Blood Propofol Concentrations Research Articles

The correlation between actual blood concentration of propofol and the difference of estimated lean body mass with actual lean body mass in target controlled infusion

Background: We evaluated the correlation between the difference of estimated lean body mass (LBME) with actual lean body mass (LBMA) and actual blood concentration of propofol, hemodynamic variables and Bispectral index (BIS) during target controlled infusion (TCI) of propofol in Korean female patients who would take total intravenous anesthesia (TIVA) using propofol-remifentanil combination. Methods: Eighty Korean women participated in this trial. Demographic data were collected and LBMA was measured using body mass analyzer. Target concentration of propofol was set at 6μg/ml during induction and 3μg/ml during maintenance. Hemodynamic variables and BIS were measured at 60 minutes after anesthetic induction. Peripheral blood sample was collected from a large forearm vein on the contralateral side of infusion for measurement of whole blood concentration of propofol at 60 minutes after anesthetic induction. Delta lean body mass (ΔLBM) was obtained by subtracting LBMA from LBME. Correlation analyses were done between ΔLBM and plasma propofol concentration, blood pressure, and BIS, respectively. Results: Blood concentrations of propofol were 1.9−6.9μg/ml. Mean plasma concentration of propofol was higher than target concentration. ΔLBM had a positive correlation with actual plasma propofol concentration. ΔLBM was not correlated with hemodynamic variables and BIS. Conclusions: TCI of propofol resulted in large variation in measured plasma concentration. We thought ΔLBM was one of interpatient variation factors of propofol plasma concentration during TCI. We found that TCI of propofol using Schnider model would result in higher blood concentration than target concentration in Korean women.

Use of Target Controlled Infusion to Derive Age and Gender Covariates for Propofol Clearance

Attempts to describe the variability of propofol pharmacokinetics in adults and to derive population covariates have been sparse and limited mainly to experiments based on bolus doses or infusions in healthy volunteers. This study aimed to identify age and gender covariates for propofol when given as an infusion in anaesthetized patients. One hundred and thirteen patients (American Society of Anesthesiologists class I or II and aged 14-92 years) were anaesthetized for elective surgical procedures with propofol using a target controlled infusion (TCI) system and with alfentanil as a baseline analgesic infusion. Frequent venous blood samples were obtained for measurement of propofol plasma concentrations. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Pharmacokinetic accuracy was determined by the percentage prediction error, bias and precision, as were wobble and divergence. The clearance of propofol from the central compartment was determined for each patient using the computerized record of the infusion profile delivered to each patient, together with relevant blood propofol concentration estimations. For each patient, the nonlinear mixed-effects modelling (NONMEM) objective function was employed to determine the goodness of fit. The population distribution of propofol clearance was subsequently found to have a Gaussian distribution only in the log domain (mean value equivalent to 26.1 mL/kg/min). The distribution in the normal domain was consequently asymmetric, with a slight predominance of patients with high values of clearance (5% and 95% confidence limits 17.7 and 42.1 mL/kg/min, respectively). Using regression analysis, gender and age covariates were derived that optimized the performance of the target controlled infusion system. The clearance (CL) of propofol in male patients changed little with age (CL [mL/kg/min]=26.88-0.029xAge; r2=0.006) whereas that in female patients had a higher initial value but decreased progressively with age (CL [mL/kg/min]=37.87-0.198xAge; r2=0.246). We achieved a relatively simple and practical covariate model in which the variability of pharmacokinetics within the study population could be ascribed principally to variability in clearance from the central compartment. Pharmacokinetic simulation predicted an improved performance of the TCI system when employing the derived covariates model, especially in elderly female patients.

Simulation of propofol anaesthesia for intracranial decompression using brain hypothermia treatment

BackgroundAlthough propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression.MethodsTheoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model.ResultsCompared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%.ConclusionThe integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.

