Arterial Propofol Concentrations Research Articles

Bispectral Index Dynamics During Propofol Hypnosis Is Similar in Red-Haired and Dark-Haired Subjects

We have previously shown that red hair is associated with increased desflurane requirement for immobility, compared with dark hair. The effect of red hair on IV anesthetic requirement remains unknown. We tested the hypothesis that the propofol concentration in the effect site associated with half maximal electroencephalogram response, Ce50, is at least 50% higher in subjects with red hair. We modeled the propofol concentration versus electroencephalogram response relationship using a 2-step approach in 29 healthy dark- and red-haired volunteers receiving a propofol infusion to produce loss of consciousness. Bispectral Index (BIS) was the measure of drug effect. The parameters of a 3-compartment pharmacokinetic model were fit to measured arterial propofol concentrations. The relationship between effect-site propofol concentration (Ce) and BIS was characterized using a sigmoid Emax model. Model performance and accuracy of the estimated parameters were evaluated using accepted metrics and bootstrap resampling. The effect of hair color on the Ce50 for BIS response in the final model was assessed using a threshold of 6.63 (P<0.01) in reduction of -2 log likelihood. The influence of body weight on the model was also assessed. The inclusion of hair color as a model covariate did not improve either the pharmacokinetic or the pharmacodynamic model. A separate analysis for the dark- and red-haired subjects estimated a median (95% confidence interval) Ce50 BIS of 2.71 μg/mL (2.28-3.36 μg/mL) and 2.57 μg/mL (1.68-3.60 μg/mL), respectively. Body weight was a significant covariate for the CL1 and V1. Red hair phenotype does not affect the pharmacokinetics or pharmacodynamics of propofol.

Pharmacokinetics and pharmacodynamics – is there anything new?

Pharmacokinetics and pharmacodynamics – is there anything new?

A two-compartment effect site model describes the bispectral index after different rates of propofol infusion

Different estimates of the rate constant for the effect site distribution (k(e0)) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg(-1) h(-1) of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal E(max) model.

Assessment of propofol concentrations in human breath and blood by means of HS-SPME–GC–MS

Background Breath analysis could offer a non-invasive means of drug monitoring if adequate analytical methods and robust correlations between drug concentrations in breath and blood can be established. We therefore applied headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME–GC–MS) to assess breath and blood concentrations of the intravenous drug propofol in patients under anesthesia or sedation. Methods Arterial, central- and peripheral-venous blood and alveolar breath samples were drawn in parallel from 16 mechanically ventilated patients. In addition, six patients undergoing lung resection were investigated. Substances were preconcentrated by means of HS-SPME, separated by GC and identified by MS. Results Propofol detection limits were 0.006 nmol/L in breath and 72.20 nmol/L in blood, the quantitation limits were 0.009 nmol/L and 75.89 nmol/L (end tidal breath/blood). Intraday precision was 8–11%, recovery 97–103%. Propofol concentrations were 0.04–0.5 nmol/L in breath and 2–120 μmol/L in blood. Only arterial propofol concentrations showed a correlation with concentrations in breath. Impaired ventilation/perfusion ratios in patients under lung resection resulted in changes of correlation coefficients. Conclusions Reliable and precise analytical methods such as HS-SPME–GC–MS represent basic requirements if breath analysis is to be set up for non-invasive monitoring of intravenous drugs and control of anesthesia.

Every Breath You Take, We’ll Be Watching You

Every Breath You Take, We’ll Be Watching You

The Minimum Infusion Rate (MIR) of Propofol for Total Intravenous Anesthesia after Premedication with Xylazine in Horses

To investigate an adequate infusion rate of propofol for total intravenous anesthesia (TIVA) in horses, the minimum infusion rate (MIR) comparable to the minimum alveolar anesthetic concentration (MAC) of inhalation anesthetic was determined under constant ventilation condition by intermittent positive pressure ventilation (IPPV). In addition, arterial propofol concentration was measured to determine the concentration corresponding to the MIR (concentration preventing reaction to stimulus in 50% of population, Cp(50)). Further, 95% effective dose (ED(95)) was estimated as infusion rate for acquiring adequate anesthetic depth. Anesthetic depth was judged by the gross purposeful movement response to painful stimulus. MIR and Cp(50) were 0.10 +/- 0.02 mg/kg/min and 5.3 +/- 1.4 microg/ml, respectively. ED(95) was estimated as 0.14 mg/kg/min (1.4MIR).

