Plasma Propofol Concentrations Research Articles

Bioelectrical impedance analysis of body composition for the anesthetic induction dose of propofol in older patients

BackgroundOlder people are currently the fastest growing segment of the worldwide population. The present study aimed to estimate propofol dose in older patients based on size descriptors measured by bioelectrical impedance analysis (BIA).MethodsA cross sectional study in adult and older patients with body mass index equal to or lower than 35 kg/m2 was carried out. BIA and Clinical Frail Scale scoring were performed during pre-operative evaluation. Propofol infusion was started at 2000 mg/h until loss of consciousness (LOC) which was defined by “loss of eye-lash reflex” and “loss of response to name calling”. Total dose of propofol at LOC was recorded. Propofol plasma concentration was measured using gas chromatography/ion trap-mass spectrometry.ResultsForty patients were enrolled in the study. Total propofol dose required to LOC was lower in Age ≥ 65 group and a higher plasma propofol concentration was measured in this group. 60% of old patients were classified as “apparently vulnerable” or “frail” and narrow phase angle values were associated with increasing vulnerability scores. In the Age ≥ 65 group, the correlation analysis showed that the relationship between propofol dose and total body weight (TBW) scaled by the corresponding phase angle value is stronger than the correlation between propofol dose and TBW or fat free mass (FFM).ConclusionsThis study demonstrates that weight-based reduction of propofol is suitable in older patients; however FFM was not seen to be more effective than TBW to predict the propofol induction dose in these patients. Guiding propofol induction dose according to baseline frailty score should also be considered to estimate individualized dosage profiles. Determination of phase angle value appears to be an easy and reliable tool to assess frailty in older patients.Trial registrationClinicalTrials.gov Identifier: NCT02713698. Registered on 23 February 2016.

Acceptability of intravenous propofol sedation for adolescent dental care

PurposePropofol is an intravenous anaesthetic agent commonly utilised in general anaesthesia, however in sub-anaesthetic concentrations can be utilised to provide sedation through automated dosing of target-controlled infusion (TCI). TCI has been shown to provide accurate and stable predicted plasma and effect-site concentrations of propofol. A four-part mixed-method prospective study was undertaken to evaluate the safety and patient acceptability of intravenous propofol sedation in adolescent patients requiring dental care. There is a paucity in the literature on patient-reported outcomes and patient safety in the management of adolescent patients for dental treatment.MethodsDemographics were recorded including age, gender, ASA Classification and Children’s Fear Survey Schedule—Dental Subscale (CFSS-DS) completed pre-operatively. Behaviour ratings of the Frankl and Houpt scales were recorded followed by post-operative questionnaire and telephone consultation. Consultation was completed following the procedure to determine patient satisfaction, memory of the procedure and any reported side effects of treatment. Qualitative thematic analysis was utilised.Results55 patients were recruited for the study, of which 49 (mean age 14.67 years) completed the sedation study and were treated safely with no post-operative complications. The mean lowest oxygen saturation was 98.12% SpO2 (SD 2.6). Thematic analysis demonstrated positive patient-reported outcomes to IV sedation.ConclusionPropofol TCI sedation is an effective treatment modality for the management of dentally anxious adolescents as a safe alternative to general anaesthesia, allowing the opportunity for increased provision of treatment per visit on those patients with a high dental need. Further randomised controlled trials comparing propofol TCI to other pharmacological managements are required.

Effect of Hemodynamic Changes in Plasma Propofol Concentrations Associated with Knee-Chest Position in Spinal Surgery: A Prospective Study.

