The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.

PURPOSE: We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. METHODS: Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15 min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30 min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. RESULTS: The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7 µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. CONCLUSIONS: Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.

Steady-state trumps accuracy: target-controlled infusion as a gain switch.

Target-controlled infusion (TCI) is a mature technology that enables the delivery of intravenous anaesthetics in the concentration domain. The accuracy of the pharmacologic models used by TCI systems is imperfect, especially regarding pharmacodynamic predictions. This shortcoming of TCI devices is not critical. That TCI systems produce steady-state effect-site concentrations at or near a specified target is a more important attribute than a high level of accuracy because anaesthesiologists titrate to a stable level of drug effect whatever the actual concentration is. In this sense, TCI functions as a 'gain switch'. Achieving a steady state is more important than perfect accuracy.

Predictive pharmacodynamic performance of the Eleveld pharmacokinetic-pharmacodynamic model for propofol: comparison of predicted and measured bispectral index.

BACKGROUND: The Eleveld pharmacokinetic-pharmacodynamic model for propofol predicts bispectral index (BIS) processed electroencephalogram values from estimated effect-site concentrations. We investigated agreement between measured and predicted BIS values during total intravenous anaesthesia (TIVA). METHODS: Forty participants undergoing lower limb surgery received TIVA using remifentanil target-controlled infusions and propofol by manually controlled, target-guided infusions based upon the Eleveld model and directed by two pharmacokinetic computer simulation applications: PKPD Tools and StelSim. We evaluated the predictive performance of the Eleveld model by calculating median prediction errors (BIS units) and by Bland-Altman analyses. We also performed |Bland-Altman analysis of supplementary data provided by the authors of the Eleveld model. RESULTS: Whereas median prediction errors were small (MDPE -1.9, MDAPE 10), the ranges were wide (-18.5 to 24.3 and 1.7 to 24.3). The proportion of MDAPE >10 BIS units was 47.8%. Bland-Altman analysis showed a small mean bias (-0.52 BIS units) with wide limits of agreement (-27.7 to 26.2). Each participant's limits of agreement did not meet the requirements for declaring interchangeability between the two measurements. The measurement differences depended on the BIS values, as indicated by the positive slopes of the differences vs BIS values. Bland-Altman analysis of the Eleveld model supplementary data revealed similar results. CONCLUSION: BIS predictions by the Eleveld model should be interpreted with caution. In spite of the acceptable MDPE and MDAPE, there are unacceptable degrees of both within-subject and between-subject variation during propofol target-controlled infusions. This limits the use of adjusting targeted concentrations to achieve desired simulated BIS values with confidence.

Pharmacokinetics of propofol in severely obese surgical patients.

BACKGROUND: Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from normal-weight up to, and including, a high number of very obese patients. METHODS: Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time-concentration data were analysed by population PK modelling using non-linear mixed-effects modelling. RESULTS: Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19-60 years with a BMI 21.6-67.3 kg/m2. Twenty one patients had a BMI above 50 kg/m2. A 3-compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post-hoc performance evaluation. CONCLUSION: We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI.

External validation of the modified Marsh and Schnider models for medium-chain triglyceride propofol in target-controlled infusion anesthesia.

BACKGROUND: Propofol formulated with medium- and long-chain triglycerides (MCT/LCT propofol) has rapidly replaced propofol formulated with long-chain triglycerides (LCT propofol). Despite this shift, the modified Marsh and Schnider pharmacokinetic models developed using LCT propofol are still widely used for target-controlled infusion (TCI) of propofol. This study aimed to validate the external applicability of these models by evaluating their predictive performance during TCI of MCT/LCT propofol in general anesthesia. METHODS: Adult patients (n = 48) undergoing elective surgery received MCT/LCT propofol via a TCI system using either the modified Marsh or Schnider models. Blood samples were collected at various target propofol concentrations and at specific time points, including the loss of consciousness and the recovery of consciousness (13 samples per patient). The actual plasma concentration of propofol was determined using high-performance liquid chromatography. The predictive performance of each pharmacokinetic model was assessed by calculating four parameters: inaccuracy, bias, divergence, and wobble. RESULTS: Both the modified Marsh and Schnider models demonstrated predictive performances within clinically acceptable ranges for MCT/LCT propofol. The inaccuracy values were 24.4% for the modified Marsh model and 26.9% for the Schnider model. Both models showed an overall positive bias, 16.4% for the modified Marsh model and 16.6% for the Schnider model. The predictive performance of MCT/LCT propofol was comparable to that of LCT propofol, suggesting formulation changes might exert only a minor impact on the reliability of the TCI system during general anesthesia. Additionally, both models exhibited higher bias and inaccuracy at target concentrations ranging from 3.5 ~ 5 ug/ml than at concentrations between 2 ~ 3 ug/ml. CONCLUSIONS: The modified Marsh and Schnider models, initially developed for LCT propofol, remain clinically acceptable for TCI with MCT/LCT propofol. TRIAL REGISTRATION: This study was registered at the Clinical Research Information Service of the Korean National Institute of Health ( https://cris.nih.go.kr ; registration number: KCT0002191; 06/01/2017).