Predictive performance of ‘Diprifusor’ TCI system in patients during upper abdominal surgery under propofol/fentanyl anesthesia

To evaluate the predictive performance of 'Diprifusor' TCI (target-controlled infusion) system for its better application in clinical anesthesia. The predictive performance of a 'Diprifusor' TCI system was investigated in 27 Chinese patients (16 males and 11 females) during upper abdominal surgery under total intravenous anesthesia (TIVA) with propofol/fentanyl. Measured arterial propofol concentrations were compared with the values predicted by the TCI infusion system. Performance was determined by the median performance error (MDPE), the median absolute performance error (MDAPE), the divergence (the percentage change of the absolute PE with time), and the wobble (the median absolute deviation of each PE from the MDPE). The median (range) values of 14.9% (-21.6%-42.9%) for MDPE, 23.3% (6.9%-62.5%) for MDAPE, -1.9% h(-1) (-32.7%-23.0% h(-1)) for divergence, and 18.9% (4.2%-59.6%) for wobble were obtained from 227 samples from all patients. For the studied population, the PE did not increase with time but with increasing target propofol concentration, particularly following induction. conclusions: The control of depth of anaesthesia was good in all patients undergoing upper abdominal surgical operation and the predictive performance of the 'Diprifusor' target controlled infusion system was considered acceptable for clinical purposes. But the relatively bigger wobble showed that the pharmacokinetic model is not so suitable and requires improvement.

Influence of propofol concentrations on multipulse transcranial motor evoked potentials

Motor evoked potentials can be affected by propofol anaesthesia. We studied how increasing target concentrations of propofol altered transcranial motor evoked potentials (tcMEP) during scoliosis surgery. Fifteen patients undergoing surgery for scoliosis were anaesthetized with remifentanil and propofol without nitrous oxide or neuromuscular blocking agents (BIS<60). tcMEP were elicited by transcranial electric multipulse stimulation of the motor cortex and recording of compound action potentials from the anterior tibialis muscle. tcMEP were obtained before surgery with propofol target values set from 4 to 8 mg litre(-1), and then during surgery. Arterial propofol concentrations were measured for each tcMEP recording. Before surgery, increasing propofol reduced tcMEP amplitude in a dose-dependent manner, with no effect on latency. During surgery, at equivalent propofol concentrations, tcMEP were not statistically different from those obtained before surgery. In all except one patient, tcMEP signals were present during the entire procedure. In this patient the loss of tcMEP was unfortunately related to an anterior spinal cord lesion, which was confirmed by a wake-up test. We found that, although propofol had a dose-dependent effect on tcMEP amplitude, anaesthesia could be maintained with remifentanil and propofol to allow recording and interpretation of tcMEP signals.

Accuracy of the ‘Paedfusor’ in children undergoing cardiac surgery or catheterization

A prototype paediatric propofol target-controlled infusion (TCI) system, the 'Paedfusor' has been developed. This system incorporates a paediatric pharmacokinetic data set and algorithm specific for children in a Graseby 3500 anaesthesia syringe driver. In this study we have evaluated the accuracy of the Paedfusor TCI system in children who underwent either cardiac surgery or cardiac catheterization procedures. Twenty-nine children aged 1-15 yr were investigated. General anaesthesia was provided using propofol administered by the Paedfusor system. Accuracy of the system was evaluated by obtaining up to 9 arterial samples for measurement of propofol concentration both during anaesthesia and in the recovery period. Measured arterial propofol concentrations were then compared with values calculated by the Paedfusor. The predictive indices of median performance error (MDPE), and median absolute performance error (MDAPE) of the Paedfusor system were found to be 4.1% and 9.7%, respectively and the median value for wobble was 8.3%. These values are much better than those found with the adult 'Diprifusor' system. The Paedfusor performance was found to be within the accepted limits for use as a TCI system.

Predictive accuracy of a model of volatile anesthetic uptake.

A computer program that models anesthetic uptake and distribution has been in use in our department for 20 yr as a teaching tool. New anesthesia machines that electronically measure fresh gas flow rates and vaporizer settings allowed us to assess the performance of this model during clinical anesthesia. Gas flow, vaporizer settings, and end-tidal concentrations were collected from the anesthesia machine (Datex S/5 ADU) at 10-s intervals during 30 elective anesthetics. These were entered into the uptake model. Expired anesthetic vapor concentrations were calculated and compared with actual values as measured by the patient monitor (Datex AS/3). Sevoflurane was used in 16 patients and isoflurane in 14 patients. For all patients, the median performance error was -0.24%, the median absolute performance error was 13.7%, divergence was 2.3%/h, and wobble was 3.1%. There was no significant difference between sevoflurane and isoflurane. This model predicted expired concentrations well in these patients. These results are similar to those seen when comparing calculated and actual propofol concentrations in propofol infusion systems and meet published guidelines for the accuracy of models used in target-controlled anesthesia systems. This model may be useful for predicting responses to changes in fresh gas and vapor settings. We compared measured inhaled anesthetic concentrations with those predicted by a model. The method used for comparison has been used to study models of propofol administration. Our model predicts expired isoflurane and sevoflurane concentrations at least as well as common propofol models predict arterial propofol concentrations.