BackgroundAnesthesia induction and maintenance with propofol can be guided by target-controlled infusion (TCI) systems using pharmacokinetic (Pk) models. Physiological variables, such as changes in cardiac output (CO), can influence propofol pharmacokinetics. Knee-chest (KC) surgical positioning can result in CO changes.ObjectivesThis study aimed to evaluate the relationship between propofol plasma concentration prediction and CO changes after induction and KC positioning.MethodsThis two-phase prospective cohort study included 20 patients scheduled for spinal surgery. Two different TCI anesthesia protocols were administered after induction. In phase I (n = 9), the loss of consciousness (LOC) concentration was set as the propofol target concentration and CO changes following induction and KC positioning were quantified. In phase II (n = 11), based on data from phase I, two reductions in the propofol target concentration on the pump were applied after LOC and before KC positioning. Propofol plasma concentrations were measured at different moments in both phases: after induction and after KC positioning.ResultsSchnider Pk model showed a good performance in predicting propofol concentration after induction; however, after KC positioning, when a significant drop in CO occurred, the measured propofol concentrations were markedly underestimated. Intended reductions in the propofol target concentration did not attenuate HD changes. In the KC position, there was no correlation between the propofol concentration estimated by the Pk model and the measured concentration in plasma, as the latter was much higher (P = 0.013) while CO and BIS decreased significantly (P < 0.001 and P = 0.004, respectively).ConclusionsOur study showed that the measured propofol plasma concentrations during the KC position were significantly underestimated by the Schnider Pk model and were associated with significant CO decrease. When placing patients in the KC position, anesthesiologists must be aware of pharmacokinetic changes and, in addition to standard monitoring, the use of depth of anesthesia and cardiac output monitors may be considered in high-risk patients.

Impact of Gender Variation on Calculated Plasma Concentration of Propofol (Cp50calc) to Prevent Movement Response to Surgical Stimulus in South Indian Population: A Comparative Study

Objective: To find out the gender differences in Cp50calc of propofol required to prevent movement response to surgical stimulus in South Indian population. Materials and Methods: A comparative study was performed on sixty American Society of Anesthesiologists I–II patients of both sexes undergoing elective surgery at a tertiary care institution. A bolus dose of 1.5 mg/kg propofol for 2 min, followed by a 150 μg/kg infusion for 10 min was administered and movement response to surgical incision was noted. Propofol maintenance infusion rate was determined by Dixon's up-and-down method, increased by 10 μg/kg/min for patient movement on surgical stimulus and reduced by 10 μg/kg/min for no movement for successive patient. The plasma concentration (Cpcalc) was calculated by formula used in the marsh pharmacokinetic model using Rugloop II propofol calculation validation Excel Spreadsheet by feeding patient's age, weight, and propofol dose. Cp50calc of propofol, the calculated plasma concentration of propofol, at which 50% of patients anesthetized with propofol do not respond to standard surgical stimulus is calculated by the mean of the midpoint concentration of all independent pair of patients who manifested a consecutive three crossovers from movement-to-no movement response to ensure reaching steady state. Results: No statistically significant difference observed in hemodynamic parameters between the groups. Cp50calc of propofol was 6.336 + 0.14 μg/ml in males and 5.664 + 0.14 μg/ml in females, which was statistically significant (P

Effect of anesthesia on motor responses evoked by spinal neural prostheses during intraoperative procedures

Objective. The overall goal of this study was to investigate the effects of various anesthetic protocols on the intraoperative responses to intraspinal microstimulation (ISMS). ISMS is a neuroprosthetic approach that targets the motor networks in the ventral horns of the spinal cord to restore function after spinal cord injury. In preclinical studies, ISMS in the lumbosacral enlargement produced standing and walking by activating networks controlling the hindlimb muscles. ISMS implants are placed surgically under anesthesia, and refinements in placement are made based on the evoked responses. Anesthesia can have a significant effect on the responses evoked by spinal neuroprostheses; therefore, in preparation for clinical testing of ISMS, we compared the evoked responses under a common clinical neurosurgical anesthetic protocol with those evoked under protocols commonly used in preclinical studies. Approach. Experiments were conducted in seven pigs. An ISMS microelectrode array was implanted in the lumbar enlargement and responses to ISMS were measured under three anesthetic protocols: (1) isoflurane, an agent used pre-clinically and clinically, (2) total intravenous anesthesia (TIVA) with propofol as the main agent commonly used in clinical neurosurgical procedures, (3) TIVA with sodium pentobarbital, an anesthetic agent used mostly preclinically. Responses to ISMS were evaluated based on stimulation thresholds, movement kinematics, and joint torques. Motor evoked potentials (MEP) and plasma concentrations of propofol were also measured. Main results. ISMS under propofol anesthesia produced large and functional responses that were not statistically different from those produced under pentobarbital anesthesia. Isoflurane, however, significantly suppressed the ISMS-evoked responses. Significance. This study demonstrated that the choice of anesthesia is critical for intraoperative assessments of motor responses evoked by spinal neuroprostheses. Propofol and pentobarbital anesthesia did not overly suppress the effects of ISMS; therefore, propofol is expected to be a suitable anesthetic agent for clinical intraoperative testing of an intraspinal neuroprosthetic system.

