanced anaesthesia (BA) using sevoflurane and remifentanil (S/R-group) for paediatric surgery. Patients and methods. A total of 120 patients aged 6 months to 16 years scheduled for elective minor lower abdominal surgery were randomly assigned to receive either propofol (5–10 mg/kg/h) and remifentanil (0.125–1.0 μg/kg/min) or sevoflurane (1.0–1.5 MAC) and remifentanil (0.125–1.0 μg/kg/min). Perioperative haemodynamics as well as recovery and discharge times, PONV and side-effects were studied. The patients vigilance, comfort and pain intensity were assessed postoperatively using the objective pain discomfort scale, the Steward post-anaesthetic recovery score and a visual analogue scale. Results. Postoperative recovery (9.0 vs 11.6 min) and extubation times (11.8 vs. 15.0 min) as well as the time taken until a Steward post-anaesthetic recovery score >3/4 (15.2 vs. 21.4 min) was reached were significantly shorter in the P/R-group. However, the length of time until discharge to the ward, postoperative comfort, pain intensity and analgesic requirements as well as PONV were comparable in both groups. Conclusions. With regards to the investigated parameters, TIVA with propofol and remifentanil is equally effective as BA with sevoflurane and remifentanil in paediatric patients. However, considering the selected dosing regimen, recovery times were significantly shorter for children after TIVA.