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Background: Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia., Methods: The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria., Results: For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce 50 ., Conclusions: The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here, the novel petal-shaped ionic liquids modified covalent organic frameworks (PS-IL-COFs) particles have been synthesized by using ionic liquids as modifying agent, which could be beneficial to avoid the aggregation of COFs during the preparation and improve its dispersing performance. The novel PS-IL-COFs particles have been used and evaluated in the one step cleanup and extraction (OSCE) procedure for human plasma prior to the analysis of 3 general anesthetics by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). In the OSCE procedure, human plasma samples are directly mixed with extraction solvent and PS-IL-COFs particles, and the extraction and cleanup procedure have been carried out simultaneously. Compared with the Oasis PRiME HLB cartridge method, the OSCE procedure using PS-IL-COFs particles as sorbents is much more effective for the minimization of ion suppression resulted from blood phospholipids. Under optimal conditions, the PS-IL-COFs particles show higher cleanup efficiency of 3 general anesthetics with recoveries in the range of 82.5%-115%. The limits of quantification (LOQs) for propofol, ketamine and etomidate are 0.18 μg/L, 0.15 μg/L and 0.016 μg/L, respectively. Validation results on linearity, specificity, precision and trueness, as well as on the application to analysis of general anesthetics in a case of a 54-year-old female suffered gallstone demonstrate the applicability to clinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The concentration of propofol in blood is an important indicator for anesthesiologists to monitor and regulate the anesthesia depth of patients during surgery. Herein, a negative photoionization ion mobility spectrometry with acetone as the dopant was developed for rapid and direct determination of intraoperative blood propofol concentration in the operating theatre. High concentration of acetone molecules in the carrier gas was used not only to enhance neutral desorption and release free propofol molecules from the whole blood, but also to increase the intensity of reactant O 2 - and reduce the amount of non-reactive CO 3 - ions simultaneously, which allowed to measure trace propofol in less than 2 min without any tedious pretreatment. Under optimized conditions, a linear calibration curve of propofol was obtained with the range of 0.5-20 ng μL -1 and with a limit of detection of 0.14 ng μL -1 , which met the clinical requirements and correlated well with standard HPLC methods. Finally, the method was applied to detect intraoperative blood propofol concentration in nearly 100 surgical patients, demonstrating its excellent detection capability and facilitating the study of propofol pharmacokinetics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The ionisation of propofol was studied on the basis of analyte adduct formation with the components of the mobile phase. The identification of an appropriate propofol adduct ion generated in an acetate salt based buffer in the negative electrospray ionisation mode made the propofol LC-MS/MS analysis with two multiple reaction monitoring experiments possible without analyte derivatisation. Since a product ion of the deprotonated analyte was also used in the detection, these two fragmentation experiments were performed with different precursor ions. Liquid-liquid extraction with 1-chlorobutane was applied for sample preparation. A Luna 5 μm C18 (2) 100 A, 150 mm × 2 mm analytical column together with a mobile phase composed of water/methanol (3/97, v/v) with 10 mmol·L -1 ammonium acetate and 0.1% acetic acid were applied. The limit of detection and quantification were 0.02 mg/L and 0.06 mg/L appropriate. Other results of the validation experiments performed like linearity of the calibration range, accuracy and precision, processed sample stability, recovery, matrix effect and selectivity revealed that this propofol quantification strategy developed can be defined as an applicable alternative to other methods presented., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The modified Marsh and Schnider pharmacokinetic models for propofol consistently produce negatively and positively biased predictions in underweight patients, respectively. We aimed to develop a new pharmacokinetic model of propofol in underweight patients., Methods: Twenty underweight (BMI<18.5 kg m -2 ) patients aged 20-68 yr were given an i.v. bolus of propofol (2 mg kg -1 ) for induction of anaesthesia. Anaesthesia was maintained with a zero-order infusion (8 mg kg -1 h -1 ) of propofol and target-controlled infusion of remifentanil. Arterial blood was sampled at preset intervals. A population pharmacokinetic analysis was performed using non-linear mixed effects modelling. The time to peak effect (t peak , maximally reduced bispectral index) was measured in 28 additional underweight patients receiving propofol 2 mg kg -1 ., Results: In total, 455 plasma concentration measurements from the 20 patients were used to characterise the pharmacokinetics of propofol. A three-compartment mammillary model well described the propofol concentration time course. BMI and lean body mass (LBM) calculated using the Janmahasatian formula were significant covariates for the rapid peripheral volume of distribution and for the clearance of the final pharmacokinetic model of propofol, respectively. The parameter estimates were as follows: V 1 (L)=2.02, V 2 (L)=12.9 (BMI/18.5) , V 3 (L)=139, Cl (L⋅min -1 )=1.66 (LBM/40) , Q 1 (L⋅min -1 )=1.44, Q 2 (L⋅min -1 )=0.87+0.0189×(LBM-40). The median t peak of propofol was 1.32 min (n=48)., Conclusions: A three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients., Clinical Trial Registration: KCT0001760., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To test the hypothesis that plasma propofol concentration (PPC) is associated with anesthetic effect in koi carp administered propofol by immersion., Study Design: Prospective study., Animals: Twenty mature koi carp (mean ± standard deviation, 409.4 ± 83.7 g)., Methods: Fish were immersed in propofol (5 mg L -1 ). Physiological variables and induction and recovery times were recorded. In phase I, blood was sampled for PPC immediately following induction and at recovery. In phase II, following induction, fish were maintained with propofol (4 mg L -1 ) via a recirculating system for 20 minutes. Following established induction, blood was sampled at 1, 10 and 20 minutes. In phase III (n = 19), fish were anesthetized as in phase II with blood sampled nine times in a sparse sampling strategy. Simultaneously, a pharmacodynamics rubric was used to evaluate anesthetic depth. PPC was determined using high performance liquid chromatography with fluorescence detection. Following evaluation of normality, data were analyzed using paired t test or Spearman correlation test (significance was set at p < 0.05)., Results: In phase I, mean PPCs at induction (20.12 μg mL -1 ) and recovery (11.62 μg mL -1 ) were different (p < 0.001). In phase II, only mean PPCs at induction (17.92 μg mL -1 ) and 10 minutes (21.50 μg mL -1 ) were different (p = 0.013). In phase III, a correlation between PPCs and the pharmacodynamic rubric scores was found (p < 0.001, r = -0.93). There was no correlation between PPCs and recovery time (p = 0.057, r = 0.433). A two-compartment open model was chosen for the pharmacokinetic model. Absorption rate constant, elimination rate constant and intercompartmental rate constant were 0.48, 0.006 and 0.02 minute -1 , respectively., Conclusions and Clinical Relevance: Measurable PPCs were achieved in koi carp anesthetized with propofol by immersion. Anesthetic depth of fish was negatively correlated with PPCs, but recovery time was not., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: The objective of this study was to apply a pharmacokinetics-pharmacodynamics approach to investigate the free propofol plasma levels in patients undergoing coronary artery bypass grafting under hypothermic conditions compared with the off-pump procedure., Methods: Nineteen patients scheduled for on-pump coronary artery bypass grafting under hypothermic conditions (n=10) or the equivalent off-pump surgery (n=9) were anesthetized with sufentanil and propofol target-controlled infusion (2 μg/mL) during surgery. The propofol concentration was then reduced to 1 μg/mL, and a pharmacokinetics-pharmacodynamics analysis using the maximum-effect-sigmoid model obtained by plotting the bispectral index values against the free propofol plasma levels was performed., Results: Significant increases (two- to five-fold) in the free propofol plasma levels were observed in the patients subjected to coronary artery bypass grafting under hypothermic conditions. The pharmacokinetics of propofol varied according to the free drug levels in the hypothermic on-pump group versus the off-pump group. After hypothermic coronary artery bypass was initiated, the distribution volume increased, and the distribution half-life was prolonged. Propofol target-controlled infusion was discontinued when orotracheal extubation was indicated, and the time to patient extubation was significantly higher in the hypothermic on-pump group than in the off-pump group (459 versus 273 min, p=0.0048)., Conclusions: The orotracheal intubation time was significantly longer in the hypothermic on-pump group than in the off-pump group. Additionally, residual hypnosis was identified through the pharmacokinetics-pharmacodynamics approach based on decreases in drug plasma protein binding in the hypothermic on-pump group, which could explain the increased hypnosis observed with this drug in this group of patients.

