Plasma Propofol Concentrations Research Articles

Design and validation of an automated solid phase extraction liquid chromatography coupled mass spectrometry method for the quantification of propofol in plasma

Propofol concentration in human plasma can be quantified by liquid chromatography coupled mass spectrometry. Sample preparation usually requires solid phase extraction to remove matrix components and enrich the analyte. To facilitate user-independent measurements and speed extraction, we developed and validated a fully automated high throughput in-line sample preparation system with direct injection into liquid chromatography coupled mass spectrometry. We assessed linearity of each method over the clinically relevant concentration range from 0.5μg/mL to 8μg/mL plasma concentration. R2 values were 0.99 for the automated process and 0.98 for manual sample preparation. The limit of detection was 6ng/mL and the lower limit of quantification was 18ng/mL for the automated method; for the manual process, the limit of detection was 1.58ng/mL and the lower limit of quantification was 4.79ng/mL. Intra-day precision for low, medium and high concentration range of the automated method was validated 4.14%, 9.68% and 3.04% relative standard deviation and 0.29%, 0.12% and 0.52% for the manual process. Carry over was 0.4% with the automated method, whereas there was no carry over with the manual method. Stability of plasma samples was tested with the manual method at concentrations of 1, 4, and 6μg/mL propofol and found to be stable over 150days at −20°C. The manual sample preparation method has successfully been transferred to a fully automated process with appropriate sensitivity and precision but the automatization failed with regard to trueness and working time due to lengthy sample preparation runtime. Therefore it is not suitable for daily use in a hospital laboratory e.g. for brain death diagnosis in the intensive care unit.

Reliability of body-weight scalars on the assessment of propofol induction dose in obese patients.

Obese patients require specific perioperative care when compared with non-obese patients. The present study aimed to analyse the ability of size descriptors to estimate propofol induction dose in class II and III obese patients. A cross-sectional study on adult patients with body mass index (BMI) equal to or greater than 35kg/m2 and on adult patients with BMI lower than 35kg/m2 was carried out. General anaesthesia was induced with remifentanil, propofol and rocuronium. Propofol infusion was started at 2000mg/h until loss of consciousness. Bioelectrical impedance analysis and Brice modified interview was completed during pre- and post-operative evaluation, respectively. Measurements of propofol plasma concentration were performed using gas chromatography/ion trap-mass spectrometry. Forty patients were enrolled in the study. The median values of fat free mass (FFM) in BMI<35kg/m2 and BMI≥35kg/m2 groups were 70% and 55% of total body weight, respectively. Our results did not demonstrate a strong correlation level between the studied size descriptors and propofol induction dose in both groups. Nevertheless, when propofol doses were normalized by FFM, an apparent convergence of the empirical cumulative distribution functions was observed. None of the size descriptors was seen to be an effective predictor of the propofol induction dose in class II and III obese patients when a fixed infusion rate was used. Due to the observed variability between patients, guiding propofol induction dose against a clinical endpoint of unconsciousness appears more appropriate in order to avoid side effects related both with under or overdosing of propofol.

Performance of TCI Propofol Using the Schnider Model for Cardiac Surgery on Cardiopulmonary Bypass–A Pilot Study

This pilot study aimed to evaluate the performance of target-controlled infusion (TCI) of propofol using the Schnider pharmacokinetic model in patients undergoing cardiac surgery requiring cardiopulmonary bypass. This was a prospective pharmacokinetic study. A tertiary care hospital. This study is comprised of 10 patients, aged between 46 and 81, who underwent elective cardiac surgery requiring the use of cardiopulmonary bypass. Anesthetic technique was standardized. Hypnosis was maintained using TCI of propofol, titrated to achieve a bispectral index of 30 to 60. Calculated plasma propofol concentrations were recorded at 5 time points in total, before, during, and after cardiopulmonary bypass. Blood propofol concentration was measured at each of these time points. The prediction errors and absolute prediction errors were calculated for each sample. From these, the median prediction error (MDPE) and its absolute value (MDAPE) were derived. Agreement between predicted and measured propofol concentrations was assessed using a Bland-Altman plot. Mean prediction errors were also compared pre-, on, and post-bypass using the generalized linear latent and mixed model. The MDPE and MDAPE were both found to be 45%, indicating significant bias toward under-prediction in the Schnider pharmacokinetic model. This bias was increased at an average propofol concentration of 4.5 μg/mL and above. A significant decrease in mean prediction error was noted while on bypass (45.6%, 95% confidence intervals 9.2-82.1). The performance of the Schnider pharmacokinetic model for TCI propofol was poor, with a tendency toward under-prediction of blood propofol concentration, especially at higher average concentrations of propofol. While mitigating the risk of awareness, the risk of other adverse effects like hypotension and cardiorespiratory depression is increased. Patients should therefore be adequately monitored, and predicted plasma propofol concentrations taken in context with other patient parameters. A lower target concentration of propofol is probably sufficient to maintain an adequate depth of anesthesia as measured by BIS.