Assessment of the antinociceptive effect of a single fentanyl bolus dose in children: A pharmacokinetic and pharmacodynamic analysis based on the nociception level index during sevoflurane general anesthesia.

BACKGROUND: The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration. AIMS: To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia. METHODS: Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 µg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®. RESULTS: After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL. CONCLUSION: The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia.

Nongenetic and genetic predictors of haemodynamic instability induced by propofol and opioids: A retrospective clinical study.

AIM: Propofol and opioids are commonly used in anaesthesia, but are highly susceptible to haemodynamic instability, thereby threatening the patient's surgical safety and prognosis. The purpose of this study was to investigate the predictors of haemodynamic instability and establish its predictive model. METHODS: A total of 150 Chinese patients undergoing thyroid or breast surgery participated in the study, with target-controlled infusion concentrations of propofol, opioids dosage, heart rate (HR), mean arterial pressure (MAP) and Narcotrend Index recorded at key points throughout the procedure. The Agena MassARRAY system was used to genotype candidate single nucleotide polymorphisms related to pharmacodynamics and pharmacokinetics of propofol and opioids. RESULTS: Among nongenetic factors, baseline HR (R = -.579, P < .001) and baseline MAP (R = -.725, P < .001) had a significant effect on the haemodynamic instability. Among genetic factors, the CT/CC genotype of GABRB1 rs4694846 (95% confidence interval [CI]: -11.309 to -3.155), AA/AG of OPRM1 rs1799971 (95%CI: 0.773 to 10.290), AA of CES2 rs8192925 (95%CI: 1.842 to 9.090) were associated with higher HR instability; the AA/GG genotype of NR1I2 rs6438550 (95%CI: 0.351 to 7.761), AA of BDNF rs2049046 (95%CI: -9.039 to -0.640) and GG of GABBR2 rs1167768 (95%CI: -10.146 to -1.740) were associated with higher MAP instability. The predictive models of HR and MAP fluctuations were developed, accounting for 45.0 and 59.2% of variations, respectively. CONCLUSION: We found that cardiovascular fundamentals and genetic variants of GABRB1, GABBR2, OPRM1, BDNF, CES2 and NR1I2 are associated with cardiovascular susceptibility, which can provide a reference for haemodynamic management in clinical anaesthesia.

Population pharmacokinetic and pharmacodynamic model of propofol externally validated in Korean elderly subjects.

The Eleveld propofol pharmacokinetic (PK) model, which was developed based on a broad range of populations, showed greater bias (- 27%) in elderly subjects in a previous validation study conducted by Vellinga and colleagues. We aimed to develop and externally validate a new PK-pharmacodynamic (PK-PD) model of propofol for elderly subjects. A population PK-PD model was constructed using propofol plasma concentrations and bispectral index (BIS) values that were obtained from 31 subjects aged 65 years older in previously published phase I studies. The predictive performance of the newly-developed PK-PD model (Choi model) was assessed in a separate Korean elderly population and compared with that of the Eleveld model. A three-compartment mammillary model using an allometric expression and a sigmoid Emax model well-described the time courses of propofol concentrations and BIS values. The V1, V2, V3, Cl, Q1, Q2, E0, Emax, Ce50, γ, and ke0 of a 60-kg subject were 8.36, 58.0, 650 L, 1.26, 0.917, 0.669 L/min, 92.1, 18.7, 2.21 µg/mL, 2.89, and 0.138 /min, respectively. In the Choi model and Eleveld model, pooled biases (95% CI) of the propofol concentration were 7.78 ( 3.09-12.49) and 16.70 (9.46-23.93) and pooled inaccuracies were 22.84 (18.87-26.81) and 24.85 (18.07-31.63), respectively. The Choi PK model was less biased than the Eleveld PK model in Korean elderly subjects (age range: 65.0-79.0 yr; weight range: 45.0-75.3 kg). Our results suggest that the Choi PK model, particularly, is applicable to target-controlled infusion in non-obese Korean elderly subjects.

