Plasma Propofol Concentrations Research Articles

Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo. Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR). Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89-128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients' sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time-plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup. No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

Bi-spectral index, entropy and predicted plasma propofol concentrations with target controlled infusions in Indian patients

Many processed electroencephalographic signals are used now to help the anaesthesiologist titrate the depth of sedation. We investigated the relationship between target plasma propofol concentration and objective end-points of sedation- Bispectral Index (BIS), State Entropy (SE) and Response Entropy (RE)-at clinical end-points as assessed by Modified Observer Assessment of Alertness/sedation Scale (MOAAS) in Indian patients. Eighteen ASA 1 and 2 Indian adult patients scheduled to undergo elective surgery were included. The target control infusion (TCI) of propofol was administered using 'Diprifusor'. The level of sedation was assessed using MOAAS by the anaesthesiologist. BIS, SE, RE were recorded throughout. TCI was started at 0.5μg/ml and increased by 0.5μg/ml every 6min till MOAAS scores reached 0 or there was sustained BIS value less than 30. The EC(50) and EC(95) of predicted plasma propofol concentration for loss of consciousness (assessed by loss of response to verbal command), were 2.3 and 2.8μg/ml respectively and for loss of response to painful stimuli (trapezius squeeze) were 4.0 and 5.0μg/ml respectively. The BIS and entropy values (EC(50) and EC(95)) for loss of consciousness and response to painful stimuli in Indian patients were estimated. The preliminary relation of target plasma propofol concentration with BIS was found to be BIS=100.5-16.4 × (Target concentration). The target plasma propofol concentrations required to produce unconsciousness and loss of response to painful stimuli in Indian patients have been estimated. Also, the relations between target plasma concentration and objective measures of different levels of anaesthesia have been established.

Cardiac Output and Propofol Concentrations in Prone Surgical Patients

The aim of this study was to compare cardiac output and plasma propofol concentrations in the supine and prone positions in healthy adult patients presenting for lumbar spine surgery. Patients received propofol and remifentanil via effect-site steered target-controlled infusions. Cardiac output and plasma propofol concentration were compared during 20 minutes in the supine position and 20 minutes after positioning on a Wilson frame. Cardiac output did not change significantly over 20 minutes in either position (P = 0.37) and was similar at 20 minutes in the supine (6.1 [1.6] l/minute) and prone positions (6.1 [1.9] l/minute) (P = 0.87). Propofol concentrations were similar in the supine and prone positions at 20 minutes (2.55 [0.89] and 2.53 [0.90] microg/ml; P = 0.93). We conclude that prone positioning on the Wilson frame does not affect cardiac output or plasma propofol concentration.

External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long‐chain triglyceride emulsion propofol in beagle dogs

This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PK-PD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.6-20.5), 1.9%/h, 7.3% (5.4-9.3), and -0.5% (-2.6 to 1.6), 8.7% (7.3-10.1), 2.5%/h, 6.0% (4.1-7.2) for microemulsion propofol, and -9.3% (-11.6 to -6.9), 20.1% (18.2-22.0), 5.1%/h, 7.6% (6.1-9.1) and 5.6% (4.1-7.1), 8.0% (6.9-9.3), 4.7%/h, 4.1% (3.1-5.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PK-PD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration.

Effects of thoracic and lumbar epidural block on depth of propofol sedation

Objective To evaluate the effects of thoracic and lumbar epidural block on the depth of propofol sedation.Methods Forty-five ASA Ⅰ or Ⅱ patients with stomach cancer ( n =15) or colorectal cancer ( n =30) aged 20-64 yr weighing 46-79 kg with body height 151-179 cm undergoing elective radical operation were enrolled in this study.The 30 patients with colorectal cancer were randomly divided into 2 groups ( n =15 each):group control (group Ⅰ ) and group lumbar epidural group(group Ⅱ ).The 15 patients with stomach cancer received thoracic epidural block (group Ⅲ ).Epidural block was performed at L2.3 interspace in groups Ⅰ and Ⅱ and at T9.10 interspace in group Ⅲ.After a test dose of 3 ml 1.5％ lidocaine,a bolus of 1.5％ lidocaine 12 ml (in groups Ⅱ and Ⅲ ) or 12 ml of normal saline (in group Ⅰ ) was injected into epidural space.Target-controlled infusion(TCI) of propofol was started at 12 min after epidural lidocaine.Target plasma concentration of propofol was set at 4 μg/ml.Fentanyl 4 μg/kg was injected iv as soon as the patients lost consciousness.Tracheal intubation was facilitated with vecuronium 0.1 ng/kg.The patients were mechanically ventilated.Radial artery was cannulated for direct BP monitoring and blood sampling.BIS value was monitored (Aspect Medical System).The number of spinal sequent affected in the subarachnoid epidural anesthesia was counted before propofol TCI.Arterial blood sampies were collected at 2,3,4 and 5 min of propofol TCI for determination of plasma concentration of propofol ( by HPLC).BIS value and plasma concentration of propofol calculated by TCI pump were recorded at 2,3,4 and 5 min of propofol TCI.Results The BIS values were significantly lower in groups Ⅱ and Ⅲ than in group Ⅰ and in group Ⅲ than in group Ⅱ.There was no significant difference in plasma propofol concentration measured by HPLC and plasma concentration of propofol calculated by TCI pump.Conclusion The efficacy of thoracic epidural block enhancing propofol sedation is higher than that of lumbar epidural block. Key words: Anesthesia, epidural; Propofol; Conscious sedation

