Schnider Pharmacokinetic Models Research Articles

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

BackgroundPropofol 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.MethodsAdult 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.ResultsBoth 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.ConclusionsThe modified Marsh and Schnider models, initially developed for LCT propofol, remain clinically acceptable for TCI with MCT/LCT propofol.Trial registrationThis 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).

Target-controlled infusion: A comparative, prospective, observational study of the conventional TCI pump and the novel smartphone-based application iTIVA.

Empirically adjusted, standard drug doses fail to address interindividual pharmacokinetic and pharmacodynamics variability. Target-controlled infusion (TCI) delivers drugs in calibrated boluses to achieve and maintain a selected target plateau drug level (plasma or effect site). Interactive total intravenous anesthesia (iTIVA™) smartphone software simulates TCI and employs 31 established pharmacokinetic models for 11 different intravenous agents and is coupled with standard volumetric infusion pumps for administering TCI. This prospective, observational, study investigates the degree of agreement between iTIVA and a conventional TCI pump (CTP) for the volume of propofol infused using the Schnider pharmacokinetic model in adult patients of either sex undergoing oncosurgery lasting 1-3 h under total intravenous anesthesia. Bland-Altman analysis of 124 data pairs from 30 patients provided bias, precision, and limits of agreement between the volumes infused by CTP and iTIVA (V-CTP and V-iTIVA) during specific identical time periods. Spearman's rho and Kendall's tau rank correlation coefficients provided the degree of association between V-CTP and V-iTIVA. Spearman's rho and Kendall's tau were 0.996 and 0.964, respectively. Bias or the mean of differences was -0.02, while the limits of agreement were 0.58 and -0.63, respectively (Bland-Altman plot). The maximum allowed difference of 2 ml was much larger than the 95% confidence intervals for the limits of agreement. The Mountain plot was short tailed (-1.28 to 1.55) and centred over zero (0.01). The volume of propofol infused using TCI pump was similar to that calculated by iTIVA in identical time periods, confirming the clinical applicability of iTIVA.

Recovery time in target controlled infusion versus manual infusion of propofol in total intravenous anaesthesia for endoscopic retrograde cholangio-pancreatography procedure using laryngeal mask airway-gastro: A randomised comparative study.

This study aimed to compare manual infusion versus target-controlled infusion (TCI) in total intravenous anaesthesia (TIVA) utilising laryngeal mask airway (LMA)-gastro during endoscopic retrograde cholangio-pancreatography (ERCP) procedures. This was a single-blind randomised trial. Patients were randomly allocated into two groups. TCI group included 27 patients, where TCI of propofol was implemented with the Schnider pharmacokinetic model driven by a computer-controlled syringe pump. The TIVA group included 27 patients with a loading dose of 2 mg/kg of propofol, followed by manual infusion of 15 mg/kg/h for the first 15 min, 13 mg/kg/h for the next 15 min, then 11 mg/kg/h for 30 min and 10 mg/kg/h for 60 min and finally maintained at 9 mg/kg/h. The primary objective was to compare recovery time following cessation of propofol infusion in both groups. The difference in the total dose of propofol, time to achieve anaesthesia induction, first attempt success rate, ease of LMA-gastro insertion, ease of insertion, success rate of endoscope device and post-anaesthesia care unit (PACU) discharge time were the secondary objectives. T-test and Chi-square test were used for statistical analysis. The time required for the recovery was significantly less in the TCI group than in the TIVA group (mean ± standard deviation; 11.60 ± 2.27 versus 15.4 ± 3.25 minutes, P < 0.001). The duration of ERCP, ease of LMA and endoscope insertion were comparable between the groups. There was no post-operative recall of intra-operative events in the groups. TCI offers earlier recovery than TIVA in patients undergoing ERCP procedures using LMA-gastro.