Pharmacokinetic Modeling of Propofol in Indian Children

Objective: To analyse the PK (pharmacokinetics) of propofol after single bolus dose in children undergoing elective general surgery and to establish a PK model of propofol after single bolus dose in children undergoing elective general surgery and to establish a PK model of propofol. Materials and Methods: Twelve healthy Indian children aged 5–12 years who underwent elective general surgery under general anesthesia received propofol at an intravenous bolus dose of 2.5 mg/kg. The plasma propofol concentration over the next 12 h was estimated using high-performance liquid chromatography. A total of 144 samples were analyzed, and PK parameters were evaluated using nonlinear mixed-effects modeling. Results were validated using bootstrap analysis, and visual predictive check was done to evaluate the final model. Results: Propofol PK in Indian children was characterized by a three-compartment model similar to adults. The model derived estimates of PK parameters are as follows: volume of the central compartment (V1) = 598.73 ml/kg, volume of the second compartment (V2) = 821.12 ml/kg, volume of the third compartment (V3) = 1097 ml/kg, systemic clearance (CL1) = 22.1 ml/kg/min, and intercompartmental clearances CL2 and CL3 which were 42.5 ml/kg/min and 10.4 ml/kg/min, respectively. Conclusion: The final PK model imparted a robust characterization of propofol PK. Inclusion of body weight as a covariate to the model exhibited a significant impact on propofol PK. The execution of this patient derived PK model should support future population PK studies that include diverse population with sparse sampling to support the dosing of propofol in Indian children undergoing surgery under total intravenous anesthesia.

A New Pharmacokinetic Model of Propofol for Japanese Patients

Target-controlled infusion (TCI) of propofol is used for general anesthesia. However, the only pharmacokinetic parameter commercially used for Japanese patients is weight, and pharmacokinetic models are based on European physical attributes. Drug metabolism also differs in races. This study aimed to identify optimal continuous doses of propofol for Japanese patients and to create a simulated pharmacokinetic (PK) model. Thirty Japanese patients were enrolled. Patients received a constant infusion of 9 mg/kg/h of propofol. Arterial blood samples were collected and the time course of plasma propofol concentrations was modeled using the nonlinear mixed effects model (NONMEM) three-compartmental PK model. We validated the model by intravenously injecting 10 patients with a TCI driver system programmed with the NONMEM model. Our model’s performance was evaluated using the median prediction error (MDPE), median absolute prediction error (MDAPE), and Wobble. We analyzed 320 blood samples for model building and 160 samples for validating our new model. The calculated parameters for the three-compartmental PK model were volume [V1, 3.58; V2, 13.0 + 0.49 × (Age—64); and V3, 186] and elimination clearance [CL1, 0.77 + (WT—54) × 0.04 + (HT—158) × 0.03; CL2, 0.89 + 0.12 × (Age—64); and CL3, 0.98 × exp ((Age—64)/10)]. The new model improved MDPE, MDAPE, and Wobble values (11.5% ± 43.8%, 14.3% ± 33.0%, and 25.0% ± 21.3%, respectively). We created a new pharmacokinetic model for Japanese patients, which is more accurate than the three existing models applied to Japanese populations. Electronic document is a “live” template. The various components of your paper [title, text, heads, etc.] are already defined on the style sheet, as illustrated by the portions given in this document.