Background: Target controlled infusion (TCI) systems use population-based pharmacokinetic (PK) models that do not take into account inter-individual residual variation. This study compares the bias and inaccuracy of a population-based vs a personalized TCI propofol titration using Bayesian adaptation. Haemodynamic and hypnotic stability, and the prediction probability of alternative PK models, was studied., Methods: A double-blinded, prospective randomized controlled trial of 120 subjects undergoing cardiac surgery was conducted. Blood samples were obtained at 10, 35, 50, 65, 75 and 120 min and analysed using a point-of-care propofol blood analyser. Bayesian adaptation of the PK model was applied at 60 min in the intervention group. Median (Absolute) Performance Error (Md(A)PE) was used to evaluate the difference between bias and inaccuracy of the models. Haemodynamic (mean arterial pressure [MAP], heart rate) and hypnotic (bispectral index [BIS]) stability was studied. The predictive performance of four alternative propofol PK models was studied., Results: MdPE and MdAPE did not differ between groups during the pre-adjustment period (control group: 6.3% and 16%; intervention group: 5.4% and 18%). MdPE differed in the post-adjustment period (12% vs. -0.3%), but MdAPE did not (18% vs. 15%). No difference in heart rate, MAP or BIS was found. Compared with the other models, the Eleveld propofol PK model (patients) showed the best prediction performance., Conclusions: When an accurate population-based PK model was used for propofol TCI, Bayesian adaption of the model improved bias but not precision., Clinical Trial Registration: Dutch Trial Registry NTR4518., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIR NM )., Study Design: Randomized crossover, unmasked, experimental design., Animals: Three male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg., Methods: Dogs were studied on three occasions at weekly intervals. Premedications were 0.9% saline (treatment P) or dexmedetomidine (1 μg kg -1 , treatment PLD; 2 μg kg -1 , treatment PHD) intravenously. Anesthesia was induced with propofol (2 mg kg -1 and then 1 mg kg -1 every 15 seconds) until intubation. Anesthesia was maintained for 90 minutes in P with propofol (0.5 mg kg -1 minute -1 ) and saline, in PLD with propofol (0.35 mg kg -1 minute -1 ) and dexmedetomidine (1 μg kg -1 hour -1 ), and in PHD with propofol (0.3 mg kg -1 minute -1 ) and dexmedetomidine (2 μg kg -1 hour -1 ). The stimulus (50 V, 50 Hz, 10 ms) was applied to the antebrachium, and propofol infusion was increased or decreased by 0.025 mg kg -1 minute -1 based on a positive or negative response, respectively. Data were analyzed using a mixed-model anova and presented as mean ± standard error., Results: Propofol induction doses were 8.68 ± 0.57 (P), 6.13 ± 0.67 (PLD) and 4.78 ± 0.39 (PHD) mg kg -1 and differed among treatments (p < 0.05). Propofol MIR NM values were 0.68 ± 0.13, 0.49 ± 0.16 and 0.26 ± 0.05 mg kg -1 minute -1 for P, PLD and PHD, respectively. Propofol MIR NM decreased 59% in PHD (p < 0.05). Plasma propofol concentrations were 14.04 ± 2.30 (P), 11.30 ± 4.30 (PLD) and 7.96 ± 0.72 (PHD) μg mL -1 and dexmedetomidine concentrations were 0.68 ± 0.12 (PLD) and 0.89 ± 0.08 (PHD) ng mL -1 at MIR NM determination., Conclusions and Clinical Relevance: Dexmedetomidine (1 and 2 μg kg -1 ) decreased propofol induction dose. Dexmedetomidine (2 μg kg -1 hour -1 ) resulted in a significant decrease in propofol MIR NM ., (Published by Elsevier Ltd.)

Objective: This study aims to describe the administration of propofol in combination with remifentanil for the induction of general anesthesia during cesarean section (CS). Our aim was to evaluate its impact on the drug concentrations of the maternal and neonatal blood at different induction of anesthesia to delivery (I-D) intervals as well as its effect on newborns., Materials and Methods: In this double-blind randomized controlled study, patients undergoing elective CS were administered anesthesia at short (n = 20) or long (n = 20) I-D intervals. Anesthesia was induced with 1 mg/kg propofol and 1 μg/kg remifentanil and maintained by continuous infusion of 3 mg/kg/h propofol and 7 μg/kg/h remifentanil., Results: The mean plasma propofol concentrations at delivery in the maternal arterial (MA) blood and the fetal umbilical arterial (UA) and venous (UV) blood in the short I-D interval group were 1.91, 1.17, and 0.51 μg/mL, respectively, while those in the long I-D interval group were 1.57, 1.07, and 0.61 μg/mL, respectively. The mean plasma remifentanil concentrations at delivery in the MA, UA, and UV in the short I-D interval group were 2.25, 1.43, and 0.65 ng/mL, respectively, and those in the long I-D interval group were 1.96, 1.25, and 0.75 ng/mL, respectively. There were no statistically significant differences in the neonatal Apgar scores and neurological adaptive capacity scores between the two groups., Conclusions: It is safe to administer propofol in combination with remifentanil by continuous infusion after the bolus dose for the induction of anesthesia during cesarean section. Prolonging the I-D interval within a certain limit will not have any significant influence on the fetus., (Copyright © 2017. Published by Elsevier B.V.)