Mechanism-based pharmacodynamic model for propofol haemodynamic effects in healthy volunteers☆.

BACKGROUND: The adverse haemodynamic effects of the intravenous anaesthetic propofol are well known, yet few empirical models have explored the dose-response relationship. Evidence suggests that hypotension during general anaesthesia is associated with postoperative mortality. We developed a mechanism-based model that quantitatively characterises the magnitude of propofol-induced haemodynamic effects during general anaesthesia. METHODS: Mean arterial pressure (MAP), heart rate (HR) and pulse pressure (PP) measurements were available from 36 healthy volunteers who received propofol in a step-up and step-down fashion by target-controlled infusion using the Schnider pharmacokinetic model. A mechanistic pharmacodynamic model was explored based on the Snelder model. To benchmark the performance of this model, we developed empirical models for MAP, HR, and PP. RESULTS: The mechanistic model consisted of three turnover equations representing total peripheral resistance (TPR), stroke volume (SV), and HR. Propofol-induced changes were implemented by Emax models on the zero-order production rates of the turnover equations for TPR and SV. The estimated 50% effective concentrations for propofol-induced changes in TPR and SV were 2.96 and 0.34 µg ml-1, respectively. The goodness-of-fit for the mechanism-based model was indistinguishable from the empirical models. Simulations showed that predictions from the mechanism-based model were similar to previously published MAP and HR observations. CONCLUSIONS: We developed a mechanism-based pharmacodynamic model for propofol-induced changes in MAP, TPR, SV, and HR as a potential approach for predicting haemodynamic alterations. CLINICAL TRIAL REGISTRATION: NCT02043938.

Asymmetric neural dynamics characterize loss and recovery of consciousness.

Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.

Arginase II polymorphisms modify the hypotensive responses to propofol by affecting nitric oxide bioavailability.

PURPOSE: Propofol anesthesia is usually accompanied by hypotensive responses, which are at least in part mediated by nitric oxide (NO). Arginase I (ARG1) and arginase II (ARG2) compete with NO synthases for their common substrate L-arginine, therefore influencing the NO formation. We examined here whether ARG1 and ARG2 genotypes and haplotypes affect the changes in blood pressure and NO bioavailability in response to propofol. METHODS: Venous blood samples were collected from 167 patients at baseline and after 10 min of anesthesia with propofol. Genotypes were determined by polymerase chain reaction. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. RESULTS: We found that patients carrying the AG + GG genotypes for the rs3742879 polymorphism in ARG2 gene and the ARG2 GC haplotype show lower increases in nitrite levels and lower decreases in blood pressure after propofol anesthesia. On the other hand, subjects carrying the variant genotypes for the rs10483801 polymorphism in ARG2 gene show more intense decreases in blood pressure (CA genotype) and/or higher increases in nitrite levels (CA and AA genotypes) in response to propofol. CONCLUSION: Our results suggest that ARG2 variants affect the hypotensive responses to propofol, possibly by modifying NO bioavailability. TRIAL REGISTRATION: NCT02442232.

Prospective clinical validation of the Eleveld propofol pharmacokinetic-pharmacodynamic model in general anaesthesia.

BACKGROUND: Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia. METHODS: The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria. RESULTS: For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce50. CONCLUSIONS: The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice.

Correlation of exhaled propofol with Narcotrend index and calculated propofol plasma levels in children undergoing surgery under total intravenous anesthesia - an observational study.