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

BackgroundThe 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. MethodsMean 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. ResultsThe 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. ConclusionsWe 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 registrationNCT02043938

Different behaviour of target-controlled infusion pumps despite apparently using the same Schnider pharmacokinetic model

BACKGROUND Target-controlled infusion (TCI) pumps deliver an initial bolus of drug to achieve a preset drug target concentration quickly. OBJECTIVE We investigated whether differences exist in the initial bolus dose between different TCI pumps despite apparently using the same pharmacokinetic (PK) model. DESIGN Observational study. SETTING Laboratory data from a German University Hospital. Experiments were performed between February 2019 and September 2020. PARTICIPANTS Four TCI pumps set to the Schnider model in effect-site mode with a target propofol concentration of 3.5 μg ml−1 were studied. The algorithms of two pumps employed a fixed equilibration rate constant (k e0) of 0.456 min−1 (Perfusor® Space® and Injectomat TIVA Agilia®), while the other two used a fixed time to peak concentration (t peak) of 1.6 min (Alaris® PK and Syramed® μSP6000). Pump performance was assessed on 13 virtual patients with different combinations of age, sex, height and weight: the initial propofol dose injected was measured on a high precision scale. MAIN OUTCOME MEASURES Propofol bolus dose, as if delivered for anaesthesia induction. RESULTS A small difference in propofol bolus doses was observed for some simulations: for example, 56.4 ± 1.2 and 59.7 ± 0.2 mg with a Syramed μSP6000 and an Alaris pharmacokinetic pump, respectively, in a virtual 54-year old man with a height of 170 cm and a weight of 74 kg. In contrast, significant differences were found in other simulated patients: for example, 72.0 ± 1.0 and 111.9 ± 1.2 mg (P &lt; 0.001) using a Perfusor Space and an Alaris TCI pump in a virtual 60-year-old, obese man with a height of 182 cm and a weight of 139 kg. CONCLUSIONS Discrepancies in the initial bolus dose can be explained by differences in k e0. Anaesthetists should be aware that differences exist in the implementation of the Schnider model between manufacturers, which could lead to disparities in the initial propofol bolus in some patients.

Propofol infusions using a human target controlled infusion (TCI) pump in chimpanzees (Pan troglodytes)

Chimpanzees are genetically and physiologically similar to humans. Several pharmacokinetic models of propofol are available and target controlled infusion (TCI) of propofol is established in humans, but not in chimpanzees. The purpose of this study was to investigate if human pharmacokinetic models can accurately predict propofol plasma concentration (Cp) in chimpanzees and if it is feasible to perform TCI in chimpanzees. Ten chimpanzees were anaesthetized for regular veterinary examinations. Propofol was used as an induction or maintenance agent. Blood samples were collected from a catheter in a cephalic vein at 3–7 time points between 1 and 100 min following the propofol bolus and/or infusion in five chimpanzees, or TCI in six chimpanzees. Cp was measured using high-performance liquid chromatography. The Marsh, Schnider and Eleveld human pharmacokinetic models were used to predict Cp for each case and we examined the predictive performances of these models using the Varvel criteria Median PE and Median APE. Median PE and Median APE for Marsh, Schnider and Eleveld models were within or close to the acceptable range. A human TCI pump was successfully maintained propofol Cp during general anesthesia in six chimpanzees. Human propofol pharmacokinetic models and TCI pumps can be applied in chimpanzees.

Infraglottic versus supraglottic jet-ventilation for endobronchial ultrasound-guided transbronchial needle aspiration: A randomised controlled trial.

For endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under general anaesthesia, both rigid bronchoscopy and laryngeal masks (LMAs) with superimposed high-frequency jet ventilation can be used. Despite the fact that in Europe rigid bronchoscopy for EBUS-TBNA is still widely used, an increasing number of centres use jet ventilation via the LMA for this procedure. To our knowledge no clinical trials have ever been made to compare these two methods. This trial aimed to evaluate whether patients recover from the procedure more quickly when a LMA is used for ventilation compared with rigid bronchoscopy where muscle relaxants and deep anaesthesia are required. We wanted to test the hypothesis that there is no difference in the postoperative recovery of patients in the postanaesthesia care unit (PACU) after EBUS-TBNA with jet ventilation via a rigid bronchoscope and a LMA. Secondary outcomes were the difference of duration of anaesthesia, the diagnostic outcome of the procedure and drug quantities for both groups. Prospective randomised single blinded two centre controlled trial. Two centres in Austria participated. Patients were enrolled from December 2016 until January 2018. Ninety patients for elective EBUS-TBNA were enrolled and assigned to one of two intervention groups. Two patients were excluded before and eleven patients were excluded after EBUS-TBNA. Seventy-seven were analysed. Patients assigned to group 1 were ventilated with a LMA; those assigned to group 2 were ventilated via a rigid bronchoscope. Vital signs, drug dosage, duration of anaesthesia, recovery, PACU stay and Aldrete score at the PACU were recorded. The primary endpoint was an integral over time of a modified Aldrete score. Secondary endpoints were the durations of the interventions, the recovery from anaesthesia and PACU stay, initial and mean Aldrete values at PACU, the effect site concentration of Propofol according to the Schnider pharmacokinetic model, the peak ultiva rates and the diagnostic outcome. We were not able to show any significant difference regarding the postoperative recovery criteria based on the Aldrete score, the durations measured and the diagnostic outcomes. Vital signs remained stable and in an equal range in both groups. There were no differences in the mean effect site propofol concentration and the peak ultiva rates. EBUS-TBNA under general anaesthesia using a LMA with SHJV is equal to rigid bronchoscopy with superimposed high-frequency jet ventilation for the variables analysed. ISRCTN (ISRCTN58911367).