Clinical effects of constant rate infusions of medetomidine\u2013propofol combined with sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery

BackgroundThe aim of the present study was to evaluate clinical efficacy of constant rate infusions (CRIs) of medetomidine–propofol combined with sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery. Thirty horses were sedated intravenously (IV) with medetomidine (6.0 μg/kg) and midazolam (0.02 mg/kg) and induced IV with ketamine (1.0 mg/kg) and propofol (1.0 mg/kg). These horses were randomly allocated to three groups and maintained with sevoflurane and CRI of either medetomidine (3.0 μg/kg/h) (Group M; n = 10); or medetomidine (3.0 μg/kg/h) and propofol (3.0 mg/kg/h) (Group MP3; n = 10); or medetomidine (3.0 μg/kg/h) and propofol (6.0 mg/kg/h) (Group MP6; n = 10). End-tidal sevoflurane concentration (ETSEVO), cardiovascular parameters, plasma propofol concentration, and recovery time and quality were compared among groups. Data were analyzed by using ANOVA with Tukey’s multiple comparison test, considering P < 0.05 significant.ResultsETSEVO (%) was 2.4 ± 0.1 in Group M, 1.7 ± 0.2 in Group MP3, and 1.4 ± 0.2 in Group MP6; ETSEVO declined significantly in a propofol-dose-dependent manner. The rates of dobutamine infusion (μg/kg/min) required to keep the mean arterial blood pressure over 70 mmHg were significantly lower in Group MP3 (0.20 ± 0.10) and Group MP6 (0.15 ± 0.06) than in Group M (0.37 ± 0.18). Recovery time and quality did not differ among groups. All horses in Group MP3 required only one attempt to stand, and recovery quality was excellent. Plasma propofol concentrations were stable throughout maintenance of anesthesia in Group MP3, whereas those in Group MP6 increased significantly with increasing duration of maintenance.ConclusionsCRIs of medetomidine–propofol reduced the sevoflurane requirement for surgical anesthesia as the propofol dose increased, compared with a CRI of medetomidine alone. Additionally, the two propofol protocols provided good maintenance of cardiovascular function. CRIs of medetomidine (3.0 μg/kg/h) and propofol (3.0 mg/kg/h) resulted in excellent-quality recovery. This protocol could therefore be an especially useful additive to sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery.

Pharmacokinetic Analysis of Propofol Target-Controlled Infusion Models in Chinese Patients with Hepatic Insufficiency.

BackgroundEffects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency.Material/MethodsWe assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 μg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software.ResultsIn the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained.ConclusionsPropofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.

Haemodynamic changes during propofol induction in dogs: new findings and approach of monitoring

BackgroundPropofol is one of the most widely used injectable anaesthetic agents in veterinary practice. Cardiovascular effects related to propofol use in dogs remain less well defined. The main objective of this study was to evaluate the haemodynamic changes during induction of general anaesthesia with propofol in healthy dogs, by a beat-to-beat continuous monitoring. All dogs were premedicated with intramuscular acepromazine (0.015 mg/kg) and methadone (0.15 mg/kg). Transthoracic echocardiography was used to measure the velocity time integral (VTI) of the left ventricular outflow tract. A syringe driver, programmed to deliver propofol 5 mg/kg over 30 s followed by a continuous infusion of 25 mg/kg/h, was used to induce and maintain anaesthesia. From the initiation of propofol administration, heart rate (HR) and mean invasive arterial blood pressure (MAP) were recorded every 5 s for 300 s, while aortic blood flow was continuously recorded and stored for 300 S. maximum cardiovascular depression was defined the lowest MAP (MAP_Tpeak) recorded during the monitored interval. VTI and VTI*HR were calculated at 0, 30, 90, 120, 150 and 300 s post administration of propofol, and at MAP_Tpeak. Haemodynamic effects of propofol in relation to plasma and biophase concentrations were also evaluated by pharmacokinetics simulation.ResultsThe median (range) HR was significantly higher (p = 0.006) at the moment of maximum hemodynamic depression (Tpeak) [105(70–148) bpm] compared with pre-induction values (T0) [65(50–120) bpm]. The median (range) MAP was significantly lower (p < 0.001) at Tpeak [61(51–69) mmHg] compared with T0 [88(72–97) mmHg]. The median (range) VTI and VTI*HR were similar at the two time points [11.9(8.1–17.3) vs 13,3(9,4-16,5) cm, and 1172(806–1554) vs 1002(630–1159) cm*bpm, respectively].ConclusionsInduction of anaesthesia with propofol causes a drop of arterial pressure in healthy dogs, however cardiac output is well maintained by compensatory chronotropic response. The magnitude of MAP_Tpeak may be strictly related with propofol plasma concentration.

