Phase lag entropy as a hypnotic depth indicator during propofol sedation.

Phase lag entropy, an electro-encephalography-based hypnotic depth indicator, calculates diversity in temporal patterns of phase relationship. We compared the performance of phase lag entropy with the bispectral index™ in 30 patients scheduled for elective surgery. We initiated a target-controlled infusion of propofol using the Schnider model, and assessed sedation levels using the Modified Observer's Assessment of Alertness/Sedation scale every 30 s with each stepwise increase in the effect-site propofol concentration. Phase lag entropy and bispectral index values were recorded. The correlation coefficient and prediction probability between phase lag entropy or bispectral index and the sedation level or effect-site propofol concentration were analysed. We calculated baseline variabilities of phase lag entropy and bispectral index. In addition, we applied a non-linear mixed-effects model to obtain the pharmacodynamic relationships among the effect-site propofol concentration, phase lag entropy or bispectral index and sedation level. As sedation increased, phase lag entropy and bispectral index both decreased. The prediction probability values of phase lag entropy and bispectral index for sedation levels were 0.697 and 0.700 (p = 0.261) and for the effect-site concentration of propofol were 0.646 and 0.630 (p = 0.091), respectively. Baseline variability in phase lag entropy and bispectral index was 3.3 and 5.7, respectively. The predicted propofol concentrations, using the Schnider pharmacokinetic model, producing a 50% probability of moderate and deep sedation were 1.96 and 3.01 µg.ml-1 , respectively. Phase lag entropy was found to be useful as a hypnotic depth indicator in patients receiving propofol sedation.

Population pharmacokinetic analysis of propofol in underweight patients under general anaesthesia.

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 (tpeak, 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: V1(L)=2.02, V2(L)=12.9(BMI/18.5), V3(L)=139, Cl (L⋅min-1)=1.66(LBM/40), Q1 (L⋅min-1)=1.44, Q2 (L⋅min-1)=0.87+0.0189×(LBM-40). The median tpeak 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.

Development of a new analgesic index using nasal photoplethysmography.

Although surrogate measures to quantify pain intensity have been commercialised, there is a need to develop a new index with improved accuracy. The aim of this study was to develop a new analgesic index using nasal photoplethysmography data. The specially designed sensor was placed between the columella and the nasal septum to acquire nasal photoplethysmography in surgical patients. Nasal photoplethysmography and Surgical Pleth Index® (GE Healthcare) data were obtained for 14 min both in the absence (pre-operatively) or presence (postoperatively) of pain in a group of surgical patients, each patient acting as their own control. Various dynamic photoplethysmography variables were extracted to quantify pain intensity; the most accurate index was selected using logistic regression as a classifier. The area under the curve of the receiver-operating characteristic curve was measured to evaluate the accuracy of final model predictions. In total, 12,012 heart beats from 89 patients were used to develop a new Nasal Photoplethysmography Index for analgesic depth quantification. The two-variable model (a combination of diastolic peak point variation and heart beat interval variation) was most accurate in discriminating between the presence and absence of pain (numerical rating scale (NRS) ≥ 3). The accuracy and area under the curve of the receiver-operating characteristic curve for the Nasal Photoplethysmography Index were 75.3% and 0.8018, respectively, and 64.8% and 0.7034, respectively, for the Surgical Pleth Index. The Nasal Photoplethysmography Index clearly distinguished pain (NRS ≥ 3) in awake surgical patients with postoperative pain. The Nasal Photoplethysmography Index performed better than the Surgical Pleth Index. Further validation studies are needed to evaluate its feasibility to quantify pain intensity during general anaesthesia.

Predictive performance of the modified Marsh and Schnider models for propofol in underweight patients undergoing general anaesthesia using target-controlled infusion.

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.

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

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

The population pharmacokinetics of fentanyl in patients undergoing living-donor liver transplantation.

Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed-effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living-donor liver transplantation (LDLT). Fentanyl was continuously infused at the rate of 200-400 µg/h throughout the operation. The time course of the fentanyl plasma concentration levels was best described in terms of a two-compartment model. Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V(1)) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) × 42.5, 113.0, and 189.0, respectively, × (body weight/69)(1.3); peripheral volume of distribution (V(2)) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 × (cardiac output (CO)/6.7)(2.5), 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance.