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 30s 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 3.01μg.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

BackgroundThe 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. MethodsTwenty 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. ResultsIn 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). ConclusionsA three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients. Clinical trial registrationKCT0001760.

Comparison of the Effects of Dexmedetomidine on the Induction of Anaesthesia Using Marsh and Schnider Pharmacokinetic Models of Propofol Target-Controlled Infusion.

The study aimed to determine the effects of dexmedetomidine on the induction of anaesthesia using different models (Marsh and Schnider) of propofol target-controlled infusion (TCI). Sixty-four patients aged 18-60 years, American Society of Anaesthesiologists (ASA) class I-II who underwent elective surgery were randomised to a Marsh group (n = 32) or Schnider group (n = 32). All the patients received a 1 μg/kg loading dose of dexmedetomidine, followed by TCI anaesthesia with remifentanil at 2 ng/mL. After the effect-site concentration (Ce) of remifentanil reached 2 ng/mL, propofol TCI induction was started. Anaesthesia induction commenced in the Marsh group at a target plasma concentration (Cpt) of 2 μg/mL, whereas it started in the Schnider group at a target effect-site concentration (Cet) of 2 μg/mL. If induction was delayed after 3 min, the target concentration (Ct) was gradually increased to 0.5 μg/mL every 30 sec until successful induction. The Ct at successful induction, induction time, Ce at successful induction and haemodynamic parameters were recorded. The Ct for successful induction in the Schnider group was significantly lower than in the Marsh group (3.48 [0.90] versus 4.02 [0.67] μg/mL; P = 0.01). The induction time was also shorter in the Schnider group as compared with the Marsh group (134.96 [50.91] versus 161.59 [39.64]) sec; P = 0.02). There were no significant differences in haemodynamic parameters and Ce at successful induction. In the between-group comparison, dexmedetomidine reduced the Ct requirement for induction and shortened the induction time in the Schnider group. The inclusion of baseline groups without dexmedetomidine in a four-arm comparison of the two models would enhance the validity of the findings.

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

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

Comparison of the clinical performance of the modified Marsh model for propofol between underweight and normal-weight patients with Crohn's disease.

BackgroundThe aim of this retrospective study was to compare the clinical performance of the modified Marsh model for propofol between underweight and normal-weight patients with Crohn's disease.MethodsThe medical records of 50 patients who underwent elective surgery for Crohn's disease were reviewed retrospectively. Propofol and remifentanil were administered using target effect-site concentration (Ce)-controlled infusion with the modified Marsh and Minto models. Target Ce values of propofol were adjusted within a range of 2.5–3 µg/ml to maintain a bispectral index (BIS) value of less than 60 during anesthesia maintenance. Dosages of anesthetic agents administered during surgery were compared between underweight and normal-weight patients. The infusion profiles of patients were applied as inputs to calculate the Ce values in the Schnider model.ResultsThe total midazolam and remifentanil dosages required for underweight patients were higher than those required for normal-weight patients to maintain BIS values at less than 60 within a target propofol Ce range of 2.5–3 µg/ml. Simulation results suggested that the Schnider model may be an appropriate pharmacokinetic model for target-controlled infusion in underweight patients, as the clearance was consistently higher in the Schnider model than the modified Marsh model, particularly in underweight patients.ConclusionsThe modified Marsh model might cause inadvertent propofol underdosing in underweight patients. Future studies are necessary to compare the predictive performance of the modified Marsh and Schnider pharmacokinetic models in underweight patients.

Modelling of the Sedative Effects of Propofol in Patients undergoing Spinal Anaesthesia: A Pharmacodynamic Analysis.

Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect-site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect-site target-controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3-4] and deep sedation (OAA/S scores of 1-2) were developed using nonlinear mixed-effects modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (p = 0.0003). The simulated Ce50 values for adequate sedation in 20-year-old patients with a T12 sensory level and in 80-year-old patients with a T4 level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation.

Modelling propofol pharmacodynamics using BIS-guided anaesthesia

Using Schnider's pharmacokinetic model, propofol pharmacodynamics were modelled during total intravenous anaesthesia. The method involved adjusting a pharmacokinetic/pharmacodynamic model according to data obtained from 42 patients having operative procedures with remifentanil analgesia. Parameters Ce50 and γ were estimated for induction and maintenance by analysing patients' bispectral index. The pharmacodynamic models were different for induction and maintenance. The mean (95% CI) Ce50 for induction and maintenance was Ce50 = 3.35 (2.79-3.91) mg.l(-1) and 2.23 (1.95-2.51) mg.l(-1) , respectively, with a higher concentration required to achieve the same effect during induction, even during remifentanil co-administration. During induction and maintenance, γ was 1.24 (1.44-2.00) and 1.58 (1.32-1.84), respectively. As γ is related to the concentration-effect slope, patient response is accentuated during maintenance compared with induction. The influence of sex and age on the model was analysed. Sex had no significant influence on the model, although a linear relation was found between age and Ce50 .

The Effective Effect-Site Propofol Concentration for Induction in Morbidly Obese Patients Using Total Body Weight with a New Pharmacokinetic Model

To the Editor: Recently Echevarría et al.1 from our group described the effect-site propofol concentration (Ce) required to be set in propofol effect-site target-controlled infusion mode to induce and intubate the tracheas of morbidly obese patients using total body weight (TBW) with the Marsh and the Schnider pharmacokinetic (PK) models.2,3 These models, however, were not derived from obese patient data and their use in obese patients is controversial. Using the same data from Echevarría et al.’s1 study, we estimated the propofol Ce to be set for induction and tracheal intubation with a new PK model available for obese patients.4 The data of 66 morbidly obese subjects aged from 18 to 50 years were analyzed. All patients were monitored with a bispectral index electroencephalographic monitor (A2000 BIS® XP monitor, version 3.2; Aspect Medical Systems Inc., Newton, MA). Fentanyl 3 μg/kg TBW was administered before starting propofol infusion. The Ce (CI95%) producing a bispectral index <60 until intubation for 50% (Ce50) and 95% (Ce95) of patients was calculated with logistic regression. The target values obtained were 3.8 (3.2–4.2) μg/mL and 5.6 (5.0–7.6) μg/mL, respectively. The mean dose of propofol estimated to reach the Ce within the range of confidence interval 95% of the Ce50 (n = 19) was 0.9 ± 0.1 and 1.6 ± 0.2 mg/kg for the Ce95 (n = 16). Mean maximum decrease of mean arterial blood pressure was around 30% with the 2 estimated Ces. Heart rate variations ranged from −22% to 12% from baseline. Figure 1 shows the concentration versus effect curves estimated for the 3 PK models.Figure 1: Dose-response curve fitted to Cortínez, Marsh, and Schnider pharmacokinetic models using logit analysis, based on total body weight. The y-axis corresponds to the probability of no response until tracheal intubation (TI) and the x-axis to the predicted propofol effect-site concentration (Ce).This new analysis suggests that when using propofol target-controlled infusion with the Cortínez PK model4 in morbidly obese patients receiving fentanyl 3 μg/kg TBW, the Ce for induction and intubation should be around 5.5 μg/mL. A significant decrease in arterial blood pressure must be expected with this recommended dosingscheme.