Pharmacokinetics of propofol in patients undergoing total hip replacement

The aim of the study was to investigate the effects of acute hypervolemic hemodilution (HHD) on the pharmacokinetics of propofol in patients undergoing total hip replacement. A total of 16 patients undergoing elective surgery for total hip replacement under general anesthesia in combination with epidural analgesia were randomly assigned to 2 groups: the control group (n = 8) or the HHD group (n = 8). All patients in both groups received lactated Ringer's solution before induction of general anesthesia. In the control group the conventional fluid replacement protocol was used. In the HHD group 4% succinylated gelatin was infused at the rate of 20ml•kg(-1)BW•h(-1 )with a targeted hematocrit of 30. Anesthesia was induced with midazolam 0.04mg•kg(-1), fentanyl 4µg•kg(-1) and propofol 1.5mg•kg(-1). Tracheal intubation was facilitated by infusion of succinylcholine 2mg•kg(-1). Anesthesia was maintained with isoflurane, fentanyl, vecuronium and epidural analgesia. Electrocardiogram (ECG), blood pressure (BP), blood oxygen saturation (SpO(2)), partial pressure of end-tidal carbon dioxide (P(ET)CO(2)) and central venous pressure (CVP) were monitored continuously. Blood samples were taken at 1, 2, 4, 6, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 300 and 360min after propofol administration to determine plasma concentrations of propofol by high performance liquid chromatography (HPLC). Plasma propofol concentrations were significantly lower in the HHD group than in the control group at 1, 2, 4, 6 and 10min after propofol administration (p < 0.01) while there were no significant differences in plasma propofol levels 15-360min after administration of propofol (p > 0.05). In the HHD group the volume of distribution of the central compartment (V(C)) increased significantly, elimination half-life (T(1/2) (γ)) was significantly prolonged, the elimination rate constant (K(10)) and the whole-body clearance (CL) were significantly decreased compared with the control group (p < 0.01 or 0.05). There were no significant differences of the half-life of the fast distribution phase (T(1/2) (α)), half-life of the slower distribution phase (T(1/2) (β)), K(12), K(21), K(13), K(31) and the area under the curve (AUC) (p > 0.05). The pharmacokinetic profile of propofol is best described by a three-compartment model in both groups using minimal Akaike information criteria (AIC). Acute HHD increases V(C), prolongs the T(1/2) (γ), and decreases K(10) and CL, which suggests that care must be taken when propofol is used in patients undergoing HHD. The induction dose should be increased, but the maintenance dose should be decreased. The time to emergency from anesthesia will likely be prolonged, especially in patients receiving prolonged continuous infusions.

Myocardial Blood Flow during General Anesthesia with Xenon in Humans

Xenon has only minimal hemodynamic side effects and induces pharmacologic preconditioning. Thus, the use of xenon could be an interesting option in patients at risk for perioperative myocardial ischemia. However, little is known about the effects of xenon anesthesia on myocardial blood flow (MBF) and coronary vascular resistance in humans. Myocardial blood flow was noninvasively quantified by H₂¹⁵O positron emission tomography in six healthy volunteers (age: 38 ± 8 yr). MBF was measured at baseline and during general anesthesia induced with propofol and maintained with xenon, 59 ± 0%. Absolute quantification of MBF was started after the calculated plasma concentration of propofol had decreased to less than 1.5 μg · ml⁻¹. Compared with baseline (MBFbaseline, 1.03 ± 0.09 ml · min⁻¹ · g⁻¹; mean ± SD), MBF was decreased insignificantly by xenon (MBFxenon, 0.80 ± 0.22 ml · min⁻¹ · g⁻¹; -21%, P = 0.11). Xenon decreased the rate-pressure product (RPP; heart rate × systolic arterial pressure), an indicator of cardiac work and myocardial oxygen consumption (-15%, P < 0.04). When correcting for the RPP, the decrease in MBF observed during xenon anesthesia was reduced to -9% (MBFcorr-xenon, 1.42 ± 0.28 ml · g⁻¹ · mmHg⁻¹ vs. MBFcorr-baseline, 1.60 ± 0.28 ml · g⁻¹ · mmHg⁻¹, P = 0.32). Xenon did not affect the dependency of MBF on the RPP. Coronary vascular resistance did not significantly change (+15 ± 23%, P = 0.18) during xenon anesthesia. In healthy subjects, xenon has only minimal effects on coronary flow dynamics. These effects are probably of indirect nature, reflecting the decrease in myocardial oxygen consumption induced by the effects of xenon anesthesia on cardiac work.