Every Breath You Take, We’ll Be Watching You

Every Breath You Take, We’ll Be Watching You

Real-time Monitoring of Propofol in Expired Air in Humans Undergoing Total Intravenous Anesthesia

The physicochemical properties of propofol could allow diffusion across the alveolocapillary membrane and a measurable degree of pulmonary propofol elimination. The authors tested this hypothesis and showed that propofol can be quantified in expiratory air and that propofol breath concentrations reflect blood concentrations. This could allow real-time monitoring of relative changes in the propofol concentration in arterial blood during total intravenous anesthesia. The authors measured gas-phase propofol using a mass spectrometry system based on ion-molecule reactions coupled with quadrupole mass spectrometry which provides a highly sensitive method for on-line and off-line measurements of organic and inorganic compounds in gases. In a first sequence of experiments, the authors sampled blood from neurosurgery patients undergoing total intravenous anesthesia and performed propofol headspace determination above the blood sample using an auto-sampler connected to the mass spectrometry system. In a second set of experiments, the mass spectrometry system was connected directly to neurosurgery patients undergoing target-controlled infusion via a T piece inserted between the endotracheal tube and the Y connector of the anesthesia machine, and end-expiratory propofol concentrations were measured on-line. A close correlation between propofol whole blood concentration and propofol headspace was found (range of Pearson r, 0.846-0.957; P < 0.01; n = 6). End-expiratory propofol signals mirrored whole blood values with close intraindividual correlations between both parameters (range of Pearson r, 0.784-0.985; n = 11). Ion-molecule reaction mass spectrometry may allow the continuous and noninvasive monitoring of expiratory propofol levels in patients undergoing general anesthesia.

Predictive performance of ‘Servin's formula’ during BIS®-guided propofol-remifentanil target-controlled infusion in morbidly obese patients

The aim of this study was to assess the predictive performance of 'Servin's formula' for bispectral index (BIS)-guided propofol-remifentanil target-controlled infusion (TCI) in morbidly obese patients. Twenty patients (ASA physical status II-III, age 32-64 yr) undergoing bilio-intestinal bypass surgery, were recruited. Anaesthesia was induced by using a TCI of propofol with an initial target plasma concentration of 6 microg ml(-1), then adapted to maintain stable BIS values ranging between 40 and 50. A TCI of remifentanil was added to achieve pain control and haemodynamic stability. For propofol, weight was corrected as suggested by Servin and colleagues. With ideal body weight (IBW) corrected according to formula suggested by Lemmens and colleagues. For remifentanil, weight was corrected according to IBW. Arterial blood samples for the determination of blood propofol concentrations were collected at different surgical times. The predictive performance of propofol TCI was evaluated by examining performance accuracy. Median prediction error and median absolute prediction error were -32.6% (range -53.4%; -2.5%) and 33.1% (10.8%; 53.4%), respectively. Wobble median value was 5.9% (2.5%; 25.2%) while divergence median value was -1.5% h(-1) (-7.7; 33.8% h(-1)). Significant bias between predicted and measured plasma propofol concentrations was found while the low wobble values suggest that propofol TCI system is able to maintain stable drug concentrations over time. As already suggested before, a computer simulation confirmed that the TCI system performance could be significantly improved when total body weight is used.

The Increase in Total and Unbound Propofol Concentrations During Accidental Hemorrhagic Shock in Patients Undergoing Liver Transplantation

