Influence of an “Electroencephalogram-Based” Monitor Choice on the Delay Between the Predicted Propofol Effect-Site Concentration and the Measured Drug Effect

Abstract

The main question we tried to answer in this study is "What is the influence of the monitor delay on the pharmacodynamic (PD) relationship monitor versus propofol when using Ce targeted target-controlled infusion (TCI) with the Schnider model?" • Finding: The monitor delay causes a PD hysteresis irrespective of which monitor is used.• Meaning: Adding a lag-time of 53 seconds and 49 seconds for qCON index (qCON) and Bispectral index (BIS), respectively, substantially corrects for this hysteresis, improving the PD model performance, increasing the "pump-monitor" synchrony, and making the estimates of effect-site concentration which produces 50% of the maximal drug effect (Ce 50 ) for propofol more realistic and less monitor dependent.BACKGROUND: Clinicians can optimize propofol titration by using 2 sources of pharmacodynamic (PD) information: the predicted effect-site concentration for propofol (Ce prop ) and the electroencephalographically (EEG) measured drug effect. Relation between these sources should be time independent, that is, perfectly synchronized. In reality, various issues corrupt time independency, leading to asynchrony or, in other words, hysteresis. This asynchrony can lead to conflicting information, making effective drug dosing challenging. In this study, we tried to quantify and minimize the hysteresis between the Ce prop (calculated using the Schnider model for propofol) and EEG measured drug effect, using nonlinear mixed-effects modeling (NONMEM). Further, we measured the influence of EEG-based monitor choice, namely Bispectral index (BIS) versus qCON index (qCON) monitor, on propofol PD hysteresis. METHODS:We analyzed the PD data from 165 patients undergoing propofol-remifentanil anesthesia for outpatient surgery. Drugs were administered using target-controlled infusion (TCI) pumps. Pumps were programmed with Schnider model for propofol and Minto model for remifentanil. We constructed 2 PD models (direct models) relating the Schnider Ce prop to the measured BIS and qCON monitor values. We quantified the models' misspecification due to hysteresis, on an individual level, using the root mean squared errors (RMSEs). Subsequently, we optimized the PD models' predictions by adding a lag term to both models (lag-time PD models) and quantified the optimization using the RMSE. RESULTS: There is a counterclockwise hysteresis between Ce prop and BIS/qCON values. Not accounting for this hysteresis results in a direct PD model with an effect-site concentration which produces 50% of the maximal drug effect (Ce 50 ) of 6.24 and 8.62 µg/mL and RMSE (median and interquartile range [IQR]) of 9.38 (7.92-11.23) and 8.41(7.04-10.2) for BIS and qCON, respectively. Adding a modeled lag factor of 49 seconds to the BIS model and 53 seconds to the qCON model improved both models' prediction, resulting in similar Ce 50 (3.66 and 3.62 µg/mL for BIS and qCON) and lower RMSE (median (IQR) of 7.87 (6.49-9.90) and 6.56 (5.28-8.57) for BIS and qCON. CONCLUSIONS: There is a significant "Ce prop versus EEG measured drug effect"...

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“…(e.g. BIS, entropy or qCON monitor) [25]. Even though a IONM EEG montage would add some useful information, there is currently no known method of using this information to guide anesthetic drug titration.…”

“…The only validated and clinically convenient way to achieve this is by using a widely available pEEG monitor.(e.g. BIS, entropy or qCON monitor) [ 25 ]. Even though a IONM EEG montage would add some useful information, there is currently no known method of using this information to guide anesthetic drug titration.…”