Pharmacokinetics of propofol when combined with remifentanil in patients with liver cirrhosis

Objective To investigate the pharmacokinetics of propofol when combined with remifentanil in patients with liver cirrhosis.Methods Ten patients (5 males, 5 females) with liver cirrhosis scheduled for endoscopic esophageal varix ligation (test group) and 10 cases (5 males, 5 females) with normal liver function scheduled for gastroscopy (control group), aged 18-55 yr, weighing 40-75 kg, were studied. The patients were unpremedicated. All the patients received iv injection of propofol 1.5 mg/kg and remifentanil 0.5 μg/kg, and 5 min later propofol 0.5 mg/kg and remifentanil 0.2 μg/kg was given again. Blood samples were taken from radial artery before administration and at 2, 5, 10, 15, 20, 30, 45, 60, 80 and 120 min after administration for determination of the plasma propofol concentration using gas chromatography-mass spectrography. The pharmacokinetic parameters were calculated using DAS 2.0 software.Results The pharmacokinetics of propofol was best described by a three-compartment open model. There was no significant difference in the distribution half-life, elimination halflife , terminal half-life, area under the curve and transfer rate constant between the two groups ( P ＞ 0.05) . The apparent volume of distribution of propofol and clearance were significantly increased in test group compared with control group (P ＜0.01) .Conclusion When propofol combined with remifentanil is used in patients with liver cirrhosis, the apparent volume of distribution of propofol and clearance are significantly increased, while no changes in the other pharmacokinetic parameters are found. Key words: Propofol; Piperidines; liver cirrhosis; Pharmacokinetics

Mo1468 Assessment of Propofol Concentration in Plasma During ERCP - A Preliminary Report of Comparison Between BIS (Bispectral Index) and Clinical Parameter in Deep Sedated Patient

Mo1468 Assessment of Propofol Concentration in Plasma During ERCP - A Preliminary Report of Comparison Between BIS (Bispectral Index) and Clinical Parameter in Deep Sedated Patient

Effect of remifentanil on plasma propofol concentration and bispectral index during propofol anaesthesia

BackgroundPropofol and remifentanil are commonly administered together in clinical anaesthesia, but the effect of remifentanil on the plasma concentration of propofol has yet to be established. The aim of the present study was to investigate the effect of remifentanil on plasma propofol concentrations (Cp) in the absence of surgical stimulation. MethodsThirty-eight patients undergoing elective gynaecologic surgery were randomly assigned to receive one of the three remifentanil doses (0, 0.5, or 1.0 µg kg−1 min−1). Anaesthesia was induced by a target-controlled infusion of propofol. After tracheal intubation, saline or remifentanil infusion was administered for 15 min. Mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) were recorded and cardiac index (CI), blood volume, and indocyanine green disappearance ratio (K-ICG) were measured using a dye densitogram analyser before and 15 min after saline or remifentanil infusion. Cp was measured using high-performance liquid chromatography. ResultsHR, K-ICG, and BIS were significantly decreased in the remifentanil 0 µg kg−1 min−1 group. The decrease in MAP, HR, CI, and K-ICG was significantly lower in the remifentanil 0.5 and 1.0 µg kg−1 min−1 groups compared with the remifentanil 0 µg kg−1 min−1 group. Cp was significantly increased after remifentanil administration, but this had no influence on BIS. ConclusionsRemifentanil reduced the CI and increased the Cp, which may be related to a decrease in the K-ICG, but had no significant effect on the BIS.