To the Editor: Hemorrhagic shock increases the sedative effects of propofol (1,2), so that a patient in hemorrhagic shock should receive only 10%–20% of the propofol dose that a healthy patient would receive (3). However, the mechanism of increase of end-organ sensitivity remains unclear. We demonstrate increases in total and unbound propofol in four patients with advanced cirrhosis who became hemodynamically unstable as a result of massive blood loss during surgery. After IRB approval and with written informed consent from patient, we induced anesthesia with vecuronium 0.1 mg/kg, and propofol 2 mg/kg and maintained anesthesia with 60% air, 0.5%–1.5% isoflurane in oxygen, fentanyl 30 g/kg, and propofol infusion of 2 mg/kg/h. After propofol injection, we collected arterial blood samples to measure blood propofol concentration. We used high-performance liquid chromatography to measure total and unbound propofol concentrations, as reported previously (4). Table 1 shows systolic arterial blood pressure, heart rate, total propofol, fraction unbound, and unbound propofol. After hemorrhagic shock, all patients were infused with lactated Ringer’s solution and mannitol adenine phosphate or were administered dopamine. All patients were adequately resuscitated within 60 min. Total propofol concentrations increased two-fold during hemorrhagic shock, as did the unbound fraction of propofol. The unbound propofol concentrations increased four-fold during hemorrhagic shock.Table 1: Hemodynamic Data and Propofol ConcentrationsThe total propofol concentration likely increased because of the physiological response to shock in our patients. Specifically, shock likely resulted in substantial reductions in hepatic and renal blood flow. Because the clearance of propofol is highly sensitive to liver and renal blood flow (4,5), the propofol clearance decreased during shock, increasing the concentrations during the infusion. This is consistent with effects of experimental hemorrhagic shock on total propofol concentrations in an animal study (1,2,6). However, relatively little attention has been given to hemorrhagic shock’s effect on unbound propofol concentrations. Propofol is a drug with a large distribution volume, high total body clearance (7), and a high degree of binding to plasma albumin, erythrocytes and lipoproteins (8,9) (unbound fraction of <3%). Therefore, the change of unbound fraction is clinically important as we reported previously (3,10). The unbound drug concentration is responsible for a drug’s pharmacological effects, as it is the unbound concentration that equilibrates between the blood and tissues. As the unbound propofol increased four-fold in our patients, this implies that the propofol dose requirements for these patients could be decreased by about 75%, consistent with Shafer’s analysis (3). Daisuke Takizawa, MD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan [email protected] Eri Takizawa, MD Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan Sohtaro Miyoshi, PhD Fuminori Kawahara, PhD Haruhiko Hiraoka, PhD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan

Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction

In a series of ex vivo and in vivo studies we investigated the ability of repetitive ketamine administration to alter the metabolism and anaesthetic effect of propofol and the role of ketamine-mediated P-450 2B induction in rats. Male Wistar rats were pretreated with 80 mg kg(-1) ketamine i.p. twice daily for 4 days. Pentoxyresorufin O-dealkylation (PROD), P-450 2B protein and mRNA were determined. Residual propofol concentration was measured after incubating hepatic microsomes with 100 muM propofol. Sleeping times induced by i.p. 80 mg kg(-1) propofol were determined. Orphenadrine, a P-450 2B inhibitor, was added in both ex vivo and in vivo studies. Finally, serial whole blood propofol concentrations were determined after i.v. infusion of 15 mg kg(-1) propofol. Ketamine pretreatment produced 5.4-, 3.4- and 1.7-fold increases in hepatic PROD activity, P-450 2B protein and mRNA, respectively. Residual propofol concentration was 46% lower after incubation with microsomes from ketamine-pretreated rats than in the control group. The addition of orphenadrine to ketamine-pretreated microsomes produced an increase in residual propofol concentration in a concentration-dependent manner. Ketamine pretreatment reduced propofol sleeping time to 12% of the control, which was reversed by orphenadrine. The whole blood propofol concentration in ketamine-pretreated rats was significantly lower than that of control rats at 1, 2, 4 and 8 min after cessation of propofol infusion. Repetitive ketamine administration enhances propofol metabolism and reduces propofol sleeping time in rats. We suggest that P-450 2B induction may produce ketamine-propofol interaction in anaesthetic practice.