A closed-loop anesthetic delivery system for real-time control of burst suppression

Objective. There is growing interest in using closed-loop anesthetic delivery (CLAD) systems to automate control of brain states (sedation, unconsciousness and antinociception) in patients receiving anesthesia care. The accuracy and reliability of these systems can be improved by using as control signals electroencephalogram (EEG) markers for which the neurophysiological links to the anesthetic-induced brain states are well established. Burst suppression, in which bursts of electrical activity alternate with periods of quiescence or suppression, is a well-known, readily discernible EEG marker of profound brain inactivation and unconsciousness. This pattern is commonly maintained when anesthetics are administered to produce a medically-induced coma for cerebral protection in patients suffering from brain injuries or to arrest brain activity in patients having uncontrollable seizures. Although the coma may be required for several hours or days, drug infusion rates are managed inefficiently by manual adjustment. Our objective is to design a CLAD system for burst suppression control to automate management of medically-induced coma. Approach. We establish a CLAD system to control burst suppression consisting of: a two-dimensional linear system model relating the anesthetic brain level to the EEG dynamics; a new control signal, the burst suppression probability (BSP) defining the instantaneous probability of suppression; the BSP filter, a state-space algorithm to estimate the BSP from EEG recordings; a proportional–integral controller; and a system identification procedure to estimate the model and controller parameters. Main results. We demonstrate reliable performance of our system in simulation studies of burst suppression control using both propofol and etomidate in rodent experiments based on Vijn and Sneyd, and in human experiments based on the Schnider pharmacokinetic model for propofol. Using propofol, we further demonstrate that our control system reliably tracks changing target levels of burst suppression in simulated human subjects across different epidemiological profiles. Significance. Our results give new insights into CLAD system design and suggest a control-theory framework to automate second-to-second control of burst suppression for management of medically-induced coma.

Reevaluación del comportamiento del curso temporal del efecto de propofol descrito por el modelo farmacocinético de Schnider

BackgroundThe first order plasma–effect-site equilibration rate constant (ke0) links the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. This constant, calculated for each specific PK drug model, allowed us to predict the course of the effect in a target controlled infusion (TCI). The PK-PD model of propofol, published by Schnider et al., calculated a ke0 value of 0.456min−1 and a corresponding time to peak effect (t peak) of 1.6min. The aim of this study was to reevaluate the ke0 value for the predicted Schnider model of propofol, with data from a complete effect curve obtained by monitoring the bispectral index (BIS). MethodsThe study included 35 healthy adult patients (18-90 years) scheduled for elective surgery with standard monitoring and using the BIS XP® (Aspect), and who received a propofol infusion to reach a plasma target of 12 μg/ml in 4min. The infusion was then stopped, obtaining a complete effect curve when the patient woke up. The Anestfusor™ (University of Chile) software was used to control the infusion pumps, calculate the plasma concentration plotted by Schnider PK model, and to store the BIS data every second. Loss (LOC) and recovery (ROC) of consciousness was assessed and recorded. Using a traditional parametric method using the “ke0 Objective function” of the PK-PD tools for Excel, the individual and population ke0 was calculated. Predictive Smith tests (Pk) and Student t test were used for statistical analysis. A P<.05 indicated significance. ResultsThe evaluation included 21 male and 14 female patients (18 to 90 years). We obtained 1,001 (±182) EEG data and the corresponding calculated plasma concentration for each case. The population ke0 obtained was 0.144min−1 (SD±0.048), very different from the original model (P<.001). This value corresponds with a t peak of 2.45min. The predictive performance (Pk) for the new model was 0.9 (SD±0.03), but only 0.78 (SD±0.06) for the original (P<.001). With a baseline BIS of 95.8 (SD±2.34), the BIS at LOC was 77.48 (SD±9.6) and 74.65(SD±6.3) at ROC (P=.027). The calculated Ce in the original model at LOC and ROC were 5.9 (SD±1.35)/1.08 μg/ml (SD±0.32) (P<.001), respectively, and 2.3 (SD±0.63)/2.0 μg/ml (SD±0.65) (NS) for the new model. The values between LOC/ROC were significantly different between the 2 models (P<.001). No differences in ke0 value were found between males and females, but in the new model the ke0 was affected by age as a covariable (0.26-[age×0.0022]) (P<.05). ConclusionsThe dynamic relationship between propofol plasma concentrations predicted by Schnider's pharmacokinetic model and its hypnotic effect measured with BIS was better characterized with a smaller ke0 value (slower t½ke0) than that present in the original model, with an age effect also not described before.