Influence of cardiac output on plasma propofol concentrations during constant infusion in swine.

As propofol is a high-clearance drug, plasma propofol concentrations can be influenced by cardiac output (CO), which can easily change in response to several factors. If propofol is metabolized in the lungs, the difference between pulmonary and arterial propofol concentrations might also be affected by CO. The objective of the current study was to assess how much plasma propofol concentrations are affected by CO and to determine how much the lungs take part in propofol elimination and in concentration changes affected by CO in anesthetized swine. Thirteen swine were studied. Propofol was administered via a peripheral vein at a rate of 6 mg x kg(-1) x h(- 1), and blood samples were simultaneously collected from pulmonary and femoral arteries at 0, 2, 3.5, 5, 7, 10, 20, and 30 min and at 20-min intervals up to 270 min. After 90 min of sampling (baseline 1), CO increased in response to a continuous infusion of dobutamine (20 microg x kg(-1) x min(- 1); high-CO state); the infusion was then stopped, and CO was allowed to return to baseline (baseline 2). Finally, CO decreased with the administration of propranolol (2.0-4.0 mg administered intravenously; low-CO state). Each hemodynamic status was maintained for 1 h. As CO increased 36% from baseline 1, plasma propofol concentrations decreased by 18% from baseline 1, and as CO decreased 42% from baseline 1, plasma propofol concentrations increased by 70% from baseline 1. Plasma propofol concentrations can be expressed by the following equation: plasma propofol concentration (micrograms per milliliter) = 6.51/CO (l/min) + 1.11 (r = 0.78, P < 0.0001). No significant differences were observed between plasma propofol concentrations in pulmonary and femoral arteries in any state, and CO caused no apparent differences between pulmonary and arterial propofol concentrations. An inverse relation was observed between CO and propofol concentrations. The lungs appear to have a minor effect on plasma propofol concentrations during constant infusion in anesthetized swine.

Predictability of processed electroencephalography effects on the basis of pharmacokinetic-pharmacodynamic modeling during repeated propofol infusions in patients with extradural analgesia.

Pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to characterize the concentration-effect relation of drugs. If the concentration-effect relation of a hypnotic drug is stable over time, an effect parameter derived from the processed electroencephalographic signal may be used to control the infusion for hypnosis. Therefore, the stability of the propofol concentration-electroencephalographic effect relation over time was investigated under non-steady state conditions. Three propofol infusions (25 mg x kg(-1) x h(-1) for 10 min, 22 mg x kg(-1) x h(-1) for 10 min, and 12.5 mg x kg(-1) x h(-1) for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephalography was recorded from bilateral prefrontal to mastoid leads. Electroencephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index were used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electroencephalographic data and arterial propofol concentrations derived during the initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroencephalographic effects was determined by the coefficient of determination (R2) and of the -2 log likelihood of the sequential infusions. The direction of electroencephalographic changes in response to the infusions was reproducible. Although PKPD parameters could be estimated well during the initial infusion (median [range] parametric R2 = 0.74 [0.56-0.95] for electroencephalographic amplitude and 0.90 [0.27-0.99] for Bispectral Index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R2 = 0.00 [-0.31-0.46] for electroencephalographic amplitude and 0.15 [-.46-0.57] for Bispectral Index; P < 0.01). The relation between blood propofol concentrations and the electroencephalographic effect under non-steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD models.

Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model

To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. Prospective, randomized animal study. University research laboratory. Five adult female merino sheep. Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 microg/min) and dopamine (10, 20, 40 microg x kg x min) in 3 x 5 min intervals followed by a 30-min washout period. Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146-169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95 % CI, p < 0.05): epinephrine to 41.8% of baseline (11.4-72), norepinephrine to 63 % (27-99) and dopamine to 52.9 % (18.5-87.3). There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The lowest blood concentrations were associated with emergence from anesthesia. Arterial concentrations were inversely related to the simultaneously determined cardiac output (r2 = 0.74, p < 0.0001). Comparison of the data with the predictions of a previously developed recirculatory model of propofol disposition in sheep showed the data were consistent with a mechanism based on increased first pass dilution and clearance of propofol secondary to the increased cardiac output. Catecholamines produced circulatory changes that reversed propofol anesthesia. These observations have potential clinical implications for the use of propofol in hyperdynamic circulatory conditions, either induced by exogenous catecholamine infusions or pathological states.

The influence of hypoxia and hyperoxia on the kinetics of propofol emulsion.