Background: : In our preliminary study, the modified Marsh (M-Marsh) model caused an inadvertent underdosing of propofol in underweight patients. However, the predictive performance of the M-Marsh and Schnider models incorporated in commercially available target-controlled infusion (TCI) pumps was not evaluated in underweight patients., Methods: : Thirty underweight patients undergoing elective surgery were randomly allocated to receive propofol via TCI using the M-Marsh or Schnider models. The target effect-site concentrations (Ces) of propofol were, in order, 2.5, 3, 4, 5, 6 and 2 μg ml -1 . Arterial blood samples were obtained at least 7 min after achieving each pseudo-steady-state., Results: A total of 172 plasma samples were used to determine the predictive performance of both models. The pooled median (95% confidence interval) biases and inaccuracies at a target Ce ≤ 3 μg ml -1 were -22.6 (-28.8 to -12.6) and 31.9 (24.8-36.8) for the M-Marsh model and 9.0 (1.7-16.4) and 28.5 (21.7-32.8) for the Schnider model, respectively. These values at Ce ≥ 4 μg ml -1 were -9.6 (-16.0 to -6.0) and 24.7 (21.1-27.9) for the M-Marsh model and 19.8 (12.9-25.7) and 36.2 (31.4-39.7) for the Schnider model, respectively., Conclusions: The pooled biases and inaccuracies of both models were clinically acceptable. However, the M-Marsh and Schnider models consistently produced negatively and positively biased predictions, respectively, in underweight patients. In particular, the M-Marsh model showed greater inaccuracy at target Ce   ≤   3 μg ml -1 and the Schnider model showed greater inaccuracy at target Ce ≥ 4 μg ml -1 . Therefore, it is necessary to develop a new pharmacokinetic model for propofol in underweight patients., Clinical Trial Registration: KCT0001502., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To evaluate the propofol requirement, cardiovascular and respiratory variables using midazolam or lidocaine with a propofol target-controlled infusion (PTCI) for induction of anaesthesia in healthy dogs., Study Design: Prospective, randomized, controlled blinded clinical trial., Animals: Sixty client-owned dogs [American Society of Anesthesiologists (ASA) I-II] undergoing surgical procedures., Methods: Thirty minutes after premedication with acepromazine (0.03 mg kg(-1) ) and morphine (0.2 mg kg(-1) ), PTCI was started and maintained at a plasma target concentration of 1 μg mL(-1) . Three minutes later, dogs (n = 20 per group) received either 5 mL 0.9% sodium chloride (SG), 2 mg kg(-1) of lidocaine (LG) or 0.2 mg kg(-1) of midazolam (MG) intravenously (IV) as a co-induction agent. Two minutes later, suitability for endotracheal intubation was assessed. If intubation was not possible, the propofol target was increased by 0.5 μg mL(-1) every 60 seconds until it was successfully achieved. Heart rate (HR), respiratory rate (fR ), and oscillometric systolic arterial pressure (SAP), mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were recorded immediately prior to commencing PTCI (B0), prior to intubation (BI), immediately after (T0), and at 3 (T3) and 5 (T5) minutes post-intubation. End-tidal partial pressures of carbon dioxide (PE(') CO2 ) were recorded at T0, T3 and T5. The occurrence of excitement at any time point was noted., Results: The median (range) propofol target concentration for endotracheal intubation was significantly lower in MG, 1.5 (1.0-4.0) μg mL(-1) compared with LG, 2.5 (1.5-4.5) μg mL(-1) or SG, 3.0 (2.0-5.0) μg mL(-1) . Heart rate, MAP, fR and PE(') CO2 were similar in the three groups at all time points. No excitement was reported in any dog., Conclusions and Clinical Relevance: Midazolam, but not lidocaine, provided a significant reduction in PTCI requirement for induction of anaesthesia thereby allowing successful intubation. However, cardiovascular and respiratory effects were not different between the groups., (© 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Combining resting-state functional magnetic resonance imaging (fMRI) connectivity and behavioral analysis during sedation, we factored out general effects of the anesthetic drug propofol and a specific index of conscious report, participants' level of responsiveness. The factorial analysis shows that increasing concentration of propofol in blood specifically decreases the connectivity strength of fronto-parietal cortical loops. In contrast, loss of responsiveness is indexed by a functional disconnection between the thalamus and the frontal cortex, balanced by an increase in connectivity strength of the thalamus to the occipital and temporal regions of the cortex.

Objective: To compare the pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol administered intravenously (IV) as a single induction dose in cats., Study Design: Prospective experimental study., Animals: Six healthy adult cats, three female intact, three male castrated, weighing 4.8 ± 1.8 kg., Methods: Cats received 8 mg kg(-1) IV of propofol (P) or propofol with 2% benzyl alcohol (P28) using a randomized crossover design. Venous blood samples were collected at predetermined time points to 24 hours after drug administration to determine drug plasma concentrations. Physiologic and behavioral variables were also recorded. Propofol and benzyl alcohol concentrations were determined using high pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were described using a 2-compartment model. Pharmacokinetic and pharmacodynamic parameters were analyzed using repeated measures anova (p < 0.05)., Results: Plasma concentrations of benzyl alcohol were below the lower limits of quantification (LLOQ) at all time points for two of the six cats (33%), and by 30 minutes for the remaining four cats. Propofol pharmacokinetics, with or without 2% benzyl alcohol, were characterized by rapid distribution, a long elimination phase, and a large volume of distribution. No differences were noted between treatments with the exception of clearance from the second compartment (CLD2), which was 23.6 and 38.8 mL kg(-1)  minute(-1) in the P and P28 treatments, respectively. Physiologic and behavioral variables were not different between treatments with the exception of heart rate at 4 hours post administration., Conclusions and Clinical Relevance: The addition of 2% benzyl alcohol as a preservative minimally altered the pharmacokinetics and pharmacodynamics of propofol 1% emulsion when administered as a single IV bolus in this group of cats. These data support the cautious use of propofol with 2% benzyl alcohol for induction of anesthesia in healthy cats., (© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Study Objective: To examine the influence of epidural and intravenous (IV) lidocaine, and height of the epidural sensory block, on the dose of propofol required for induction of general anesthesia., Design: Randomized controlled study., Setting: University hospital., Patients: 66 adult, ASA physical status 1 and 2 patients, aged 25 to 65 years, undergoing elective abdominal surgery., Interventions: Patients were randomized to 4 groups: the epidural saline control group (Group C; L2-L3 puncture, epidural and IV saline), the IV lidocaine group (Group IV; L2-L3 puncture, saline epidural, IV lidocaine 1 mg/kg), the lumbar epidural lidocaine group (Group EL; L2-L3 puncture, 1.5% lidocaine epidural, IV saline), and the thoracic epidural lidocaine group (Group ET; T9-T10 puncture, 1.5%lidocaine epidural, IV saline). Two minutes after the beginning of the infusion of IV lidocaine or saline, propofol anesthesia was initiated., Measurements: Mean arterial blood pressure (MAP), heart rate (HR), and sensory block height were monitored. The induction dose of propofol, its estimated effect-site concentration (Ce), and plasma concentration were measured at various time points. Finally, we recorded the time taken for the bispectral index (BIS) to decrease to 60, the plasma concentration of lidocaine at induction, and the occurrence of adverse events. The induction time (when BIS reached 60) also was recorded., Main Results: The induction propofol dose, Ce, and plasma concentration of propofol when BIS equaled 60 were significantly lower in Group IV, Group EL, and Group ET than Group C. The above parameters in Group ET (T9 - T10 puncture) were significantly less than in Group EL (L2 - L3 puncture). The induction doses of propofol and plasma concentration of propofol and lidocaine were significantly higher in Group IV than in Groups EL or ET., Conclusions: Epidural and IV lidocaine reduce the dose of propofol required to induce general anesthesia. Administration of lidocaine via the epidural route reduces anesthetic requirements more so than the IV route. Propofol requirements were further reduced in patients with higher sensory epidural block., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Although pilot studies have reported that exhaled propofol concentrations can reflect intraoperative plasma propofol concentrations in an individual, the blood/exhaled partial pressure ratio RBE varies between patients, and the relevant factors have not yet been clearly addressed. No efficient method has been reported for the quick evaluation of RBE and its association with inter-individual variables., Methods: We proposed a novel method that uses a surface acoustic wave (SAW) sensor combined with a fast gas chromatograph (GC) to simultaneously detect propofol concentrations in blood and exhaled gas in 28 patients who were receiving propofol i.v. A two-compartment pharmacokinetic (PK) model was established to simulate propofol concentrations in exhaled gas and blood after a bolus injection. Simulated propofol concentrations for exhaled gas and blood were used in a linear regression model to evaluate RBE., Results: The fast GC-SAW system showed reliability and efficiency for simultaneous quantitative determination of propofol in blood (correlation coefficient R(2)=0.994, P<0.01) and exhaled gas (R(2)=0.991, P<0.01). The evaluation of RBE takes <50 min for a patient. The distribution of RBE in 28 patients showed inter-individual differences in RBE (median 1.27; inter-quartile range 1.07-1.59)., Conclusions: Fast GC-SAW, which analyses samples in seconds, can perform both rapid monitoring of exhaled propofol concentrations and fast analysis of blood propofol concentrations. The proposed method allows early determination of the coefficient RBE in individuals. Further studies are required to quantify the distribution of RBE in a larger cohort and assess the effect of other potential factors., Clinical Trial Registration: ChiCTR-ONC-13003291., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Objective: To determine the effects of a small-dose ketamine-propofol combination used for sedation during spinal anesthesia on tourniquet-induced ischemia-reperfusion injury., Study Design: Prospective randomized study., Setting: Training and research hospital., Patients: 60 adult, ASA physical status 1 and 2 patients, ages 20-60 years, scheduled for elective arthroscopic knee surgery for meniscal and chondral lesions., Interventions: The initial hemodynamic parameters were recorded and blood samples were collected at baseline (T1); then spinal anesthesia was performed. In Group I (n=30), a combination of 0.5 mg/kg/hr of ketamine and 2 mg/kg/hr of propofol was administered; Group II (n=30) received an equivalent volume of saline as an infusion. A pneumatic tourniquet was applied., Measurements: Malondialdehyde (MDA), superoxide dismutase (SOD), and catalase levels were measured one minute before tournique deflation in the ischemic period (T2), then 5 (T3) and 30 (T4) minutes following tourniquet deflation in the reperfusion period., Main Results: No differences were noted between groups in hemodynamic data (P > 0.05) or SOD levels (P > 0.05). In Group I, MDA levels at T2 were lower than in Group II (P < 0.05). In Group I, catalase levels were lower at T2 and T4 than they were in Group II (P < 0.05)., Conclusion: Small-dose ketamine-propofol combination may be useful in reducing tourniquet-induced ischemia-reperfusion injury in arthroscopic knee surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cytochrome P450 2B6 (CYP2B6) is responsible for the initial biotransformation of profol, an extensively metabolized intravenous anesthetic. In this study we examined the effect of the apparently functional CYP2B6 c.516G>T polymorphism on the distribution of propofol concentrations, quantified by GC/MS analysis following a single bolus dose, in the blood of 44 Greek women undergoing oocyte retrieval. Univariate analysis using age, height, weight and smoking status as covariates, as well as the Mann-Whitney non-parametric test, revealed a strong trend of association of the T allele with high propofol concentrations determined in whole blood, shortly after a single bolus dose. Propofol concentrations which were higher than one standard deviation of the mean were almost invariably associated with carriage of the T allele.