Effectiveness, safety, and pharmacokinetic and pharmacodynamic characteristics of microemulsion propofol in patients undergoing elective surgery under total intravenous 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.

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs.

BACKGROUND AND PURPOSE: Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations. EXPERIMENTAL APPROACH: The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg kg(-1) min(-1)) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling. KEY RESULTS: Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC(last) and AUC(inf) between both formulations were acceptable for bioequivalence, whereas that of C(max) was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E(0) (baseline ApEn)-E(max) (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V(1) of both formulations and sex for k(21) of microemulsion propofol. The blood-brain equilibration rate constants (k(e0), min(-1)) were 0.476 and 0.696 for microemulsion and LCT propofol respectively. CONCLUSIONS AND IMPLICATIONS: Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.

Machine learning methods applied to pharmacokinetic modelling of remifentanil in healthy volunteers: a multi-method comparison.

This study compared the blood concentrations of remifentanil obtained in a previous clinical investigation with the predicted remifentanil concentrations produced by different pharmacokinetic models: a non-linear mixed effects model created by the software NONMEM; an artificial neural network (ANN) model; a support vector machine (SVM) model; and multi-method ensembles. The ensemble created from the mean of the ANN and the non-linear mixed effects model predictions achieved the smallest error and the highest correlation coefficient. The SVM model produced the highest error and the lowest correlation coefficient. Paired t-tests indicated that there was insufficient evidence that the predicted values of the ANN, SVM and two multi-method ensembles differed from the actual measured values at alpha = 0.05. The ensemble method combining the ANN and non-linear mixed effects model predictions outperformed either method alone. These results indicated a potential advantage of ensembles in improving the accuracy and reducing the variance of pharmacokinetic models.

Enzyme-linked immunosorbent assay, single radial immunodiffusion, and indirect methods for the detection of failure of transfer of passive immunity in dairy calves.

BACKGROUND: Confirmatory tests for failure of transfer of passive immunity (FTPI) in dairy calves require direct measurements of the serum immunoglobulin G concentration. Enzyme-linked immunosorbent assay (ELISA) has advantages over single radial immunodiffusion (SRID) in terms of cost and time. OBJECTIVES: To evaluate the agreement between ELISA and SRID, and to compare the diagnostic performance of ELISA with indirect methods, in the detection of FTPI in calves. ANIMALS: One hundred and fifteen dairy calves (aged 0-10 days) from 23 calf-rearing facilities. METHODS: Prospective, observational study. The agreement between SRID and ELISA was determined by the Bland-Altman method. Fixed bias (SRID - ELISA) was calculated. For comparison of the diagnostic performance of ELISA with indirect methods, sensitivity, specificity, and area under the curve (AUC) of receiver operating characteristic (ROC) curves were calculated at cut-off values of 500 and 1,000 mg/dL. RESULTS: The agreement between SRID and ELISA was 94%. Fixed bias (SRID - ELISA) was 140 +/- 364 mg/dL. The AUC and sensitivity of ELISA at the cut-off value of 1,000 mg/dL were higher than those of indirect methods (P<.004). The specificity of ELISA at the cut-off value of 1,000 mg/dL was not higher than that of indirect methods, except for serum total protein concentration assay. CONCLUSION AND CLINICAL IMPORTANCE: ELISA exhibited good diagnostic performance and good agreement with SRID. ELISA is an adequate method for both screening and confirmatory tests for FTPI in dairy calves at the cut-off value of 500 mg/dL.

Population pharmacokinetic and pharmacodynamic models of remifentanil in healthy volunteers using artificial neural network analysis.