The effect of positive end‐expiratory pressure ventilation on propofol concentrations during general anesthesia in humans

The present study investigated the effects of positive end-expiratory pressure (PEEP) on propofol concentrations in humans. Eleven patients undergoing elective surgery were enrolled in this study. Anesthesia was induced with propofol, then maintained using 60% nitrous oxide in oxygen, fentanyl 10-20 microg/kg and continuous infusion of propofol. Vecuronium was used to facilitate the artificial ventilation of the lungs. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration of 6.0 microg/mL at intubation and 2.0 microg/mL after intubation. Before, during and after PEEP level of 10 cmH(2)O, cardiac output (CO) and effective liver blood flow (LBF) was measured using indocyanine green as an indicator and blood propofol concentration was determined using high-performance liquid chromatography. Data are expressed as median and range. After PEEP of 10 cmH(2)O was applied, CO and effective LBF was significantly decreased from 5.5 (3.8-6.8) L/min to 4.5 (3.2-5.8) L/min (P < 0.05), 0.78 (0.65-1.21) L/min to 0.65 (0.50-0.89) L/min (P < 0.05), respectively. Propofol concentration was significantly increased from 2.21 (1.46-2.63) microg/mL to 2.45(1.79-2.89) microg/mL (P < 0.05). These data indicate that propofol concentrations can be increased by PEEP, suggesting the possibility of overdosing following PEEP.

The effect of gender and age on bispectral index and effective concentration 50 for propofol-remifentanil target-controlled infusion at two clinical end-points -A multi-center clinical research

Objective To study the effect of gender and ages on predict blood and effect-site EC50 for propofol and remifentanil TCI and bispectral index at loss of consciousness and response to a standard noxious painful stimulus. Methods 405 ASA Ⅰ-Ⅱunpremedicated Chinese patients in 5 medical centers for elective operation were involved. Patients were allocated to 4 groups according to ages (group1: 18age30, group2: 30≤age40, group3: 40≤age50, group4: 50≤age65). The propofol was started a predict blood concentration of 1.2 mg/L delivered by Diprifusor, and increased by 0.3 mg/L every 30 s until patients lost their consciousness. After that, effect-site concentration of propofol kept constant and infused remifentanil a predict blood concentration of 2.0 μg/L and increased by 0.3 μg/L every 30 s until they lost response to a standard noxious stimulus. Bispectral index was measured. Probit regression was used to estimate population values for predicted blood and effect-site propofol and remifentanil concentrations at the two clinical end-points and BIS. Results The effect-site and the predict blood propofol concentrations EC50 of male and female were similar. The predict blood and effect-site propofol concentrations EC50 of younger were higher than that of older and BIS values were lower. The blood and effect-site remifentanil ancentrations EC50 at no response to painful stimulus of male and female were similar. The blood and effect-site remifentanil concentrations EC50 and BIS values at this point of each group were similar. 50% of male and female patients lost their consciousness at a BIS value with 54.0 and 59.0 respectively; and at loss of response to painful stimulus with 60.8 and 67.3 respectively. Conclusion Gender didn't affect the predicted propofol and remifentanil blood and effect-site concentration but affected the BIS values. The propofol concentrations of older were lower than that of younger. And that of remifentanil were not different between younger and older.

Rapid Measurement of Blood Propofol Levels: a Proof of Concept Study

Despite many advantages over traditional volatile anaesthetic techniques, propofol total intravenous anaesthesia (TIVA) makes up a small percentage of general anaesthetics administered. One of the reasons for this is the absence of a clinically useful method for measuring blood propofol concentrations. We have designed and tested a prototype system for rapidly measuring blood plasma levels of propofol using solid phase extraction (SPE) methodology, coupled with colorimetric and spectrometric techniques. Multiple venous blood samples were taken from 17 subjects during induction of anaesthesia with propofol. Samples were analysed in duplicate on both the prototype system and using High Performance Liquid Chromatography (HPLC). The prototype monitor response was calibrated against known methanol-based propofol standards and an estimate of the plasma concentration of propofol derived from regression analysis of the standard responses. Bland Altman analysis from a total of 87 samples gave 95% limits of agreement between the two methods of -0.34 to 0.42 microg mL(-1) (with no significant bias). The mean absolute prediction error was 8.9(7.5)%. The run time per sample on the prototype system was 4.5 min, including sample preparation. The results show that this methodology may be suitable for rapid and accurate clinical monitoring of propofol levels during general anaesthesia.