Background: The influence of frontal brain tumours on bispectral index (BIS) measurements and propofol requirements is unknown. The primary aim of our study was to determine whether BIS values recorded at loss and return of consciousness (LOC and ROC, respectively) differ between patients with unilateral frontal brain tumours and control patients. Secondary goals were to compare propofol requirements for LOC and to determine whether there were significant inter-hemispheric differences between BIS values in tumour and control patients., Methods: We enrolled 20 patients with a frontal brain tumour and 20 control patients. Bilateral BIS measurements were done during induction of propofol anaesthesia, during recovery of consciousness, and during a second induction of anaesthesia. The isolated-forearm test was used to determine the moments of LOC1, ROC, and LOC2. Arterial blood samples were obtained every 4 min for determination of measured propofol concentrations., Results: The median BIS values recorded at LOC1, ROC, and LOC2 did not differ between the groups. There were no significant inter-hemispheric differences in BIS in tumour and control patients. The median [inter-quartile range (IQR)] total propofol doses at LOC1 were 82 (75-92) and 78 (68-91) mg in tumour and control patients, respectively. The median (IQR) measured plasma propofol concentrations at LOC1 were 12 (9-14) and 13 (11-15) µg ml(-1) in the tumour and control groups, respectively., Conclusions: The presence of a frontal brain tumour did not affect ipsilateral BIS values, and so need not influence the placement of unilateral BIS electrodes if BIS monitoring is used to titrate propofol anaesthesia.

The authors present a case where a drug-effect parameter, the bispectral index, was used to guide propofol infusion when propofol-remifentanil anesthesia was used for liver transplantation. The target concentration of remifentanil was kept constant throughout the operation, and the bispectral index indicated that propofol infusion was not required during the anhepatic and neohepatic phases of the operation. The measured plasma propofol concentrations during the neohepatic phase were far below the usual values that are used to maintain anesthesia. However, the bispectral index indicated a state of unconsciousness. The patient regained consciousness rapidly several minutes after administration of neostigmine and cessation of remifentanil infusion. The measured plasma propofol concentrations were similar before and after recovery of consciousness. The possible mechanisms for the maintenance of anesthesia at reduced propofol concentrations are multifactorial and may be related to reduced liver function as well as an interaction between propofol and remifentanil or the use of a neuromuscular relaxant to suppress somatic afferent activity., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Background: HX0969w is a novel water-soluble prodrug designed to release propofol and gamma-hydroxybutyrate (GHB) and has a sedative-hypnotic effect. This study was performed to compare the efficacy of HX0969w with fospropofol in mice and rats., Methods: We performed hydrolysis studies in the plasma from mice and rats. The half-maximal effective doses (ED50) and half-maximal lethal doses (LD50) of fospropofol and HX0969w were determined. A pharmacodynamics comparison of these two compounds was also performed. Time to loss of righting reflex, time to return of righting reflex, recovery time, and adverse effects were recorded., Results: The hydrolysis studies demonstrated that HX0969w released propofol as expected. HX0969w ED50 values in mice and rats were 133.03 and 53.79 mg kg(-1), respectively, and LD50 values were 607.11 and 283.79 mg kg(-1), respectively. The calculated therapeutic index (TI), safety index (SI), and certain safety factor (CSF) of HX0969w were 4.56, 3.33, and 2.92 for mice, and 5.28, 3.94, and 3.49 for rats, respectively. The pharmacodynamic comparison studies suggest that HX0969w has a longer onset time and shorter duration than fospropofol., Conclusions: Similar to fospropofol, HX0969w is an effective, water-soluble prodrug that is capable of inducing a sedative-hypnotic effect in mice and rats. Unlike fospropofol, HX0969w releases GHB instead of formaldehyde. Further studies regarding the efficacy and safety of HX0969w are necessary.