Evidence of hysteresis in propofol pharmacodynamics.

It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7-min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) μg.ml-1 and 1.6 (0.6-3.3) μg.ml-1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia.

Plasma propofol concentrations and pharmacodynamic effects in koi carp (Cyprinus carpio) following exposure via immersion

Plasma propofol concentrations and pharmacodynamic effects in koi carp (Cyprinus carpio) following exposure via immersion

Anaesthetic depth control using closed loop anaesthesia delivery system vs. target controlled infusion in patients with moderate to severe left ventricular systolic dysfunction

ObjectivesTo compare the efficacy of anaesthetic depth control using Closed Loop Anaesthesia Delivery System (CLADS) and Target Controlled Infusion (TCI) in patients with moderate to severe left ventricular dysfunction (LVSD). DesignRandomized control trial. PatientsForty ASA III/IV adult patients with moderate to severe LVSD scheduled for open heart surgery. InterventionsPropofol was administered using CLADS or TCI for maintaining BIS of 50. Induction and maintenance doses were controlled automatically in CLADS. Dixon's up and down method was used to estimate the plasma concentration needed for induction in TCI. MeasurementPercentage of total anaesthesia time (“valid CLADS time”) for which BIS remained within ±10 of target (BIS=50). Main resultsBIS remained within ±10 of the target for a significantly longer duration of time in CLADS group (p=0.001). Performance parameters like Median Performance Error (MDPE), p=0.024; Median Absolute Performance Error (MDAPE), p=0.0212; and global score p=0.017 were significantly better in CLADS group. Total propofol consumption was significantly less in CLADS group (p=0.014). Mean value (95% CI) of EC50 and EC95 for target plasma propofol concentration for induction was 1.62 (1.45–1.79) μgml−1 and 1.87 (1.73–2.96) μgml−1 respectively using probit analysis. ConclusionsClosed loop delivery of propofol using CLADS performed significantly better than TCI in this subset of patients. Clinical trials registration no.www.ClinicalTrials.gov-NCT02645994

Effect of ear point embedding on plasma and effect site concentrations of propofol-remifentanil in elderly patients after target-controlled induction

To observe the clinical effect of ear point embedding on plasma and effect site concentrations of propofol-remifentanil in elderly patients who underwent abdominal external hernia surgery at the time of consciousness and pain disappearing by target-controlled infusion (TCI) and bispectral index (BIS). Fifty patients who underwent elective abdominal hernia surgery were randomly assigned into an observation group and a control group, 25 cases in each one. In the observation group, 30 minutes before anesthesia induction, Fugugou (Extra), Gan (CO12), Pizhixia (AT4), and Shenmen (TF4) were embedded by auricular needles until the end of surgery, 10 times of counter press each point. In the control group, the same amount of auricular tape was applied until the end of surgery at the same points without stimulation 30 minutes before anesthesia induction. Patients in the two groups were given total intravenous anesthesia, and BIS was monitored by BIS anesthesia depth monitor. Propofol was infused by TCI at a beginning concentration of 1.5μg/L and increased by 0.3μg/L every 30s until the patients lost their consciousness. After that, remifentanil was infused by TCI at a beginning concentration of 2.0μg/L and increased by 0.3μg/L every 30s until the patients had no body reaction to pain stimulation (orbital reflex). Indices were recorded, including mean arterial pressure (MAP), heart rate (HR) and the BIS values, at the time of T0 (entering into the operation room), T1 (losing consciousness) and T2 (pain relief), the plasma and effect site concentrations of propofol at T1, the plasma and effect site concentrations of remifentanil at T2. After surgery we recorded the total amounts of propofol and remifentanil, surgery time and anesthesia time. At T1 and T2, MAP and HR of the observation group were higher than those of the control group (P<0.05, P<0.01). At T1, the plasma and effect site concentrations of propofol in the observation group were significantly lower than those in the control group (P<0.05, P<0.01). At T2, the plasma and effect site concentrations of remifentanil in the observation group were significantly lower than those in the control group (P<0.05, P<0.01). There was no significant difference in BIS values at T1 and T2 between the two groups (bothP>0.05). There was no significant difference in operation time and anesthesia time between the two groups (bothP>0.05). The total amount of remifentanil in the observation group was significantly lower than that in the control group (P<0.01). There was no significant difference in the total amount of propofol between the two groups (P>0.05). Ear points embedding combined with propofol-remifentanil TCI could reduce the plasma and effect site concentrations of propofol and remifentanil and the total amount of remifentanil in elderly patients with extra-abdominal hernia surgery, and had the effect of assisting sedation and analgesia.