Effect-compartment equilibrium rate constant (keo) for propofol during induction of anesthesia with a target-controlled infusion device

The effect-compartment concentration (C(e)) of a drug at a specific pharmacodynamic endpoint should be independent of the rate of drug injection. We used this assumption to derive an effect-compartment equilibrium rate constant (k(eo)) for propofol during induction of anesthesia, using a target controlled infusion device (Diprifusor). Eighteen unpremedicated patients were induced with a target blood propofol concentration of 5 microg x ml(-1) (group 1), while another 18 were induced with a target concentration of 6 microg x ml(-1) (group 2). The time at loss of the eyelash reflex was recorded. Computer simulation was used to derive the rate constant (k(eo)) that resulted in the mean C(e) at loss of the eyelash reflex in group 1 being equal to that in group 2. Using this population technique, we found the k(eo) to be 0.57 min(-1). The mean (SD) effect compartment concentration at loss of the eyelash reflex was 2.39 (0.70) microg x ml(-1). This means that to achieve a desired C(e) within 3 min of induction, the initial target blood concentration should be set at 1.67 times that of the desired C(e) for 1 min, after which it should revert to the desired concentration.

Changes in the effect of propofol in response to altered plasma protein binding during normothermic cardiopulmonary bypass

During normothermic cardiopulmonary bypass (CPB), the effect on propofol pharmacokinetics of changes in its binding to plasma proteins is consistent with the predictions of the well-stirred model of hepatic elimination for nonrestrictively cleared drug. However, whether changes in binding lead to clinically significant changes in the drug effect remains unclear. The purpose of this study was to assess changes in the drug effect of propofol in response to altered plasma binding using quantitative EEG measurements. Thirty patients undergoing cardiac surgery were assigned randomly to receive propofol infusions at 4 (Group P-4) or 6 (Group P-6) mg kg(-1) h(-1) during surgery. The concentration of propofol in blood samples, collected from the radial artery at predetermined intervals, was determined by HPLC. The unbound fraction of drug in plasma was estimated using equilibrium dialysis. Bispectral index (BIS) and burst suppression ratio (BSR) were measured at the time blood samples were collected. The total concentration of propofol in blood was unchanged during CPB relative to the pre-CPB value in both groups. However, the fraction of unbound propofol in blood increased by 2-fold during CPB. While BIS values were unchanged during CPB in Group P-4, there was a slight, but significant, decrease in Group P-6. In both groups, BSR significantly increased during CPB. BIS values showed a weak correlation with the concentration of unbound propofol (r(2)=0.19, P<0.001). BSR showed a moderate correlation with the concentration of unbound propofol (r(2)=0.56, P<0.001). The anaesthetic effect of propofol significantly increased during CPB without any alteration in the total drug concentration. The enhanced efficacy may be caused by a reduction in plasma binding of the drug.

Herbal monoterpene alcohols inhibit propofol metabolism and prolong anesthesia time

2,6-Diisopropylphenol (Propofol) is a short-acting intravenous anesthetic that is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. The goal of this research was to determine whether dietary monoterpene alcohols (MAs) could be used to prolong the anesthetic effect of propofol by inhibiting propofol metabolism in animals. Mice were injected intraperitoneally (i.p.) with MAs (100–200) mg/kg followed by the administration of 100 mg/kg propofol 40 min later via an i.p. injection. The time of the anesthesia of each mouse was recorded. It was found that (±)-borneol, (−)-carveol, trans-sobrerol, and menthol significantly extended the anesthetic effect of propofol (> 3 times). The concentration of propofol in the mouse blood over time (up to 180 min) also increased in mice pre-treated with (−)-borneol, (−)-carveol, and trans-sobrerol. The volume of distribution of propofol decreased in the (−)-borneol ( p < 0.05), pre-treated group as compared to the propofol control group. Moreover, the maximum blood concentration of propofol and the concentration of propofol in the blood as indicated by the area under the curve were significantly increased in (−)-borneol and (−)-carveol pre-treated groups. Additional evidence using rat hepatocytes showed that (−)-borneol inhibited propofol glucuronidation whereas trans-sobrerol and (−)-carveol inhibited cytochrome P450 dependent microsomal aminopyrine N-demethylation. These results suggest that (−)-borneol extends propofol-induced anesthesia by inhibiting its glucuronidation in the mouse whereas trans-sobrerol (−)-carveol extends propofol-induced anesthesia by inhibiting P450 catalyzed propofol metabolism.