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

IntroductionTo examine whether sex and polymorphisms of cytochrome P450 (CYP) 2B6 and UDP-glucuronosyltransferase (UGT) 1A9 affect the difference between predicted and measured plasma propofol concentration during continuous infusion by target-controlled infusion.ResultsBlood samples of 69 patients (48 men and 21 women) were obtained at 4 h after initial propofol infusion. Percentage performance error (PE) was calculated to assess the difference between measured and predicted propofol concentration. Regression coefficients (β) and 95% confidence intervals (CI) of sex and the polymorphisms of CYP2B6 and UGT1A9 for PE were, separately and mutually, estimated with linear regression. Covariates included age and body mass index in the minimal adjusted model, and additionally included clinical factors (mean blood pressure, heart rate, volume of intravenous fluid, surgical site, surgical position, and pneumoperitoneum) in the full adjusted model. PE was higher in men than in women (28.7% versus 10.5%, p = 0.015). Female sex was inversely associated with PE: the minimal adjusted β = − 8.84 (95% CI, − 16.26 to − 1.43); however, the fully adjusted β with clinical factors became not significant. The average of PE did not differ between polymorphisms of CYP2B6 and UGT1A9, and β of CYP2B6 516G>T polymorphisms mutually adjusted with female sex was not significant. Mean blood pressure, heart rate, and volume of intravenous fluid were independently associated with PE in the full adjusted model.ConclusionsUnder 4 h anesthesia with propofol target-controlled infusion in our population, sex differences appeared to exist in the propofol concentration, which might be largely mediated by clinical factors, such as hemodynamic status.Trial registrationUMIN-CTR UMIN000009015, Registered 1 October 2012

Advances in pharmacokinetic modeling

The use of conventional pharmacokinetic parameters sets 'models' derived from nonobese patients has proven inadequate to administer intravenous anesthetics in the obese population and is commonly associated with higher than anticipated plasma propofol concentrations when used with target (plasma or effect site) controlled infusion pumps. In this review we will describe recent modeling strategies to characterize the disposition of intravenous anesthetics in the obese patient and will show clinically relevant aspects of new model's performance in the obese population. Because clearance of a drug increases in a nonlinear manner with weight, nonlinear relationships better scale infusion rates between lean and obese individuals. Allometric concepts have been successfully used to describe size-related nonlinear changes in clearances. Other nonlinear scaling options include the use of descriptors such as body surface area, lean body weight, fat-free mass, and normal fat mass. Newer pharmacokinetic models, determined from obese patient data, have been developed for propofol and remifentanil using allometric concepts and comprehensive size descriptors. Pharmacokinetic models to perform target-controlled infusion in the obese population should incorporate descriptors that reflect with greater precision the influence of body composition in volumes and clearances of each drug. It is our hope that commercially available pumps will soon incorporate these new models to improve the performance of this technique in the obese population.

Dopant-assisted photoionization positive ion mobility spectrometry coupled with time-resolved purge introduction for online quantitative monitoring of intraoperative end-tidal propofol

Online monitoring of end-tidal propofol provides important information of anesthesia deepness for anesthetists as propofol concentrations in plasma and breath are well correlated. In this work, a dopant-assisted photoionization positive ion mobility spectrometry (DAPI-PIMS) coupled with time-resolved purge introduction was developed for online quantitative monitoring end-tidal propofol. With optimized dopant, toluene, the selectivity and sensitivity of propofol was improved as interference from sevoflurane was eliminated. Using the time-resolved purge introduction, the response of propofol and moisture was separated due to their absorption differences on the inwall of the fluorinated ethylene propylene (FEP) sample loop, ensuring sensitive measurement of end-tidal propofol with a short response time of 4 s. The quantitative equation derived from the second order reaction kinetics model extended the quantitative range of propofol from 0.2 ppbv to 45 ppbv. Finally, the method was used to monitor the intraoperative end-tidal propofol of six patients, and the results nicely demonstrated its feasibility in practical clinical environment.