Dogs mean arterial pressure and heart rate responses during high propofol plasma concentrations estimated by a pharmacokinetic model

Propofol total intravenous anesthesia should provide stability of the cardiovascular system. In this study, mean arterial pressure and heart rate were evaluated in eight healthy dogs anesthetized with increasing rates of propofol. The cerebral state index (CSI) was studied as an additional parameter. Although the estimated propofol plasma concentration reached a maximal value of 15.3 μg ml −1, no hypotension or bradycardia were observed. Exploration of each animal’s data revealed high inter-individual variability regarding mean arterial pressure and heart rate. Considering the logarithmic of the concentration, a moderate depressant effect of propofol on mean arterial pressure was revealed in five dogs but the effect was not followed on heart rate.

Effects of propofol on isoflurane minimum alveolar concentration and cardiovascular function in mechanically ventilated goats

ObjectiveTo evaluate the effects of propofol, on isoflurane minimum alveolar concentration (MAC) and cardiovascular function in mechanically ventilated goats. Study designProspective, randomized, crossover experimental study. AnimalsSix goats, three does and three wethers. MethodsGeneral anaesthesia was induced with isoflurane in oxygen. Following endotracheal intubation, anaesthesia was maintained with isoflurane in oxygen. Intermittent positive pressure ventilation was applied. Baseline isoflurane MAC was determined, the noxious stimulus used being clamping a claw. The goats then received, on separate occasions, three propofol treatments intravenously: bolus of 0.5 mg kg−1 followed by a constant rate infusion (CRI) of 0.05 mg kg−1 minute−1 (treatment LPROP); bolus of 1.0 mg kg−1 followed by a CRI of 0.1 mg kg−1 minute−1 (treatment MPROP), bolus of 2.0 mg kg−1 followed by a CRI of 0.2 mg kg−1 minute−1 (treatment HPROP). Isoflurane MAC was re-determined following propofol treatments. Plasma propofol concentrations at the time of MAC confirmation were measured. Cardiopulmonary parameters were monitored throughout the anaesthetic period. Quality of recovery was scored. The Friedman test was used to test for differences between isoflurane MACs. Medians of repeatedly measured cardiovascular parameters were tested for differences between and within treatments using repeated anova by ranks (p < 0.05 for statistical significance). ResultsIsoflurane MAC [median (interquartile range)] was 1.37 (1.36–1.37) vol%. Propofol CRI significantly reduced the isoflurane MAC, to 1.15 (1.08–1.15), 0.90 (0.87–0.93) and 0.55 (0.49–0.58) vol% following LPROP, MPROP and HPROP treatment, respectively. Increasing plasma propofol concentrations strongly correlated (Spearman rank correlation) with decrease in MAC (Rho = 0.91). Cardiovascular function was not affected significantly by propofol treatment. Quality of recovery was satisfactory. Conclusions and clinical relevanceIn goats, propofol reduces isoflurane MAC in a dose-dependent manner with minimal cardiovascular effects.

Individual Differences in Pharmacokinetics and Pharmacodynamics of Anesthetic Agent Propofol with Regard to CYP2B6 and UGT1A9 Genotype and Patient Age

Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42-84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fsucata fsucata)

ObjectiveTo describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model. Study designProspective experimental trial. AnimalsFour male macaques (5-6 years old, 8.0-11.2 kg). MethodsThe macaque was restrained and 8 mg kg−1 of propofol was administrated intravenously at 6 mg kg−1 minute−1. Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI. ResultsMacaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5) minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute−1 and 72-144 beats minute−1, respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V1 = 10.4 L, V2=8.38 L, V3=72.7 L, CL1= 0.442 L minute−1, CL2= 1.14 L minute−1, CL3= 0.313 L minute−1, (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively). ConclusionsIntravenous administration of propofol (8 mg kg−1) at 6 mg kg−1 minute−1 to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours. Clinical relevanceThe developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.

Effects of propofol on the minimum alveolar concentration of sevoflurane for immobility at skin incision in adult patients

Study Objective To determine the effect of propofol on skin incision at target plasma concentrations of one to 6 μg/mL on the minimum alveolar concentration (MAC) of sevoflurane. Design Prospective, randomized, single-blinded study. Setting Operating room of a university hospital. Patients 122 adult, ASA physical status I and II patients with cholecystitis and gastric cancer, presenting for elective abdominal surgery. Interventions Each group received propofol at different target-controlled plasma concentrations of 0, 1, 2, 3, 4, 5 and 6 μg/mL, respectively. The end-tidal concentration of sevoflurane was stable at a predetermined value for at least 15 minutes. Skin incision was performed after return of neuromuscular function. Measurements Patients were observed for gross purposeful movement for one minute after skin incision. Heart rate and mean arterial pressure were recorded before induction of anesthesia, before incision, and after incision. Main Results The MAC of sevoflurane when used alone was 2.2% ± 0.11%. Propofol decreased the MAC of sevoflurane by 12.3% at one μg/mL, 30.5% at two μg/mL, 35% at three μg/mL, 46.8% at 4 μg/mL, 57.7% at 5 μg/mL, and 72.7% at 6 μg/mL. The linear regression equation of the interaction between sevoflurane and propofol was Y = 2.1679 – 0.256 X, R 2 = 0.9407, where X = plasma propofol concentration, Y = sevoflurane concentration, and R 2 = correlation coefficient. Conclusions Propofol decreases the MAC of sevoflurane in a concentration-dependent manner in adult patients.