BACKGROUND: Exhaled propofol concentrations correlate with propofol concentrations in adult human blood and the brain tissue of rats, as well as with electroencephalography (EEG) based indices of anesthetic depth. The pharmacokinetics of propofol are however different in children compared to adults. The value of exhaled propofol measurements in pediatric anesthesia has not yet been investigated. Breathing system filters and breathing circuits can also interfere with the measurements. In this study, we investigated correlations between exhaled propofol (exP) concentrations and the Narkotrend Index (NI) as well as calculated propofol plasma concentrations. METHODS: A multi-capillary-column (MCC) combined with ion mobility spectrometry (IMS) was used to determine exP. Optimal positioning of breathing system filters (near-patient or patient-distant) and sample line (proximal or distal to filter) were investigated. Measurements were taken during induction (I), maintenance (M) and emergence (E) of children under total intravenous anesthesia (TIVA). Correlations between ExP concentrations and NI and predicted plasma propofol concentrations (using pediatric pharmacokinetic models Kataria and Paedfusor) were assessed using Pearson correlation and regression analysis. RESULTS: Near-patient positioning of breathing system filters led to continuously rising exP values when exP was measured proximal to the filters, and lower concentrations when exP was measured distal to the filters. The breathing system filters were therefore subsequently attached between the breathing system tubes and the inspiratory and expiratory limbs of the anesthetic machine. ExP concentrations significantly correlated with NI and propofol concentrations predicted by pharmacokinetic models during induction and maintenance of anesthesia. During emergence, exP significantly correlated with predicted propofol concentrations, but not with NI. CONCLUSION: In this study, we demonstrated that exP correlates with calculated propofol concentrations and NI during induction and maintenance in pediatric patients. However, the correlations are highly variable and there are substantial obstacles: Without patient proximal placement of filters, the breathing circuit tubing must be changed after each patient, and furthermore, during ventilation, a considerable additional loss of heat and moisture can occur. Adhesion of propofol to plastic parts (endotracheal tube, breathing circle) may especially be problematic during emergence. TRIAL REGISTRATION: The study was registered in the German registry of clinical studies (DRKS-ID:  DRKS00015795 ).

Do epoch lengths of hypnotic depth indicators affect estimated of blood-brain equilibration rate constants of propofol?

This study aimed to investigate the effect of epoch length of hypnotic depth indicators on the blood-brain equilibration rate constant (ke0) estimates of propofol. Propofol was administered by zero-order infusion (1.5, 3.0, 6, and 12 mg·kg-1·h-1) for one hour in 63 healthy volunteers. The ke0 of propofol was estimated using an effect-compartment model linking pharmacokinetics and pharmacodynamics, in which response variables were electroencephalographic approximate entropy (ApEn) or bispectral index (BIS) (n = 32 each for propofol infusion rates of 6 and 12 mg·kg-1·h-1). Epoch lengths of ApEn were 2, 10, 30, and 60 seconds (s). The correlations between plasma propofol concentrations (Cp) and BIS and ApEn 2, 10, 30, and 60 s were determined, as was the Ce associated with 50% probability of unconsciousness (Ce50,LOC). The pharmacokinetics of propofol were well described by a three-compartment model. The correlation coefficient between Cp and ApEn 2, 10, 30, and 60 s were -0.64, -0.54, -0.39, and -0.26, respectively, whereas correlation coefficient between Cp and BIS was -0.74. The blood-brain equilibration half-life based on the ke0 estimates for ApEn at 2, 10, 30, 60 s and BIS were 4.31, 3.96, 5.78. 6.54, 5.09 min, respectively, whereas the Ce50,LOC for ApEn at 2, 10, 30, 60 s and BIS were 1.55, 1.47, 1.28, 1.04, and 1.55 µg·ml-1, respectively. Since ke0, which determines the onset of drug action, varies according to the epoch length, it is necessary to consider the epoch length together when estimating ke0.

Effective dose of intravenous oxycodone depending on sex and age for attenuation of intubation-related hemodynamic responses