Prospective randomised comparison of Marsh and Schnider pharmacokinetic models for propofol during induction of anaesthesia in elective cardiac surgery

Haemodynamic stability during induction is a cornerstone of cardiac anaesthesia. The evaluation of pharmacokinetic models for propofol during induction is lacking. To compare haemodynamics during cardiac anaesthesia induction with two pharmacokinetic models. Randomised controlled trial. Department of Cardiothoracic Surgery, São João Hospital; July to December 2010. Ninety consecutive elective adult cardiac surgical patients. Random assignment to effect-site target-controlled infusion by Marsh (n = 45) or Schnider (n = 45) pharmacokinetic models with an equilibration constant of 1.2 min(-1) adapted to Marsh's model. Invasive blood pressure measurements, propofol dose, and bispectral index (BIS) were recorded. After an initial target concentration of 1.5 μg ml(-1), concentrations were upward-titrated in 0.5 μg ml(-1) increments until the BIS was <50. No differences were observed between Marsh and Schnider models in required propofol dose (0.99 ± 0.26 vs. 0.93 ± 0.31 mg kg(-1), P = 0.322), decrease in mean blood pressure (25 ± 13 vs. 22 ± 14%, P = 0.192) or the need for vasopressors (20 vs. 24%, P = 0.800), but the use of the Marsh model resulted in a lower predicted effect-site concentration (2.3 ± 0.4 vs. 2.7 ± 0.6 μg ml(-1), P = 0.006) and shorter time to induction (296 ± 59 vs. 338 ± 87 s, P = 0.024). There was a greater decrease in mean blood pressure in older patients (>60 years; 29 ± 10 vs. 22 ± 11%, P = 0.004) irrespective of model, but obese (BMI ≥30 kg m(-2)) and nonobese patients did not differ. Decrease in mean blood pressure. In effect-site targeting with a 1.2 min(-1) equilibration constant, Marsh's model is comparable to Schnider's during induction of anaesthesia.

The peak bispectral index time cannot predict early phase propofol pharmacodynamics with effect site-controlled infusion algorithm

Objectives:The plasma-effect site equilibration rate constant (ke0) of propofol was determined with peak bispectral index (BIS) time (TPEAK) in our previous study. The present study has been conducted to evaluate the ke0's performance with effect site-controlled infusion algorithm.Materials and Methods:Forty unpremedicated patients were randomized to group TE1 (Schnider's pharmacokinetic model with ke0 adapted to TPEAK = 74s) and TE2 (TPEAK = 96s). In stage 1, all patients received propofol with effect-site concentration (Ce) controlled infusion. Once the pump had injected the mass of propofol necessary to achieve pre-set Ce and while the infusion was stopped, target was reset at 0 μg/ml. When BIS returned to 80 or above, then, in stage 2, the patients received plasma concentration controlled infusion for 10 min. The time of loss of responsiveness (LOR) and BIS were recorded. The differences of Ce at the time of LOR, lowest BIS between stages 1 and 2, hysteresis loop were used to evaluate the performance of ke0.Results:In both groups, the calculated propofol Ce at the time of LOR in stages 1 and 2 differed significantly (P<0.01); the mean lowest BIS in stage 1 were significantly higher than those in stage 2 (P < 0.05).The relations of propofol Ce versus BIS revealed the apparent hysteresis loop.Conclusions:The study cannot clinically validate the accuracy of application of ke0 derived from the TPEAK = 74 s of BIS with Schnider propofol pharmacokinetic model.

Predicted and Measured Plasma Propofol Concentration and Bispectral Index During Deep Sedation in Patients With Impaired Left Ventricular Function

To evaluate the ability of the Schnider pharmacokinetic model to predict plasma propofol concentration during target-controlled propofol infusion in patients with impaired left ventricular function and to investigate the predictive value of the bispectral index (BIS) to indicate deep sedation in this patient group. Prospective, observational study. Thirty-four patients (mean left ventricular ejection fraction 31% +/- 9%) undergoing the implantation of a cardioverter-defibrillator during deep sedation. None. Predicted and measured propofol plasma concentrations and BIS were assessed during steady-state conditions with the propofol infusion rate constant for at least 20 minutes. The plasma propofol concentration was significantly underestimated by the pharmacokinetic model used (mean percentage prediction error 37% +/- 49%). The 50% probability of deep sedation was calculated at a predicted propofol concentration of 2.09 (95% confidence interval [CI], 2.04-2.14) mug/mL and at a measured propofol concentration of 2.70 (95% CI, 2.62-2.78) mug/mL. BIS values showed a marked variability among individuals during deep sedation (5th-95th percentiles: 25-81). The pharmacokinetic model used markedly underestimated propofol plasma levels in the patient group studied. The large variability among patients suggests that BIS monitoring is not suitable for indicating an exact endpoint corresponding to deep sedation.