Background: Propofol is increasingly used in paediatric anaesthesia, but can be challenging to titrate accurately in this group. Mid-latency auditory-evoked potentials (MLAEPs) can be used to help titrate propofol. However, the effects of propofol on MLAEP in children are unclear. Therefore, we investigated the relationship between propofol and MLAEP in children undergoing anaesthesia., Methods: Fourteen healthy children aged 4-16 yr received anaesthesia for elective surgery. Before surgery, propofol was administered in three concentrations (3, 6, 9 µg ml(-1)) through a target-controlled infusion pump using Kataria and colleagues' model. MLAEPs were recorded 5 min after having reached each target propofol concentration at each respective concentration. Additionally, venous propofol blood concentrations were assayed at each measuring time point., Results: Propofol increased all four MLAEP peak latencies (peaks Na, Pa, Nb, P1) in a dose-dependent manner. In addition, the differences in amplitudes were significantly smaller with increasing propofol target concentrations. The measured propofol plasma concentrations correlated positively with the latencies of the peaks Na, Pa, and Nb., Conclusions: Propofol affects MLAEP latencies and amplitudes in children in a dose-dependent manner. MLAEP measurement might therefore be a useful tool for monitoring depth of propofol anaesthesia in children.

Background: Over a 5 yr period, we have encountered three patients in whom remifentanil appeared to have no clinical effect during general anaesthesia (GA). We describe seven anaesthetics in these three patients., Methods: We reviewed the literature on this subject. A simple reproducible test to explore this response was designed. This involved a controlled infusion of increasing doses of remifentanil while observing respiratory variables, pain threshold, pupil size, and Glasgow coma scale score. In addition, blood was sampled for genotyping., Results: No description of this impaired response was found in the review of the literature. Two of the patients agreed to participate in the test. In both patients, we found a seemingly normal analgesic response but a lack of respiratory depression and almost no depression of consciousness, even at doses well above the recommended level for clinical use. The genotyping did not explain the results of the test., Conclusions: The potential causes of this effect are discussed. We advise clinicians to be aware of this unusual response to remifentanil. If such a response is suspected, we recommend the use of another opioid. If this is suspected before GA, we propose the use of our test as a diagnostic tool.

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed., (Copyright © 2012 Wiley Periodicals, Inc.)

The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: I.V. lidocaine is increasingly used as an adjuvant during general anaesthesia. The aim of this study was to evaluate the effect of i.v. lidocaine in reducing propofol anaesthetic requirements during total i.v. anaesthesia (TIVA) maintenance and to evaluate its effect on early recovery from anaesthesia., Methods: Forty adult patients undergoing elective laparoscopic cholecystectomy under TIVA were randomly allocated into the lidocaine group (administered 1.5 mg kg(-1) i.v. lidocaine over 5 min followed by 2 mg kg(-1) h(-1)) and the control group (administered an equal volume of saline). Propofol was administered using a target-controlled infusion to maintain the bispectral index values between 40 and 60. After surgery, all infusions were discontinued and the time to extubation was recorded. Serial arterial blood samples were drawn to assess drug plasma levels., Results: The maintenance dose of propofol was significantly lower in the lidocaine group [6.00 (0.97) mg kg(-1) h(-1)] vs the control group [7.25 (1.13) mg kg(-1) h(-1); P=0.01]. Propofol plasma levels measured at the end of the infusion were 3.71 (0.89) μg ml(-1) in the lidocaine group and 3.67 (1.28) μg ml(-1) in the control group (P=0.91). The median time to extubation was longer (11.0 min; range: 10.0-21.0) in the lidocaine group vs the control group (8.3 min; range: 5.5-12.5; P=0.02)., Conclusions: I.V. lidocaine reduces propofol requirements during the maintenance phase of TIVA, particularly during surgical stimulation. This sparing effect is associated with an increased time to extubation. Owing to its effect on early recovery from anaesthesia, i.v. lidocaine should be taken into account when used as a component of i.v. anaesthesia.

Objective: To evaluate if the cerebral state index (CSI), measured by a Cerebral State Monitor (CSM), can predict depth of anaesthesia as assessed clinically or by estimated propofol plasma concentrations., Study Design: Prospective clinical study., Animals: Fourteen mixed breed dogs, weighing 24.5 ± 4.7 kg, scheduled to undergo neutering procedures., Methods: Dogs were premedicated with 0.05 mg kg(-1) acepromazine intramuscularly. The CSM and cardiovascular monitoring equipment were attached. Anaesthesia was induced with propofol using a target controlled infusion (TCI) to varying plasma propofol targets (PropCp). Following endotracheal intubation the dogs were ventilated with oxygen. Anaesthetic maintenance was with propofol by TCI. A PropCp of 3 μg dL(-1) was set initially, then PropCps were increased in 1 μg dL(-1) steps to 7, 9 and then 11 μg dL(-1). Each PropCp was held constant for a 5 minute period, at the end of which depth of anaesthesia was classified using a previously evaluated scale of 'planes' based on palpebral and corneal reflexes and eye position. Cerebral state index (CSI), burst suppression (BSR) and electromyogram were measured at these time points. The prediction probability (PK) of these variables, or of the PropCp in predicting depth of anaesthesia was calculated., Results: The PKs for predicting anaesthetic planes were 0.74, 0.91, 0.76 and 0.78 for CSI, BSR, EMG and PropCp, respectively. The PKs for PropCp to predict CSI, BSR and EMG were 0.65, 0.71 and 0.65 respectively., Conclusion and Clinical Relevance: The Cerebral State Monitor was able to detect very deep planes of anaesthesia when BSR occurs, but was not able to distinguish between the intermediate anaesthetic planes likely to be used in clinical anaesthesia., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Background: The increase in remifentanil concentration during haemorrhagic shock and the difference between this effect and that for propofol are not fully understood. We investigated the influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a porcine model and compared the changes with those for propofol., Methods: After infusion of remifentanil (0.5 µg kg⁻¹ min⁻¹) and propofol (6 mg kg⁻¹ h⁻¹ after 2 mg kg⁻¹ bolus infusion) for 60 min, nine swine [mean (standard deviation) body weight=26.3 (1.3) kg] were studied using a stepwise haemorrhage model (10% of estimated blood volume removed every 30 min until 1.5 h, and stepwise removal of 5% every 30 min thereafter until circulatory collapse). Haemodynamic and metabolic variables and plasma remifentanil and propofol concentrations were measured at every step., Results: A mean volume of 913 (82) ml of blood was drained before reaching circulatory collapse. The increases in plasma concentrations from the prehaemorrhagic value fitted the following equations: % increase in remifentanil=2.1 × cumulative blood loss (% of initial blood volume) and % increase in propofol = 0.7 × cumulative blood loss during compensated shock; and % increase in remifentanil = 27.4 × cumulative blood loss-897 and % increase in propofol = 9.5 × cumulative blood loss-306 during uncompensated shock. Remifentanil concentrations were highly correlated with the reciprocal of cardiac output., Conclusions: During haemorrhage, the plasma remifentanil concentration showed a three-fold greater increase than that of propofol in administration by continuous infusion.