Lethal self administration of propofol (Diprivan): A case report and review of the literature

The death of a female anaesthesiologist is reported. Although the situation at the scene indicated propofol overdose-related death, self-administration of such high doses of propofol was unlikely, given the pharmacological properties of this drug. The analysis of the situation at the scene and the toxicological analysis in which the blood and liver propofol concentrations were 2.40 μg/ml and 0.56 μg/g, respectively, supported the conclusion that the death was a consequence of propofol self-administration at therapeutic doses from a person who used the drug on chronic basis seeking to its euphoric effects. However, because the toxic concentrations of propofol in non-intubated patients may be different from those intubated and fully supported in the operating room or in the intensive care unit, a mere interpretation of the blood and tissue concentrations of propofol in the toxicological analysis can confirm the drug intake but it may be of limited diagnostic significance without taking into account this difference.

Influence of Atropine on the Dose Requirements of Propofol in Humans

The purpose of this study was to evaluate the effect of atropine on the dose requirement of propofol for induction of anesthesia and propofol concentrations during continuous infusion. Study 1: Forty patients were randomly allocated to the control or atropine groups. Induction of anesthesia commenced 3 min following the administration of 0.9% saline or atropine (0.01 mg kg(-1)), using a Diprifuser set to achieve propofol concentration of 6.0 microg mL(-1). The primary end point was the propofol dose per kg at the moment of loss of response to a command. Study 2: Fifteen patients undergoing elective surgery were enrolled. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 2.0 microg mL(-1) after intubation. Before and after administration of atropine (0.01 mg kg(-1)), cardiac output (CO) was measured using indocyanine green as an indicator and blood propofol concentration was determined using high-performance liquid chromatography. Study 1: The propofol dose for each group was 2.22+/-0.21 mg kg(-1) for control group and 2.45+/-0.28 mg kg(-1) for atropine, respectively (p=0.014). Study 2: After the administration of atropine, CO was significantly increased from 4.28+/-0.83 to 5.76+/-1.55 l min(-1) (p<0.0001). Propofol concentration was significantly decreased from 2.12+/-0.28 to 1.69+/-0.27 microg mL(-1) (p<0.0001). Following the administration of atropine, the propofol requirements for the induction of anesthesia were increased and propofol concentrations were decreased during continuous infusion by the administration of atropine.

Effect of Continuous Infusion of Propofol on Its Concentration in Blood With and Without the Liver in Pigs

In living donor liver transplantation, propofol, an intravenous anesthetic drug, has recently been used in both donors and recipients. Propofol is known to have intra- and extrahepatic metabolic pathways, but the effect of its continuous infusion during a long-term anhepatic state is yet to be determined. Recently, we successfully established a simplified pig model of the complete anhepatic state. In this state, we first evaluated hemodynamic parameters relating to the pharmacokinetics of continuously infused propofol (6 mg · kg −1 · h −1). No significant changes in the concentration of hemoglobin or in hemodynamic parameters other than the heart rate were observed during the anhepatic phase when porpofol was continuously infused at the rate that maintains the state. Blood propofol concentrations in the mixed vein, artery, and portal vein were stable during the anhepatic phase. Finally, we confirmed the pharmacokinetics of continuously infused propofol using orthotropic liver transplantation in miniature pigs. The propofol concentration did not change markedly during the transplant procedure. In conclusion, the pharmacokinetics of continuously infused propofol was almost stable with and without the liver in pigs. Extrahepatic metabolism of propofol might help prevent changes in propofol concentrations.