Background/aim: Preoperative intravenous oxycodone may help to prevent or attenuate intubation-related hemodynamic responses (IRHRs), but its pharmacokinetics differs according to age and sex. Therefore, we investigated the 95% effective dose (ED95) of intravenous oxycodone for attenuating all IRHRs, depending on the age and sex of the study population. Materials and methods: All patients were allocated to one of 6 groups: 1) 20­40 year old males, 2) 41­65yearold males, 3) 66­80 year old males, 4) 20­40 year old females, 5) 41­65yearold females, and 6) 66­80 year old females (groups YM, OM, EM, YF, OF, and EF, respectively). Using Dixon's up-and-down method, the first patient in each group was slowly injected with intravenous oxycodone (0.1 mg kg­1) 20 min before intubation. The subsequent patient received the next oxycodone dose, which was decreased or increased by 0.01 mg kg­1, depending on the "success" or "failure" of attenuation of all IRHRs to within 20% of the baseline values at 1 min after intubation in the previous patient. After obtaining 8 crossover points, predictive ED95 was estimated with probit regression analysis. Results: ED95 varied greatly according to age and sex. ED95was 0.133 mg kg­1, 0.181 mg kg­1, 0.332 mg kg­1, 0.183 mg kg­1, 0.108 mg kg­1, and 0.147 mg kg­1in groups YM, OM, EM, YF, OF, and EF, respectively. Conclusion: ED95 is higher in males with increasing age but is ambiguous for females. ED95 is higher in males than in females over 40 years of age but is higher in females than in males under 41 years of age. However, after considering the age and sex of the study population, these results can be used as reference doses for further studies to verify the clinical effects of oxycodone for attenuating all IRHRs.

Prevalence of Isoelectric Electroencephalography Events in Infants and Young Children Undergoing General Anesthesia.

BACKGROUND: In infants and young children, anesthetic dosing is based on population pharmacokinetics and patient hemodynamics not on patient-specific brain activity. Electroencephalography (EEG) provides insight into brain activity during anesthesia. The primary goal of this prospective observational pilot study was to assess the prevalence of isoelectric EEG events-a sign of deep anesthesia-in infants and young children undergoing general anesthesia using sevoflurane or propofol infusion for maintenance. METHODS: Children 0-37 months of age requiring general anesthesia for surgery excluding cardiac, intracranial, and emergency cases were enrolled by age: 0-3, 4-6, 7-12, 13-18, and 19-37 months. Anesthesia was maintained with sevoflurane or propofol infusion. EEG was recorded from induction to extubation. Isoelectric EEG events (amplitude <20 µV, lasting ≥2 seconds) were characterized by occurrence, number, duration, and percent of isoelectric EEG time over anesthetic time. Associations with patient demographics, anesthetic, and surgical factors were determined. RESULTS: Isoelectric events were observed in 63% (32/51) (95% confidence interval [CI], 49-76) of patients. The median (interquartile range [IQR]) number of isoelectric events per patient was 3 (0-31), cumulative isoelectric time per patient was 12 seconds (0-142 seconds), isoelectric time per event was 3 seconds (0-4 seconds), and percent of total isoelectric over anesthetic time was 0.1% (0%-2.2%). The greatest proportion of isoelectric events occurred between induction and incision. Isoelectric events were associated with higher American Society of Anesthesiologists (ASA) physical status, propofol bolus, endotracheal tube use, and lower arterial pressure during surgical phase. CONCLUSIONS: Isoelectric EEG events were common in infants and young children undergoing sevoflurane or propofol anesthesia. Although the clinical significance of these events remains uncertain, they suggest that dosing based on population pharmacokinetics and patient hemodynamics is often associated with unnecessary deep anesthesia during surgical procedures.

The Performance of an Artificial Neural Network Model in Predicting the Early Distribution Kinetics of Propofol in Morbidly Obese and Lean Subjects.

BACKGROUND: Induction of anesthesia is a phase characterized by rapid changes in both drug concentration and drug effect. Conventional mammillary compartmental models are limited in their ability to accurately describe the early drug distribution kinetics. Recirculatory models have been used to account for intravascular mixing after drug administration. However, these models themselves may be prone to misspecification. Artificial neural networks offer an advantage in that they are flexible and not limited to a specific structure and, therefore, may be superior in modeling complex nonlinear systems. They have been used successfully in the past to model steady-state or near steady-state kinetics, but never have they been used to model induction-phase kinetics using a high-resolution pharmacokinetic dataset. This study is the first to use an artificial neural network to model early- and late-phase kinetics of a drug. METHODS: Twenty morbidly obese and 10 lean subjects were each administered propofol for induction of anesthesia at a rate of 100 mg/kg/h based on lean body weight and total body weight for obese and lean subjects, respectively. High-resolution plasma samples were collected during the induction phase of anesthesia, with the last sample taken at 16 hours after propofol administration for a total of 47 samples per subject. Traditional mammillary compartment models, recirculatory models, and a gated recurrent unit neural network were constructed to model the propofol pharmacokinetics. Model performance was compared. RESULTS: A 4-compartment model, a recirculatory model, and a gated recurrent unit neural network were assessed. The final recirculatory model (mean prediction error: 0.348; mean square error: 23.92) and gated recurrent unit neural network that incorporated ensemble learning (mean prediction error: 0.161; mean square error: 20.83) had similar performance. Each of these models overpredicted propofol concentrations during the induction and elimination phases. Both models had superior performance compared to the 4-compartment model (mean prediction error: 0.108; mean square error: 31.61), which suffered from overprediction bias during the first 5 minutes followed by under-prediction bias after 5 minutes. CONCLUSIONS: A recirculatory model and gated recurrent unit artificial neural network that incorporated ensemble learning both had similar performance and were both superior to a compartmental model in describing our high-resolution pharmacokinetic data of propofol. The potential of neural networks in pharmacokinetic modeling is encouraging but may be limited by the amount of training data available for these models.