The Performance of Compartmental and Physiologically Based Recirculatory Pharmacokinetic Models for Propofol

With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. Three compartmental PK models for propofol, called the "Marsh," the "Schnider," and the "Schüttler" models, and 1 physiologically based recirculatory model called the "Upton" model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

Effects of cerebral hypoperfusion on bispectral index: A randomised, controlled animal experiment during haemorrhagic shock

Background The aim of this porcine haemorrhagic shock model was to investigate the changes of bispectral index (BIS) after slow and fast recovery of cerebral perfusion, and its correlation with plasma propofol concentrations. Methods After Animal Investigational Committee approval, 16 pigs during propofol anaesthesia underwent a liver trauma with severe hypotension, and were randomly assigned to receive therapy for either slow recovery (fluid resuscitation; slow group; n = 8) or fast recovery of cerebral perfusion (vasopressor combined with hypertonic-saline-starch; fast group; n = 8), respectively. Cerebral perfusion pressure (CPP = MAP − ICP), cerebral tissue oxygenation index (TOI), BIS, and plasma concentrations of propofol and haemoglobin were measured at baseline (Pre-shock), haemodynamic decompensation (Shock), and 5 (Therapy) and 30 min (End) after therapy, respectively. Results CPP, TOI, and BIS decreased significantly during shock (pre-shock vs. shock, fast: CPP: 65 ± 14 vs. 15 ± 4 mm Hg; TOI: 64 ± 6 vs. 47 ± 7%; BIS 60 ± 5 vs. 9 ± 10; slow: CPP: 60 ± 12 vs. 13 ± 7 mm Hg; TOI: 68 ± 7 vs. 49 ± 7%; BIS 63 ± 5 vs. 13 ± 12; P < 0.05). In the fast group, CPP, TOI, and BIS increased after therapy compared to the slow group (Therapy, fast: CPP: 47 ± 15 mm Hg, TOI: 61 ± 7%, BIS: 47 ± 21; slow: CPP: 18 ± 9 mm Hg, TOI: 51 ± 5%, BIS: 21 ± 19; P < 0.05). Propofol and haemoglobin concentrations were comparable between groups throughout the resuscitation phase. Conclusions In a haemorrhagic shock scenario, therapies with different impact on cerebral perfusion resulted in differing changes of BIS values, while plasma propofol and haemoglobin concentrations were comparable during the resuscitation phase; this suggests that BIS may also have reflected changes of cerebral perfusion.

Thromboelastographic and pharmacokinetic profiles of micro‐ and macro‐emulsions of propofol in swine

Compared with traditional macroemulsion propofol formulations currently in clinical use, microemulsion formulations of this common intravenous anesthetic may offer advantages. The pharmacokinetics and coagulation effects as assessed by thromboelastography of these formulations were characterized in swine. Yorkshire swine (20-30 kg, either sex, n=15) were sedated, anesthetized with isoflurane, and instrumented to obtain a tracheostomy, internal jugular access and carotid artery catheterization. Propofol (2 mg/kg, 30 s) was administered as a macroemulsion (10 mg/ml; Diprivan; n=7) or a custom (2 mg/kg, 30 s) microemulsion (10 mg/ml; n=8). Arterial blood specimens acquired pre- and post-injection (1 and 45 min) were used for thromboelastography. Arterial blood specimens (n=12 samples/subject, 60 min) were serially collected, centrifuged and analysed with solid-phase extraction with UPLC to determine propofol plasma concentrations. Non-compartmental pharmacokinetic analysis was applied to plasma concentrations. No changes were noted in the thromboelastographic R time (p=0.74), K time (p=0.41), alpha angle (p=0.97), or maximal amplitude (p=0.71) for either propofol preparation. Pharmacokinetic parameters k (p=0.45), t(1/2) (p=0.26), C(o) (p=0.89), AUC(0-infinity) (p=0.23), CL (p=0.14), MRT (p=0.47), V(ss) (p=0.11) of the two formulations were not significantly different. The microemulsion and macroemulsion propofol formulations had similar pharmacokinetics and did not modify thromboelastographic parameters in swine.

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.