Development of a rapid and sensitive LC–ESI/MS/MS assay for the quantification of propofol using a simple off-line dansyl chloride derivatization reaction to enhance signal intensity

A rapid, selective and sensitive method was developed for the determination of propofol concentration using an off-line dansyl chloride derivatization step to enhance signal intensity. The method consisted of a protein precipitation extraction followed by derivatization with dansyl chloride and analysis by liquid chromatography ionspray tandem mass spectrometry (LC–ESI/MS/MS). The separation was achieved using a 100 mm × 2 mm C 8 analytical column combined with an isocratic mobile phase composed of 80:20 acetonitrile: 0.5%formic acid in water. Signal intensity of the propofol-dansyl chloride derivative was increased up to 200-fold as compared to the underivatized propofol in positive electrospray mode. An analytical range of 20–20,000 ng/mL was used in the calibration curve of plasma and blood samples. The novel method met all requirements of specificity, sensitivity, linearity, precision, accuracy and stability. A pharmacokinetic study was performed in rats and the novel analytical method was used as a routine analysis to provide enhanced measurements of plasma and blood concentrations of propofol. Blood and plasma pharmacokinetic results show that a very important fraction of propofol distributes into red blood cells. In conclusion, a rapid and sensitive LC–ESI/MS/MS method using a derivatization agent was developed to enhance signal intensity of propofol. Routine analysis with the novel method provided accurate results and enhanced the detection levels of plasma and blood concentrations of propofol to better characterize the in vivo biodiposition of propofol.

Une perfusion de dopamine diminue la concentration de propofol pendant le bloc péridural sous anesthésie générale

It is common clinical practice to use dopamine to manage the reduction in blood pressure accompanying epidural blockade. As propofol is a high-clearance drug, propofol concentrations can be influenced by cardiac output (CO). The purpose of the present study was to investigate the effects of dopamine infusions on propofol concentrations administered by a target-controlled infusion system during epidural block under general anesthesia. 12 patients undergoing abdominal surgery were enrolled in this study. Anesthesia was induced with propofol and vecuronium 0.1 mg.kg(-1), and maintained using 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 6.0 microg.mL(-1) at intubation and 2.0 microg.mL(-1) after intubation. Before and after the administration of 10 mL of 1.5% mepivacaine from the epidural catheter and dopamine infusion at 5 microg.kg(-1).min(-1), CO and effective liver blood flow (LBF) were measured using indocyanine green. Blood propofol concentration was also determined using high-performance liquid chromatography. At one hour after epidural block and dopamine infusion, CO was significantly increased from 4.30 +/- 1.07 L.min(-1) to 5.82 +/- 0.98 L.min(-1) (P < 0.0001), and effective LBF was increased 0.75 +/- 0.17 L.min(-1) to 0.96 +/- 0.18 L.min(-1) (P < 0.0001). Propofol concentration was significantly decreased from 2.13 +/- 0.24 microg.mL(-1) to 1.59 +/- 0.29 microg.mL(-1) (P < 0.0001). Propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.

Blood Concentration of Propofol in a Patient with Delayed Emergence from Propofol-nitrous Oxide Anesthesia

We measured the blood concentration of propofol in a patient with delayed emergence from propofol-nitrous oxide anesthesia. A 78-year-old man underwent subtotal gastrectomy under both epidural and propofol-nitrous oxide anesthesia and did not regain consciousness soon after termination of propofol infusion. Preoperative laboratory examination revealed anemia and a low blood total protein concentration, but there was no evidence of impaired liver function. While the anesthesiologists were waiting for the patient to regain consciousness, a surgeon mentioned that the common hepatic artery might have been occluded during surgical manipulation. Arterial blood samples were obtained 50 and 80 minutes after termination of propofol infusion, and the blood concentration of propofol was measured. We considered that clearance of propofol through the hepatic route may have been impaired; however, the actual blood concentrations of propofol were not significantly increased compared with the respective blood concentrations obtained in the simulation. Therefore, the acute liver damage did not significantly impair elimination of propofol. Because most propofol molecules in the blood bind to proteins and erythrocytes, it is suspected that the anemia and low blood total protein concentration led to an increase in the free fraction of propofol in the blood, thereby delaying emergence from anesthesia.