Effect of dexmedetomidine on the minimum infusion rate of propofol preventing movement in dogs

ObjectiveTo determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIRNM). Study designRandomized crossover, unmasked, experimental design. AnimalsThree male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg. MethodsDogs 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. ResultsPropofol 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 MIRNM 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 MIRNM 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 MIRNM determination. Conclusions and clinical relevanceDexmedetomidine (1 and 2 μg kg−1) decreased propofol induction dose. Dexmedetomidine (2 μg kg−1 hour−1) resulted in a significant decrease in propofol MIRNM.

Propofol in combination with remifentanil for cesarean section: Placental transfer and effect on mothers and newborns at different induction to delivery intervals

ObjectiveThis 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 methodsIn 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. ResultsThe 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. ConclusionsIt 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.

The influence of storage time and temperature on propofol concentrations in canine blood and plasma.

Propofol is an intravenous anesthetic commonly used due to its favorable pharmacokinetic and pharmacodynamic profile. There are discrepancies in the literature about the most appropriate sample for determining propofol concentrations. Although plasma has been used for determining propofol concentrations, whole blood has been the preferred sample. There is also a lack of consistency in the literature on the effect of storage time and temperature on propofol concentrations and this may lead to errors in the design of pharmacokinetic/pharmacodynamics studies. The purpose of this study was to determine the difference in propofol concentrations in whole blood versus plasma and to evaluate the influence of storage time (56 days) and temperature (4 °C, −20 °C, −80 °C) on the stability of propofol concentrations in blood and plasma samples. Results from the study indicate that whole blood and plasma samples containing propofol stored at −80 °C have concentrations as high as or higher than those stored at 4 °C or −20 °C for 56 days; thus, −80 °C is an appropriate temperature for propofol sample storage. Plasma propofol concentrations were consistently higher than whole blood for all three storage temperatures. Consequently, plasma is the most appropriate sample for propofol analysis due to its consistent determinations.

Pharmacokinetics and pharmacodynamics of propofol: changes in patients with frontal brain tumours

BackgroundModels of propofol pharmacokinetics and pharmacodynamics developed in patients without brain pathology are widely used for target-controlled infusion (TCI) during brain tumour excision operations. The goal of this study was to determine if the presence of a frontal brain tumour influences propofol pharmacokinetics and pharmacodynamics and existing PK-PD model performance. MethodsTwenty patients with a frontal brain tumour and 20 control patients received a propofol infusion to achieve an induction–emergence–induction anaesthetic sequence. Propofol plasma concentration was measured every 4 min and at each transition of the conscious state. Bispectral index (BIS) values were continuously recorded. We used non-linear mixed-effects modelling to analyse the effects of the presence of a brain tumour on the pharmacokinetics and pharmacodynamics of propofol. Subsequently we calculated the predictive performance of Marsh, Schnider, and Eleveld models in terms of median prediction error (MdPE) and median absolute prediction error (MdAPE). ResultsPatients with brain tumours showed 40% higher propofol clearance than control patients. Performance of the Schnider model (MdPEpk −20.0%, MdAPEpk 23.4%) and Eleveld volunteer model (MdPEpk −8.58%, MdAPEpk 21.6%) were good. The Marsh model performed less well (MdPEpk −14.3%, MdAPEpk 41.4%), as did the Eleveld patient model (MdPEpk −30.8%, MdAPEpk 32.1%).The first-order rate constant (ke0; 0.108 min−1), the concentration in the effects compartment associated with 50% of the maximum effect (Ce50; 2.77 ml litre−1) and γ (1.49) did not significantly differ between groups. Lower baseline BIS values were found in patients with brain tumours (90 vs 95). ConclusionsBrain tumours might alter the pharmacokinetics of propofol. Caution should be exerted when using propofol TCI in patients with frontal brain tumours due to higher clearance. Trial registry numberNCT01060631.