AIMS: An ordinary sigmoid E(max) model could not predict overshoot of electroencephalographic approximate entropy (ApEn) during recovery from remifentanil effect in our previous study. The aim of this study was to evaluate the ability of an artificial neural network (ANN) to predict ApEn overshoot and to evaluate the predictive performance of the pharmacokinetic model, and pharmacodynamic models of ANN with respect to data used. METHODS: Using a reduced number of ApEn instances (n = 1581) to make NONMEM modelling feasible and complete ApEn data (n = 24 509), the presence of overshoot was assessed. A total of 1077 measured remifentanil concentrations and ApEn data, and a total of 24 509 predicted concentrations and ApEn data were used in the pharmacodynamic model A and B of ANN, respectively. The testing subset of model B (n = 7352) was used to evaluate the ability of ANN to predict overshoot of ApEn. Mean squared error (MSE) was calculated to evaluate the predictive performance of the ANN models. RESULTS: With complete ApEn data, ApEn overshoot was observed in 66.7% of subjects, but only in 37% with a reduced number of ApEn instances. The ANN model B predicted 77.8% of ApEn overshoot. MSE (95% confidence interval) was 57.1 (3.22, 71.03) for the pharmacokinetic model, 0.148 (0.004, 0.007) for model A and 0.0018 (0.0017, 0.0019) for model B. CONCLUSIONS: The reduced ApEn instances interfered with the approximation of true electroencephalographic response. ANN predicted 77.8% of ApEn overshoot. The predictive performance of model B was significantly better than that of model A.

Changes in visual and auditory response time during conscious sedation with propofol.

BACKGROUND: Using a push-button device, we investigated whether visual or auditory response time would increase with increasing sedation, and assessed the responsiveness score of the Observer's Assessment of Alertness/Sedation (OAA/S) scale at the point of first loss of response to visual or auditory stimulation. METHODS: In experiment 1 we applied visual and auditory stimulation to 19 patients as the propofol target plasma concentration (CPT) was increased to determine whether the visual or auditory response would be lost first. Thirty patients were each then infused with propofol, starting at a CPT of 0.3 microg ml(-1) and increasing by increments of 0.2 microg ml(-1), during which visual (experiment 2) or auditory (experiment 3) stimulation was applied when the effect-site concentration (CE) of propofol reached CPT. Visual response time (VRT), auditory response time (ART), CE and total amounts of propofol, and OAA/S score at the first loss of visual/auditory response were measured. RESULTS: Visual response disappeared earlier than auditory response in 84.2% of the patients. Visual response time and ART were linearly prolonged as the CE of propofol increased. The CE and total amounts of propofol at the first loss of visual response were 1.2 +/- 0.4 microg ml(-1) and 57.9 +/- 16.7 mg, compared with 1.4 +/- 0.5 microg ml(-1) and 71.6 +/- 26.1 mg, respectively, at the first loss of auditory response. The median (range) OAA/S scores at the first loss of visual and auditory response were 4 (3-4) and 3 (2-4), respectively. CONCLUSION: VRT and ART were linearly prolonged with increasing sedation. Visual response may be useful in monitoring conscious sedation.

Thermosoftening treatment of the nasotracheal tube before intubation can reduce epistaxis and nasal damage.

UNLABELLED: We evaluated whether a thermosoftening treatment with warm saline of a nasotracheal preformed tube can improve navigability through the nasal passageways and reduce epistaxis and nasal damage. A total of 150 patients were randomly allocated to three groups: Group I (untreated tube group, n = 50), Group II (35 degrees C treated tube group, n = 50), and Group III (45 degrees C treated tube group, n = 50). In Groups II and III, the tubes were softened at 35 +/- 2 degrees C and 45 +/- 2 degrees C with warm saline, respectively. In Group I the tube was prepared at room temperature (25 +/- 2 degrees C). The incidence of epistaxis and nasal damage in Groups II and III was significantly less than that of Group I (P: < 0.05). Despite the more frequent incidence of smooth passage in Group III, no statistical difference was found among the groups. Logistic regression analysis also confirmed that epistaxis was more likely to be reduced when the tube had been thermosoftened (odds ratio = 1.46, 95% confidence interval = 1.02, 2.11). We conclude that simple thermosoftening treatment of the nasotracheal tube with warm saline helps to reduce epistaxis and nasal damage. IMPLICATIONS: Thermosoftening treatment of a nasotracheal tube with warm saline before intubation can effectively reduce epistaxis and nasal damage. This technique is safe, easy, and suitable for all types of tubes and does not require additional implements.