2,6-Diisopropylphenol (propofol) is a potent anesthetic drug with fast onset of the anesthetic effect and short recovery time for the patients. Outside of the United States, propofol is widely used in performing target controlled infusion anesthesia. With the long term vision of an electrochemical sensor for in vivo monitoring and feedback controlled dosing of propofol in blood, different alternatives for the electrochemical quantification of propofol using diverse working electrodes and experimental conditions are presented in this contribution. When the electrochemical oxidation of propofol takes place on a glassy carbon working electrode, an electrochemically active film grows on the electrode surface. The reduction current of the film is proportional to the propofol concentration and the accumulation time. Based on these findings a stripping analytical method was developed for the detection of propofol in acidic solutions between 0 and 30 μM, with a detection limit of 5.5±0.4 μM. By restricting the scanned potential window between 0.5 V and 1.0 V in cyclic voltammetric experiments, the formation of the electrochemically active polymer can be prevented. This allowed the development of a direct voltammetric method for assessing propofol in acidic solutions between 0 and 30 μM, with a 3.2±0.1 μM (n=3) detection limit. The stripping method has a better sensitivity but somewhat worse reproducibility because the electrode surface has to be renewed between each experiment. The direct method does not require the renewal of the electrode surface between measurements but has no adequate selectivity towards the common interfering compounds., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The performance of eight currently available paediatric propofol pharmacokinetic models in target-controlled infusions (TCIs) was assessed, in healthy children from 3 to 26 months of age., Methods: Forty-one, ASA I-II children, aged 3-26 months were studied. After the induction of general anaesthesia with sevoflurane and remifentanil, a propofol bolus dose of 2.5 mg kg(-1) followed by an infusion of 8 mg kg(-1) h(-1) was given. Arterial blood samples were collected at 1, 2, 3, 5, 10, 20, 40, and 60 min post-bolus, at the end of surgery, and at 1, 3, 5, 30, 60, and 120 min after stopping the infusion. Model performance was visually inspected with measured/predicted plots. Median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated to measure bias and accuracy of each model., Results: Performance of the eight models tested differed markedly during the different stages of propofol administration. Most models underestimated propofol concentration 1 min after the bolus dose, suggesting an overestimation of the initial volume of distribution. Six of the eight models tested were within the accepted limits of performance (MDPE<20% and MDAPE<30%). The model derived by Short and colleagues performed best., Conclusions: Our results suggest that six of the eight models tested perform well in young children. Since most models overestimate the initial volume of distribution, the use for TCI might result in the administration of larger bolus doses than necessary.

Background: Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult., Methods: To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts., Results: Complete data were available for seven subjects (four responders and three non-responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus., Conclusions: The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.

Background: Propofol 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., Methods: Thirty-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., Results: HR, 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., Conclusions: Remifentanil 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.

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.

Objective: To evaluate the effects of propofol, on isoflurane minimum alveolar concentration (MAC) and cardiovascular function in mechanically ventilated goats., Study Design: Prospective, randomized, crossover experimental study., Animals: Six goats, three does and three wethers., Methods: General 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)., Results: Isoflurane 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 Relevance: In goats, propofol reduces isoflurane MAC in a dose-dependent manner with minimal cardiovascular effects., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Objective: In operating theaters and burn units, propofol is commonly used for sedation and anesthesia in patients with major burns. This study determined the population pharmacokinetics of propofol in burns and identified clinically significant covariates., Method: Seventeen adults, age 42±10 (mean±SD) years, with 41±19% total body surface area burns, were enrolled at 16±14 days after-burn. Non-burn adults (n=19) served as controls. After an intravenous bolus of 2mg/kg propofol, the plasma concentration was determined at designated times for up to 4.5h. Concentration-time profiles were analyzed using nonlinear mixed-effect modeling., Results: A three-compartment model gave the best fit. The volume of distribution of the central compartment (V(1)) was considerably greater in the burned than non-burned group (48.4 L vs. 27.6 L, respectively). The clearances of the central (CL(1)) and slow peripheral (CL(3)) compartments were higher in burn patients (4.2 L/min vs. 1.7 L/min and 3.6 L/min vs. 1.1 L/min, respectively). Adding the covariates BURN to V(1), CL(1), and CL(3) and WT (weight) to CL(1) significantly improved the model performance., Conclusion: The pharmacokinetic characteristics of a propofol bolus administered in patients with major burns were enhanced clearance and expanded volume of distribution. BURN and WT were the important covariates. For sedation or anesthesia induction, a higher than recommended dose of propofol may be required to maintain therapeutic plasma drug concentrations in patients with severe burns. Vigilance regarding the burned individual and careful titration of hypnotics to the desired effect cannot be overemphasized., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

Background: The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters., Methods: Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-6-5 mg kg(-1) h(-1) infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10-20 min during propofol infusion, and every 10-30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time-concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model., Results: The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44-160 kg; age 46 sd 16 yr, range 25-81 yr; BMI 33 sd 9 kg m(-2), range 16-52 kg m(-2)). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age., Conclusions: We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients.

Background: The patient state index (PSI) and the bispectral index (BIS) quantify anaesthetic depth based on the EEG using different algorithms. We compared both indices with regard to the prediction of the depth of propofol anaesthesia., Methods: In 17 patients, propofol was infused until burst suppression occurred and stopped thereafter until BIS recovered to values above 60. This was repeated; afterwards, patients were intubated, for subsequent surgery. Without surgical stimulus, PSI and BIS were measured simultaneously and compared with the estimated effect-site concentrations of propofol. These were derived from simultaneous pharmacokinetic and -dynamic modelling in an individual two-stage and a population-based NONMEM approach., Results: A close sigmoid relationship was observed between the propofol effect-site concentration and both PSI [coefficient of determination rho(2)=0.91 (sd 0.05)] and BIS [rho(2)=0.92 (0.03)], which was significantly steeper for PSI [gamma=2.2 (0.6)] than for BIS [gamma=1.8 (0.4)], and reached significantly lower values for PSI [E(max)=0.3 (1.1)] than for BIS [E(max)=5.3 (6.7)] at maximal propofol concentrations. A significantly smaller k(e0) was obtained for PSI [0.09 (0.03) min(-1)] compared with BIS [0.10 (0.02) min(-1)]. PSI and BIS correlated significantly with each other (rho(2)=0.866) and predicted propofol effect-site concentration with a comparable probability [P(K)=0.87 (0.05) and 0.86 (0.05), respectively]. NONMEM revealed E(0)=89.3 and 92.3, E(max)=1.9 and 8.6, C(e50)=1.38 and 1.92 microg ml(-1), gamma=1.6 and 1.48, and k(e0)=0.103 and 0.131 min(-1) as typical values for PSI and BIS, respectively., Conclusions: The PSI and the BIS monitors performed equally well in predicting depth of propofol anaesthesia. However, PSI was lower than BIS by approximately 10-15 points at high propofol concentrations.

Background: Central orexinergic and noradrenergic neurones are involved in the control of sleep and wakefulness. In addition, previous reports suggest that both neurones may have an important role to play in general anaesthesia. In the present study, we have determined whether general anaesthesia would affect plasma orexin A (OXA) and norepinephrine concentrations., Methods: Twenty-two patients undergoing elective ophthalmic surgery under general anaesthesia with propofol, fentanyl, and vecuronium were studied. Arterial blood was collected before and 1 and 2 h after induction of anaesthesia and at emergence to measure plasma OXA, propofol, norepinephrine, and epinephrine concentrations. During anaesthesia, the propofol infusion rate was changed to maintain the bispectral index between 40 and 50., Results: Plasma OXA and norepinephrine did not change during anaesthesia but significantly increased after emergence compared with pre-anaesthesia [from 19.9 (sd 3.2) to 28.3 (4.3) pM, P<0.01, and from 1351 (146) to 1798 (251) pM, P<0.05, respectively]. Plasma epinephrine did not change. There was a significant correlation between plasma OXA and norepinephrine (P<0.05) and also between plasma propofol and OXA (P<0.05) and norepinephrine (P<0.01)., Conclusions: We found that plasma OXA and norepinephrine significantly increased during emergence from propofol-fentanyl anaesthesia.