Validation of liquid and gaseous calibration techniques for quantification of propofol in breath with sorbent tube Thermal Desorption System GC–MS

Plasma concentrations of intravenous drugs cannot currently be evaluated in real time to guide clinical dosing. However, a system for estimating plasma concentration of the anesthetic propofol from exhaled breath may soon be available. Developing reliable calibration and analytical validation techniques is thus necessary. We therefore compared the established sorbent tube liquid injection technique with a gas injection procedure using a reference gas generator. We then quantified propofol with Tenax sorbent tubes in combination with gas-chromatography coupled mass spectrometry in the breath of 15 patients (101 measurements). Over the clinically relevant concentration range from 10 to 50 ppbv, coefficient of determination was 0.995 for gas calibration; and over the range from 10 to 100ng, coefficient of determination was 0.996 for liquid calibration. A regression comparing gas to liquid calibration had a coefficient of determination of 0.89; slope 1.05±0.01 (standard deviation). The limit of detection was 0.74ng and the lower limit of quantification was 1.12ng for liquid; the limit of detection was 0.90 ppbv and the lower limit of quantification was 1.36 ppbv for gas. Loaded sorbent tubes were stable for at least 14days without significant propofol loss as determined with either method. Measurements from liquid or gas samples were comparably suitable for evaluation of patient breath samples.

Sedative interaction between dexmedetomidine and propofol

Objective To evaluate the sedative interaction between dexmedetomidine and propofol. Methods Sixty-four American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients, aged 20-60 yr, with body mass index of 19.0-25.0 kg/m2, scheduled for elective surgery under general anesthesia, were allocated into 4 groups (n=16 each) using a random number table: different target concentrations of dexmedetomidine groups (D1-4 groups). Dexmedetomidine was administered by target-controlled infusion (TCI) with the Markku model.The target plasma concentrations of dexmedetomidine were 0, 0.4, 0.6 and 0.8 ng/ml in D1-4 groups, respectively.At 15 min of dexmedetomidine TCI, propofol was given by TCI with Schnider model, and the initial target effect-site concentration was set at 1.0 μg/ml.After the target effect-site and plasma concentrations were balanced, the target effect-site concentration of propofol was gradually increased in increments of 0.2 μg/ml until loss of consciousness (Observer′s Assessment of Alertness/Sedation Scale score was 1). The model of pharmacodynamic interaction was used to analyze the sedative interaction between the two drugs. Results There was no statistically significant difference in residual sums of squares fitted by using the model of pharmacodynamic interaction between the target effect-site concentration of propofol and target plasma concentration of dexmedetomidine at loss of consciousness (P> 0.05). The linear dimensionless parameter of pharmacodynamic interaction was 0.The median effective effect-site concentration of propofol was 2.38 μg/ml at loss of consciousness, and the median effective plasma concentration of dexmedetomidine was 2.03 ng/ml at loss of consciousness. Conclusion Dexmedetomidine and propofol interact additively in terms of sedation. Key words: Dexmedetomidine; Propofol; Conscious sedation; Drug interactions

Optimization of initial propofol bolus dose for EEG Narcotrend Index-guided transition from sevoflurane induction to intravenous anesthesia in children.

Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia (TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram (EEG) during the transition phase. The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg-1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg-1 ·h-1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 μg·kg-1 ·min-1 . Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [IQR 0.9-2.5] mg·kg-1 and median NI thereafter was 33 [IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg-1 . Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg-1 after sevoflurane induction. Decrease in mean arterial blood pressure correlated significantly with propofol bolus dose (P = 0.038). After 25 min of TIVA, children younger than 2 years had a higher NI (median difference 14.0, 95%CI: 6.0-20.0, P = 0.001), higher deviations from the expected Narcotend Index (median difference 4.1, 95%CI: 3.9-4.2, P < 0.001) and lower calculated propofol plasma concentrations (median difference 0.2 μg·ml-1 , 95% CI: 0.1-0.3 μg·ml-1 , P < 0.001) than older children. After sevoflurane induction, a reduced propofol bolus dose of 1 mg·kg-1 followed by TIVA according to McFarlan's regime resulted in a NI within the recommended range in children aged 1-8 years. During the course of TIVA, children younger than 2 years displayed higher NI values and more pronounced interindividual variation. Processed EEG monitoring is recommended to find adequate individual age-dependent doses.