Online Monitoring of Intraoperative Exhaled Propofol by Acetone-Assisted Negative Photoionization Ion Mobility Spectrometry Coupled with Time-Resolved Purge Introduction.

Online monitoring of exhaled propofol concentration is important for anesthetists to provide adequate anesthesia as propofol concentrations in plasma and breath are correlated reasonably well. Exhaled propofol could be detected by 63Ni ion mobility spectrometry in negative ion mode; however, the radioactivity of 63Ni source restricts its clinical application due to safety, environmental, and regulatory concerns. An acetone-assisted negative photoionization ion mobility spectrometer (AANP-IMS) using a side-mounted vacuum ultraviolet (VUV) lamp in the unidirectional (UD) flow mode was developed for sensitive measurement of exhaled propofol by producing a high percentage of O2-(H2O) n. An adsorption sampling and time-resolved purge introduction system was developed to eliminate the interference of residual inhaled anesthetic sevoflurane based on their different adsorptions between propofol and sevoflurane on the inwall of the fluorinated ethylene propylene (FEP) sample loop. The effects of the inner diameter and the length of the sample loop on the signal intensity of propofol and the time-resolution between propofol and sevoflurane were theoretically and experimentally investigated. A sample loop with 3 mm i.d. and 150 cm length allowed sensitive measurement of exhaled propofol with a response time of 4 s, a linear response range for propofol was achieved to be 0.2 to 14 ppbv with a limit of detection (LOD) of 60 pptv, and the quantification of propofol was not influenced by the change of the sevoflurane concentration. Finally, the performance of monitoring exhaled propofol during surgery was demonstrated on a patient undergoing laparoscopic distal pancreatectomy combined with cholecystectomy.

Pharmacokinetics and pharmacodynamic effects in koi carp (Cyprinus carpio) following immersion in propofol

ObjectiveTo test the hypothesis that plasma propofol concentration (PPC) is associated with anesthetic effect in koi carp administered propofol by immersion. Study designProspective study. AnimalsTwenty mature koi carp (mean ± standard deviation, 409.4 ± 83.7 g). MethodsFish 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). ResultsIn 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 relevanceMeasurable 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.

Effects of isoflurane, sevoflurane, propofol and alfaxalone on brain metabolism in dogs assessed by proton magnetic resonance spectroscopy (1H MRS)

BackgroundThe purpose of this study was to determine the effects of isoflurane, sevoflurane, propofol and alfaxalone on the canine brain metabolite bioprofile, measured with single voxel short echo time proton magnetic resonance spectroscopy at 3 Tesla. Ten adult healthy Beagle dogs were assigned to receive isoflurane, sevoflurane, propofol and alfaxalone at 3 different dose rates each in a randomized cross-over study design. Doses for isoflurane, sevoflurane, propofol and alfaxalone were FE’Iso 1.7 vol%, 2.1 vol%, 2.8 vol%, FE’Sevo 2.8 vol%, 3.5 vol% and 4.7 vol%, 30, 45 and 60 mg kg− 1 h− 1 and 10, 15 and 20 mg kg− 1 h− 1 respectively. A single voxel Point Resolved Spectroscopy Sequence was performed on a 3 T MRI scanner in three brain regions (basal ganglia, parietal and occipital lobes). Spectral data were analyzed with LCModel. Concentration of total N-acetylaspartate (tNAA), choline, creatine, inositol and glutamine and glutamate complex (Glx) relative to water content was obtained. Plasma concentration of lactate, glucose, triglycerides, propofol and alfaxalone were determined. Statistics were performed using repeated measures ANOVA or Wilcoxon Sign Rank test with alpha = 5%.ResultsPlasma glucose increased with isoflurane, sevoflurane and alfaxalone but decreased with propofol. Plasma lactate increased with all anesthetics (isoflurane > sevoflurane > propofol > alfaxalone). Cerebral lactate could not be detected. Only minor changes in cerebral metabolite concentrations of tNAA, choline, inositol, creatine and Glx occurred with anesthetic dose changes.ConclusionThe metabolomic profile detected with proton magnetic resonance spectroscopy at 3 Tesla of canine brain showed only minor differences between doses and anesthetics related to tNAA, choline, creatine, inositol and Glx.

Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics.

Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics. Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15min after administering a single intravenous bolus of propofol at a dose of 2.0ml/kg to measure propofol plasma concentration. Area under the time-plasma concentration curve from zero up to the last measurable time point (AUC15min) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann-Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of<0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis. Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC15min (p<0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC15min. This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates. University Hospital Medical Information Network (UMIN000022948).

Propofol Pharmacodynamics and Bispectral Index During Key Moments of Awake Craniotomy.

During awake craniotomy, the patient's language centers are identified by neurological testing requiring a fully awake and cooperative patient. Hence, anesthesia aims for an unconscious patient at the beginning and end of surgery but an awake and responsive patient in between. We investigated the plasma (Cplasma) and effect-site (Ceffect-site) propofol concentration as well as the related Bispectral Index (BIS) required for intraoperative return of consciousness and begin of neurological testing. In 13 patients, arterial Cplasma were measured by high-pressure liquid chromatography and Ceffect-site was estimated based on the Marsh and Schnider pharmacokinetic/dynamic (pk/pd) models. The BIS, Cplasma and Ceffect-site were compared during the intraoperative awakening period at designated time points such as return of consciousness and start of the Boston Naming Test (neurological test). Return of consciousness occurred at a BIS of 77±7 (mean±SD) and a measured Cplasma of 1.2±0.4 μg/mL. The Marsh model predicted a significantly (P<0.001) higher Cplasma of 1.9±0.4 µg/mL as compared with the Schnider model (Cplasma=1.4±0.4 µg/mL) at return of consciousness. Neurological testing was possible as soon as the BIS had increased to 92±6 and measured Cplasma had decreased to 0.8±0.3 µg/mL. This translated into a time delay of 23±12 minutes between return of consciousness and begin of neurological testing. At begin of neurological testing, Cplasma according to Marsh (Cplasma=1.3±0.5 µg/mL) was significantly (P=0.002) higher as compared with the Schnider model (Cplasma=1.0±0.4 µg/mL). To perform intraoperative neurological testing, patients are required to be fully awake with plasma propofol concentrations as low as 0.8 µg/mL. Following our clinical setup, the Schnider pk/pd model estimates propofol concentrations significantly more accurate as compared with the Marsh model at this neurologically crucial time point.

Comparison of plasma propofol concentration for apnea, response to mechanical ventilation, and airway device between endotracheal tube and supraglottic airway device in Beagles.

The relationships between propofol plasma concentrations and the pharmacodynamic endpoints may differ according to a type of airway device. To clarify these relationships in different airway devices would be useful to avoid the complication such as apnea and intraoperative awareness. The aim of this study was to investigate the influence of difference of airway device on propofol requirement during maintenance of anesthesia in dogs. We compared the influence of airway devices on the plasma propofol concentrations for apnea, response to mechanical ventilation, and response to airway device between endotracheal tube (ETT) and supraglottic airway device (SGAD) in Beagles. The pharmacodynamic effects were repeatedly assessed at varying propofol concentrations. The plasma concentrations (mean ± SD) of propofol in the ETT and SGAD groups were 10.2 ± 1.8 and 10.9 ± 2.4 µg/ml for apnea (P=0.438), 7.9 ± 1.2 and 7.4 ± 1.5 µg/ml for response to mechanical ventilation (P=0.268), and 5.2 ± 0.7 and 5.4 ± 1.5 µg/ml for response to airway device (P=0.580), respectively. Required propofol concentration during maintenance of anesthesia may be similar between ETT and SGAD. Without moderate to strong stimuli such as airway device insertion or painful stimulation during surgery, the type of airway device may have little impact on required propofol concentration during maintenance of anesthesia in dogs.

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.