Background: The aims of this study were to investigate the effectiveness, safety, pharmacokinetics, and pharmacodynamics of microemulsion propofol, Aquafol (Daewon Pharmaceutical Co., Ltd, Seoul, Republic of Korea)., Methods: In total, 288 patients were randomized to receive 1% Aquafol or 1% Diprivan (AstraZeneca, London, UK) (n=144, respectively). A 30 mg test dose of propofol was administered i.v. over 2 s for assessing injection pain. Subsequently, a bolus of propofol 2 mg kg(-1) (-30 mg) was administered. Anaesthesia was maintained with a variable rate infusion of propofol and a target-controlled infusion of remifentanil. Mean infusion rates of both formulations and times to loss of consciousness (LOC) and recovery of consciousness (ROC) were recorded. Adverse events and pharmacokinetic and pharmacodynamic characteristics were evaluated., Results: Mean infusion rate of Aquafol was not statistically different from that of Diprivan (median: 6.2 vs 6.3 mg kg(-1) h(-1)). Times to LOC and ROC were slightly prolonged in Aquafol (median: 21 vs 18 s, 12.3 vs 10.8 min). Aquafol showed similar incidence of adverse events to Diprivan. Aquafol (vs Diprivan caused more severe (median VAS: 72.0 vs 11.5 mm) and frequent (81.9 vs 29.2%) injection pain. The dose-normalized AUC(last) of Aquafol and Diprivan was 0.71 (0.19) and 0.74 (0.20) min litre(-1). The V(1) of both formulations were proportional to lean body mass. Sex was a significant covariate for k(12) and Ce(50) of Aquafol, and for k(e0) of Diprivan., Conclusions: Aquafol was as effective and safe as Diprivan, but caused more severe and frequent injection pain. Aquafol demonstrated similar pharmacokinetics to Diprivan.

Background: In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Shüttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability to maintain a constant bispectral index (BIS), while using the respective effect-site-controlled target-controlled infusion (TCI) algorithms., Methods: We randomized 60 patients to Group M (Marsh's model with k(e0)=0.26 min(-1)), Group S1 or Group S2 (Schnider's model with a fixed k(e0)=0.456 min(-1) or a k(e0) adapted to a fixed time-to-peak effect=1.6 min, respectively). All patients received propofol at a constant rate until loss of consciousness. The corresponding Ce(PROP), as calculated by the respective models, was set as a target for effect-site-controlled TCI. We observed BIS for 20 min. We hypothesized that BIS remains constant, if Ce(PROP) remains constant over time., Results: All patients in Group M woke up, one in Group S1 and none in Group S2. In Groups S1 and S2, BIS remained constant after 11 min of constant Ce(PROP), at a more pronounced level of hypnotic drug effect than intended., Conclusions: Targeting Ce(PROP) at which patients lose consciousness with effect-site-controlled TCI does not translate into an immediate constant effect.

Background: To define the pharmacokinetic profile of propofol 5% microemulsion formulation in horses., Methods: First, propofol was administered as bolus injection (2 mg kg(-1)) to six xylazine-sedated horses. Secondly, after sedation and bolus injection, propofol was maintained with continuous infusion for 3 h [8.1 (sd 3.2) mg kg(-1) h(-1)] to the same six horses. Thirdly, in two horses, a commercial propofol was used for comparison. Response to noxious stimulation was used to evaluate analgesia. Venous blood samples were obtained to measure propofol plasma concentration using liquid chromatography-mass spectrometry analysis. The plasma concentrations were related to the anaesthesia characteristics to determine the ED(50)., Results: The pharmacokinetic profile of propofol is best characterized by a non-compartmental model. The mean (confidence interval) for area under plasma concentration-time curve, elimination half-life, mean residence time, and clearance was 41 min microg ml(-1) (+/-7.7), 44.8 min (+/-21.3), 13.7 min (+/-3.2), and 45.8 ml min(-1) kg(-1) (+/-6.5), respectively. Linear regression analysis showed a correlation between plasma concentration and infusion rate (r(2)=0.47). Most propofol infusion rates did not inhibit the response to noxious stimulation and rates above 11.9 mg kg(-1) h(-1) caused involuntary muscle contractions. Better recoveries were associated with lower propofol plasma concentrations. Propofol plasma concentration frequently increased when horses woke from anaesthesia., Conclusions: Caution is warranted when propofol is used for continuous infusion due to variable kinetics, myoclonal activity, poor analgesia, and less desirable recovery quality.

In spite of comparatively high therapeutic concentrations in blood, the quantitation of propofol may cause analytical challenges due to its pharmacokinetic (e.g. short half life, high distribution volume) and physicochemical (significant volatility) particularities. Moreover, a considerable and concentration dependent protein binding and a substance association to erythrocytes result in an irreproducible distribution between whole blood and serum. A possible redistribution in stored samples needs to be compensated during sample preparation or included into the result interpretation. The new analytical approach is based on a formation of N-methylpyridinium derivatives of propofol and corresponding internal standards and permits a significant ( approximately 300 fold) increase of detection limits in LC-MS/MS. Derivatization is achieved by a direct conversion of the acetonitrile supernatant of a protein precipitation with 2-fluoro-1-methyl-pyridinium-p-toluene-sulfonate using triethylamine as catalyst. The derivative exhibits a high solvent stability and provides--in contrast to the unchanged parent compound--a sufficient number of diagnostic qualifier fragments to fulfil common identification criteria. By using 2-tert-butyl-6-methylphenol as internal standard (instead of the commonly applied thymol), a better compensation of matrix effects could be achieved. Owing to its high robustness, appropriate quantitation limits (LLOQ approximately 13 ng/mL), minimum sample amount and preparation effort, the assay could efficiently be applied for quantitative propofol analyses in pharmacokinetic studies with high sampling rates.

Background: We aimed to measure propofol concentrations in exhaled air with an ion mobility spectrometer coupled to a multicapillary column for pre-separation (MCC-IMS). In addition, we aimed to compare the values of these measurements with serum propofol concentrations, as determined by gas chromatography-mass spectrometry (GC-MS)., Methods: Thirteen patients, ASA I or II, undergoing elective ENT surgery were studied. Anaesthesia was induced with propofol 2.1 (0.7) mg kg(-1), rocuronium 0.5 (0.1) mg kg(-1), and remifentanil 0.5 microg kg(-1) min(-1). After tracheal intubation, anaesthesia was maintained with a continuous infusion of propofol 3.9 (1.8) mg kg(-1) h(-1) and remifentanil 0.5 microg kg(-1) min(-1). Simultaneously, a venous blood sample was obtained. Propofol concentrations in serum were determined by GC-MS and compared with the height of the respective propofol signals achieved by MCC-IMS., Results: Twenty-four pairs of samples were obtained. The comparison of propofol concentrations in exhaled air and serum presented a bias of -10.5% and a precision of +/- 12.3%. With these values, the 95% limits of agreement were 14.1% and -35.1%., Conclusions: MCC-IMS may be a suitable method to determine propofol concentrations in exhaled air, and may be used to predict propofol concentrations in serum.

