Dexmedetomidine pharmacokinetic–pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation P.J. Colin,

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Dexmedetomidine pharmacokinetic–pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation P.J. Colin, L.N. Hannivoort, D.J. Eleveld, K.M.E.M. Reyntjens, A.R. Absalom, H.E.M. Vereecke, M.M.R.F. Struys British Journal of Anaesthesia Volume 119, Issue 2, Pages 200-210 (August 2017) DOI: 10.1093/bja/aex085 Copyright © 2017 The Author(s) Terms and Conditions

Fig 1 Median filtered BIS values and MOAA/S observations for the step-up TCI administration for four representative subjects. Dashed vertical lines indicate when a new TCI target was set. Immediately before this, MOAA/S was assessed. BIS, bispectral index; MOAA/S, Modified Observer's Assessment of Alertness/Sedation; TCI, target-controlled infusion. British Journal of Anaesthesia 2017 119, 200-210DOI: (10.1093/bja/aex085) Copyright © 2017 The Author(s) Terms and Conditions

Fig 2 Goodness-of-fit plots for the final model. The left panels show the observed BIS vs the post hoc predictions and the CWRES against post hoc predictions and time. The continuous red line depicts a non-parametric smoother through the data to illustrate lack of bias in the different plots. The right panels show individual GOF plots for the three subjects with the best, median, and worst fit, respectively. The continuous black line shows the observed MOAA/S scores, whereas grey circles denote the probability of observing the MOAA/S scores, with bigger circles having higher probabilities. These probabilities were estimated by simulation using the post hoc predicted parameters. Red crosses indicate regions where, according to the simulations, the probability for the observed MOAA/S is <10%. These points served as ‘residuals’ to instruct on how to refine the model. BIS, bispectral index; CWRES, conditionally weighted residuals; GOF, goodness of fit; MOAA/S, Modified Observer's Assessment of Alertness/Sedation. British Journal of Anaesthesia 2017 119, 200-210DOI: (10.1093/bja/aex085) Copyright © 2017 The Author(s) Terms and Conditions

Fig 3 Relationship between effect-site concentrations and BIS and MOAA/S. The continuous black line is the predicted BIS, whereas the MOAA/S with the highest probability is shown with a continuous red line. Stacked bar plots illustrate the distribution of MOAA/S probabilities at effect-site concentrations of 0.01, 1.0, 2.5, and 10 ng ml−1, corresponding to predicted BIS values of 96, 70, 50, and 20, respectively. Ce, effect-site concentration; BIS, bispectral index; MOAA/S, Modified Observer's Assessment of Alertness/Sedation. British Journal of Anaesthesia 2017 119, 200-210DOI: (10.1093/bja/aex085) Copyright © 2017 The Author(s) Terms and Conditions

Fig 4 Observed (pink lines) and post hoc predicted BIS (blue lines) for the subjects with the best, median, and worst fit. The dashed vertical lines indicate when a new TCI target was set. Immediately before this, MOAA/S was assessed. BIS, bispectral index; MOAA/S, Modified Observer's Assessment of Alertness/Sedation; TCI, target-controlled infusion. British Journal of Anaesthesia 2017 119, 200-210DOI: (10.1093/bja/aex085) Copyright © 2017 The Author(s) Terms and Conditions