The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing abdominal aortic surgery.

Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2-3 µg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients' age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient's responses to both drugs.

Age progression from vicenarians (20-29 year) to nonagenarians (90-99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has made an enormous contribution to intravenous anesthesia. Because of their altered physiological, pharmacological and pathological aspects, titrating general anesthesia in the elderly is a challenging task. METHODS: Eighty patients were consecutively enrolled divided by decades from vicenarians (20-29 year) to nonagenarians (90-99 year) into eight groups. Using target controlled infusion (TCI) and electroencephalographic (EEG)-derived bispectral index (BIS) we set propofol plasma concentration (Cp) to gradually reach 3.5 µg mL-1 over 3.5-min. In each patient, we constructed a PK/PD model and conducted a population PK/PD (PopPK-PD) covariate analysis. RESULTS: Age was significant covariate for baseline BIS effect (E0), inhibitory propofol concentration at 50% BIS decline (IC50) and maximum BIS decline (Emax). First-order rate constant Ke0 of 0.47 min-1 in vicenarians (20-29 year) gradually increased with age-progression to 1.85 min-1 in nonagenarians (90-99 year). Simulation modelling showed that clinically recommended Cp of 3.5 µg mL-1 for 20-29 year BIS 50 should be reduced to 3.0 for 30-49 year, 2.5 for 50-69 year and 2.0 for 80-89 year. CONCLUSION: We quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades' age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5 µg mL-1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5 µg mL-1 for 20-29 year should be gradually decreased to 2.0 µg mL-1 for 80-89 year. CLINICAL TRIAL REGISTRY NUMBERS: European Community Clinical Trials Database EudraCT (http://eudract.emea.eu) initial trial registration number: 2011-002847-81, and subsequently registered at www.clinicaltrials.gov; trial registration number: NCT02585284. Xijing Hospital of Fourth Military Medical University ethics committee approval number 20110707-4.

External Validation of a Pharmacokinetic Model of Propofol for Target-Controlled Infusion in Children under Two Years Old.

BACKGROUND: Previously, a linked pharmacokinetic-pharmacodynamic model (the Kim model) of propofol with concurrent infusion of remifentanil was developed for children aged 2-12 years. There are few options for pharmacokinetic-pharmacodynamic model of propofol for children under two years old. We performed an external validation of the Kim model for children under two years old to evaluate whether the model is applicable to this age group. METHODS: Twenty-four children were enrolled. After routine anesthetic induction, a continuous infusion of 2% propofol and remifentanil was commenced using the Kim model. The target effect-site concentration of propofol was set as 2, 3, 4, and 5 µg/mL, followed by arterial blood sampling after 10 min of each equilibrium. Population estimates of four parameters-pooled bias, inaccuracy, divergence, and wobble-were used to evaluate the performance of the Kim model. RESULTS: A total of 95 plasma concentrations were used for evaluation of the Kim model. The population estimate (95% confidence interval) of bias was -0.96% (-8.45%, 6.54%) and that of inaccuracy was 21.0% (15.0%-27.0%) for the plasma concentration of propofol. CONCLUSION: The pooled bias and inaccuracy of the pharmacokinetic predictions are clinically acceptable. Therefore, our external validation of the Kim model indicated that the model can be applicable to target-controlled infusion of propofol in children younger than 2 years, with the recommended use of actual bispectral index monitoring in clinical settings that remifentanil is present. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0001752.