Propofol-fentanyl interaction in Beagles - Apnea, response to mechanical ventilation, endotracheal tube, and tetanic stimulation

The objective of this study was to characterize the propofol-fentanyl interaction in Beagles for four pharmacodynamic endpoints: apnea, response to mechanical ventilation, endotracheal tube, and tetanic stimulation.After anesthesia was induced with varying combinations of propofol and fentanyl, the pharmacodynamic endpoints were assessed in intubated dogs (n=6) using the cross-over design. Effective concentrations of propofol plasma concentration (Cp) and fentanyl Cp were assessed using additive, reduced Greco, Minto, and hierarchical interaction models.The interaction was best described as synergistic by the hierarchical model. A 1ng/mL fentanyl Cp reduced the effective propofol Cp to half or less of that without fentanyl for all endpoints. An additional increment of fentanyl Cp to 5ng/mL or higher hardly reduced effective propofol Cp for all endpoints except response to tetanic stimulation. Additionally, the effective propofol Cp in 50% dogs for response to tetanic stimulation (15% increase of heart rate) was lower than that for the other endpoints at fentanyl Cp >7ng/mL. Peripheral oxygen saturation decreased below 90% after extubation in five treatments in which fentanyl Cps were ≥5ng/mL.Propofol and fentanyl interacted synergistically. To avoid patient-ventilator dyssynchrony and hypoxemia after extubation, fentanyl Cp at 1–5ng/mL may be appropriate in intubated dogs. When a dog responds to mechanical ventilation or endotracheal tube at a high fentanyl Cp >5ng/mL under propofol anesthesia even if the dog tolerate to tetanic stimulation, it may be necessary to increase propofol Cp to eliminate the responses because an additional fentanyl may be little impact.

Novel Methods for Measuring Depth of Anesthesia by Quantifying Dominant Information Flow in Multichannel EEGs.

In this paper, we propose novel methods for measuring depth of anesthesia (DOA) by quantifying dominant information flow in multichannel EEGs. Conventional methods mainly use few EEG channels independently and most of multichannel EEG based studies are limited to specific regions of the brain. Therefore the function of the cerebral cortex over wide brain regions is hardly reflected in DOA measurement. Here, DOA is measured by the quantification of dominant information flow obtained from principle bipartition. Three bipartitioning methods are used to detect the dominant information flow in entire EEG channels and the dominant information flow is quantified by calculating information entropy. High correlation between the proposed measures and the plasma concentration of propofol is confirmed from the experimental results of clinical data in 39 subjects. To illustrate the performance of the proposed methods more easily we present the results for multichannel EEG on a two-dimensional (2D) brain map.

Ion mobility spectrometry as a simple and rapid method to measure the plasma propofol concentrations for intravenous anaesthesia monitoring.

The plasma propofol concentration is important information for anaesthetists to monitor and adjust the anaesthesia depth for patients during a surgery operation. In this paper, a stand-alone ion mobility spectrometer (IMS) was constructed for the rapid measurement of the plasma propofol concentrations. Without any sample pre-treatment, the plasma samples were dropped on a piece of glass microfiber paper and then introduced into the IMS cell by the thermal desorption directly. Each individual measurement could be accomplished within 1 min. For the plasma propofol concentrations from 1 to 12 μg mL−1, the IMS response was linear with a correlation coefficient R2 of 0.998, while the limit of detection was evaluated to be 0.1 μg mL−1. These measurement results did meet the clinical application requirements. Furthermore, other clinically-often-used drugs, including remifentanil, flurbiprofen and atracurium, were found no significant interference with the qualitative and quantitative analysis of the plasma propofol. The plasma propofol concentrations measured by IMS were correlated well with those measured by the high performance liquid chromatography (HPLC). The results confirmed an excellent agreement between these two methods. Finally, this method was applied to monitor the plasma propofol concentrations for a patient undergoing surgery, demonstrating its capability of anaesthesia monitoring in real clinical environments.