Background: Left ventricular (LV) pressure-volume (PV) loops were used to compare the functional effects that accompany the cardioprotection seen with desflurane, sevoflurane, and propofol in a rabbit preparation of coronary ischaemia-reperfusion (IR)., Methods: Male New Zealand White rabbits (n=48) were anaesthetized with propofol (70 mg kg(-1) h(-1)), desflurane (8.9%), or sevoflurane (3.8%) and randomized to receive IR or non-ischaemic time-matched (TC) perfusion protocol. IR groups (desIR, propIR, and sevIR) underwent 30 min of left anterior descending coronary artery occlusion and then 120 min of reperfusion. TC groups (desTC, propTC, and sevTC) were anaesthetized for 150 min without ischaemia. Haemodynamic endpoints included mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, preload-recruitable stroke-work, time constant of relaxation (tau), and end-diastolic PV relationship (EDPVR). Ventricles in the IR groups were excised and stained with 2,3,5-triphenyl-tetrazolium chloride in order to measure infarct size., Results: Myocardial infarction size was greater in the propIR group [35.74 (sd 11.32)%] compared with the desIR [13.44 (3.09)%] and sevIR [17.96 (6.63)%] groups (P<0.001). EDPVR deteriorated in the sevIR and propIR groups compared with their TC groups, sevTC (P=0.03) and propTC (P=0.044), respectively. There was no difference in any haemodynamic endpoints for the desIR group compared with its TC control (desTC)., Conclusions: During ischaemia, all anaesthetics provide haemodynamic stability and preservation of LV contractility, whereas propofol and sevoflurane, but not desflurane, caused increased LV diastolic stiffness. Desflurane and sevoflurane provide superior cardioprotection compared with propofol.

A new method for the quantitative analysis of monkey serum propofol, which is widely used as an anaesthetic agent, was developed by utilizing a temperature-responsive polymer of N-isopropylacrylamide (NIPAAm) and butyl methacrylate (BMA) as the stationary phase of HPLC-fluorescence detection. This poly(NIPAAm-co-BMA) copolymer undergoes a reversible phase transition from a hydrophilic to a hydrophobic microstructure when triggered by change in the temperature. Also this chromatographic system is possible to separate the analytes by using only water as a mobile phase. A pretreatment of the serum (80 microL) was only solid-phase extraction, and the recovery rate of propofol and internal standard was more than 77%, respectively. This method covered the calibration range from 0.5 microg/mL to 10 microg/mL and allowed a reproducible quantification of the serum propofol in administrated monkey serum. The intra- and inter-assay relative standard deviations were less than 14.1%. In addition, there was good relationship of the quantification values between the developed method and the widely used reversed-phase HPLC method. Our developed method has proven to be useful for a simple analysis of propofol in clinical practice, because the avoidance of complicated mobile phase preparation was possible, and only temperature changing could regulate the retention time of the analyte. In addition, by using water instead of fossil fuel, it is the ideal analytical method according to green chemistry.

The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh and Schnider pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weight proportional. The Schnider model was developed during combined pharmacokinetic-pharmacodynamic modelling studies. It has fixed values for V1, V3, k(13), and k(31), adjusts V2, k(12), and k(21) for age, and adjusts k(10) according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the small, fixed V1 results in very small initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model. Users of the Schnider model should be aware that in the morbidly obese the LBM equation can generate paradoxical values resulting in excessive increases in maintenance infusion rates. Finally, the two currently available open TCI systems implement different methods of effect-site targeting for the Schnider model, and in a small subset of patients the induction doses generated by the two methods can differ significantly.

Propofol is a short acting intravenous anaesthetic, active agent of Diprivan. The abuse potential of propofol has not completely defined, but there are anecdotal case reports in the literature about propofol abuse and dependency. This report presents a fatal case of a middle age female victim who died of self-administered propofol intoxication. The propofol level of the blood sample was measured with gas chromatography-mass spectrometry after liquid-liquid extraction. The results of toxicological investigation suggested that death was not directly caused by propofol intoxication, however, based on the pathomorphological changes detected during the medico-legal autopsy we supposed that the fatal outcome was resulted by respiratory depression after rapid injection.

Background: Measuring propofol concentration in plasma (c(P)PL) and in exhaled alveolar gas (c(P)G) during constant infusion provides information about their respective time courses. In the present study, we compared these time courses in patients undergoing cardiac surgery from the beginning of propofol anaesthesia until eye opening upon awakening., Methods: The c(P)G was measured before, during, and after continuous infusion of propofol for general anaesthesia in 12 patients at two randomly allocated doses (3 or 6 mg kg(-1) h(-1)). Gas samples were collected on Tenax tubes. After thermodesorption, c(P)G was measured by gas chromatography mass spectrometry. Simultaneously with exhaled gas, arterial blood was sampled for measuring c(P)PL by reversed-phase high-performance liquid chromatography with fluorescence detection. In order to compare the time courses of c(P)PL and c(P)G as dimensionless values directly, each gas and plasma value was normalized by relating it to the corresponding value at the end of the initial infusion after 40 min., Results: The c(P)G ranged between 2.8 and 22.5 ppb, whereas the corresponding c(P)PL varied between 0.3 and 3.3 microg ml(-1). Normalized concentration values showed a delayed increase in c(P)G compared with c(P)PL under constant propofol infusion before the onset of cardiopulmonary bypass, and a delayed decrease after stopping the propofol at the end of anaesthesia., Conclusions: Propofol can be measured in exhaled gas from the beginning until the end of propofol anaesthesia. The different time courses of c(P)PL and c(P)G have to be considered when interpreting c(P)G.

Background: This study has compared the predictive performance of four pharmacokinetic models, two of which are currently incorporated in commercial target-controlled infusion pumps for the administration of propofol., Methods: Arterial propofol concentrations and patient characteristic data were available from nine patients who, in a published study, had received a standardized infusion of propofol. Predicted concentrations with 'Diprifusor' (Marsh), 'Schnider', 'Schuttler', and 'White' models were obtained by computer simulation. The predictive performance of each model was assessed overall and over the following phases: rapid infusion (1-5 min), early (1-21 min), maintenance (21-min end-infusion), and recovery (2-20 min post-infusion)., Results: The overall assessment, based on 29-36 samples from each patient, indicated that all four models were clinically acceptable. However, the negligible bias (-0.1%) with the 'Schnider' model was accompanied by overprediction in the rapid infusion phase and underprediction during recovery. This changing bias over time was not detected as 'divergence' when assessed on absolute performance error (APE), (1.4% h(-1)) but became significant (13.2% h(-1)) when based on changes in signed PE over time. The 'Schuttler' model performed well at most phases but overpredicted concentrations during recovery. The White model led to a marginal improvement over 'Diprifusor' and would be expected to reduce the positive bias usually seen with 'Diprifusor' systems., Conclusions: In assessing the predictive performance of pharmacokinetic models, additional information can be obtained by analysis of bias at different phases of an infusion. The evaluation of divergence should involve linear regression analysis of both absolute and signed PEs.