To study the effect of hypoxia and hyperoxia on the pharmacokinetics of propofol emulsion, hepatic blood flow and arterial ketone body ratio in the rabbit. Twenty four male rabbits were anesthetized with isoflurane (1.5-2%) in oxygen. After the surgical procedure, isoflurane administration was discontinued and intravenous propofol infusion (30 mg x kg(-1) x hr(-1)) was started. The infusion rate of propofol was maintained throughout the study. After an initial 90 min period of propofol infusion, rabbits were randomly allocated to one of three groups: hypoxia (F(I)O2 = 0.1), normoxia (F(I)O2 = 0.21), and hyperoxia (F(I)O2 = 1.0). Propofol infusion was continued under the allocated F(I)O2 for 60 min. Propofol concentrations in arterial blood, total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were measured. The mean arterial propofol concentration at the end of infusion was higher in the hypoxia group (15.2 +/- 2.8 microg x mL(-1), mean +/- SD) than in the normoxia (7.4 +/- 1.7) and hyperoxia (8.0 +/- 1.9) groups (P < 0.05). Total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were all reduced in the hypoxia group (P < 0.05). Total ketone body concentration in arterial blood increased in the hyperoxia group (P < 0.01). Hypoxia produced an accumulation of propofol in blood and reduced propofol clearance. These changes could result from decreased hepatic blood flow and low cellular energy charge in the liver. Hyperoxia, on the other hand, increased total ketone body in arterial blood.

The effect of rate of administration on brain concentrations of propofol in sheep.

A marked reduction in the dose of propofol required to achieve the onset of anesthesia with slower administration rates has previously been reported, but the mechanism of this phenomenon is unclear. We used a chronically instrumented sheep preparation to examine the effects of different administration rates of propofol on its distribution in the brain using mass balance principles to calculate brain concentrations. The administration of 100 mg of propofol i.v. at rates of 200, 50, and 20 mg/min had minimal effect on both the peak brain concentrations of propofol and the total amount of drug entering the brain. The more rapid administration rates increased the rate of uptake into the brain but resulted in large increases in peak arterial blood propofol concentrations. These faster administration rates have previously been associated with high arterial propofol concentrations and an increased risk of hypotension. Simulation of titration to an end point revealed that the dose sparing previously reported at induction with slow administration rates relates only to improved titration to effect, and does not result in more anesthesia for a given dose. Therefore, we conclude that the administration of propofol over 2 min provides a reasonable rate of induction and improved titration to effect, yet avoids excessively high arterial concentrations. Alterations in the rate of administration of propofol in sheep have been shown to have little effect on the quantity of propofol delivered to the brain. At induction of anesthesia, administration rates of approximately 50 mg/min seem likely to provide improved titration to effect without excessively prolonging induction.

The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep.

The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied. We therefore examined the influence of the injection rate of i.v. bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received i.v. propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly.

The Arterial Blood Propofol Concentration Preventing Movement in 50% of Healthy Women After Skin Incision

The Arterial Blood Propofol Concentration Preventing Movement in 50% of Healthy Women After Skin Incision

Comparison of arterialized venous with arterial blood propofol concentrations during sub-anaesthetic infusions in volunteers

We have compared propofol concentrations in arterial and arterialized venous blood (from the radial artery at the wrist and a vein in the opposite forearm) in five volunteers during a sub-anaesthetic increasing infusion regimen designed to produce pseudo-steady-state arterial concentrations of 0.06, 0.17 and 0.43 micrograms ml-1. As in a previous study, we found no statistically significant difference between sampling sites (P = 0.66). However, changes in the method of arterialization yielded a reduction in the observed variability, with the arterialized venous propofol concentration lying within +/- 23% (95% reference interval) of the corresponding arterial concentration compared with 1 +/- 43%, as reported previously.

Arterial and Jugular Venous Bulb Blood Propofol Concentrations During Induction of Anesthesia

The aim of this study was to show that blood propofol concentrations at loss of consciousness vary with the rate of administration. Eighteen patients were allocated to receive a propofol infusion at 6 or 12 mg.kg-1.h-1 (approximately 8 and 15 mg/min) for induction of anesthesia. Propofol concentrations were analyzed from simultaneous arterial and jugular bulb venous blood samples. There were no significant differences in the dose of propofol administered to induce anesthesia (0.52 mg/kg both groups). However there were significant differences between the groups in the mean induction times (309 and 156 s), and in median arterial and venous concentrations at induction. Arterial concentrations were 1.93 and 2.70 and venous 1.11 and 1.51 micrograms/mL. There were no significant differences between the groups in the area between the arterial and venous time concentration curves from start of infusion to loss of consciousness (3.14 and 3.05 micrograms.mL-1.min-1). This study confirms that a target blood concentration of propofol cannot be identified with loss of consciousness under nonsteady state conditions. Both arterial and venous blood propofol concentrations at loss of consciousness depend on the rate of administration.