The effect of UGT1A9, CYP2B6 and CYP2C9 genes polymorphism on individual differences in propofol pharmacokinetics among Polish patients undergoing general anaesthesia

Propofol (2,6-diisopropylphenol) is one of the safest and most commonly used anaesthetic agents for intravenous general anaesthesia. However, in clinical practice, a large inter-individual variability in response to propofol is observed. To limit the risk of adverse effects, pharmacogenetic investigations are recommended. The aim of our study was to verify the impact of genetic changes c.516G>T in the CYP2B6, c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes on the individual propofol pharmacokinetic profile in the Polish patients undergoing general anaesthesia. Eighty-five patients from the Department of Anaesthesiology and Intensive Therapy, Regional Hospital in Poznan, Poland, anaesthetised with propofol for surgery, were enrolled in the study. We have genotyped CYP2B6, UGT1A9 and CYP2C9 polymorphisms with the use of pyrosequencing. HPLC measurements of propofol plasma concentration were applied for a pharmacokinetic analysis of the anaesthetic. We identified poor (20), intermediate (42) and rapid (23) metabolisers of propofol, which constituted 24%, 49% and 27% of the group, respectively. Homozygotes c.516 T/T in the CYP2B6 gene were statistically more often found in the rapid metabolisers group (p < 0.05). However, polymorphisms c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes did not affect the pharmacokinetic profile of propofol. The mean propofol retention time (MRT) correlated with the patient’s body mass index (BMI) (p < 0.05). From all the analysed changes, only polymorphism c.516G>T in the CYP2B6 gene and BMI affect the metabolism rate of propofol and may play an important role in the optimisation of propofol anaesthesia.

Driving impairment due to propofol at effect-site concentrations relevant after short propofol-only sedation.

Australian guidelines state "Following brief surgery or procedures with short acting anaesthetic drugs, the patient may be fit to drive after a normal night's sleep. After long surgery or procedures requiring longer lasting anaesthesia, it may not be safe to drive for 24 hours or more". The increasing use of the short-acting anaesthetic drug propofol as a solitary sedative medication for simple endoscopy procedures suggests a need to review this blanket policy. Thirty patients presenting for elective day surgery were recruited as volunteers for a pre-procedure driving simulation study and randomised to propofol or placebo arms. Driving ability was assessed at baseline and then, in the propofol group, at three effect-site concentrations. Driving impairment at these concentrations of propofol was compared to that of a third group of volunteers with a blood alcohol concentration of 0.05% (g/100 ml). Driving impairment at 0.2 µg/ml propofol effect-site concentration was not statistically different to placebo. Impairment increased with propofol effect-site concentration (P=0.002) and at 0.4 µg/ml it was similar to that found with a blood alcohol concentration of 50 mg/100 ml (0.05%). Plasma propofol concentrations of 0.2 µg/ml, as might be found approximately an hour after short (<1 hour duration) propofol-only sedation for endoscopy, were not associated with driving impairment in our young cohort of volunteers.

Assessment of sedation-analgesia by means of Poincaré analysis of the electroencephalogram.

Monitoring the levels of sedation-analgesia may be helpful for managing patient stress on minimally invasive medical procedures. Monitors based on EEG analysis and designed to assess general anesthesia cannot distinguish reliably between a light and deep sedation. In this work, the Poincaré plot is used as a nonlinear technique applied to EEG signals in order to characterize the levels of sedation-analgesia, according to observed categorical responses that were evaluated by means of Ramsay Sedation Scale (RSS). To study the effect of high frequencies due to EMG activity, three different frequency ranges (FR1=0.5-110 Hz, FR2=0.5-30 Hz and FR3=30-110 Hz) were considered. Indexes from power spectral analysis and plasma concentration of propofol and remifentanil were also compared with the bispectral index BIS. An adaptive Neurofuzzy Inference System was applied to model the interaction of the best indexes with respect to RSS score for each analysis, and leave-one-out cross validation method was used. The ability of the indexes to describe the level of sedation-analgesia, according with the RSS score, was evaluated using the prediction probability (Pk). The results showed that the ratio SD1/SD2FR3 contains useful information about the sedation level, and SD1FR2 and SD2FR2 had the best performance classifying response to noxious stimuli. Models including parameters from Poincaré plot emerge as a good estimator of sedation-analgesia levels.