SV is influenced by the drug effect and negative feedback through MAP (SV∗) and by direct inverse relationship through HR (represented by HR_SV). Propofol decreases the zero-order production rates ( k in) of the turnover equations for TPR and SV. The influences of negative feedback through MAP on TPR, HR, and SV are represented by three linked turnover equations. MAP equals the product of TPR, HR, and SV. k out, first-order dissipation rate constant of SV, HR, and TPR Base SV, Base HR, and Base TPR, baseline SV, HR, and TPR, respectively EC 50 TPR and EC 50 SV, concentrations that produce half of the maximal propofol effect on TPR and SV, respectively E max_SV and E max_TPR, maximal effect of propofol on SV and TPR, respectively FB, magnitude of the feedback HR_SV, magnitude of the effect on HR on SV k, first-order dissipation rate constant of the time-dependent effect LTDE, percentage of increased baseline HR caused by the time-dependent effect γ, Hill coefficient for TPR sigmoid AGE_ E max_SV, covariate effect of age on the maximal propofol effect on SV BSV, between-subject variability ρ, correlation coefficient σRUV, residual unexplained variability RSE, relative standard error.įig 1 Structure of the mechanism-based model that describes the propofol effect and the interdependency between MAP, HR, SV, and TPR. Table 1 Parameter estimates of final mechanism-based model. η 1 and η 2 are random variables representing BSV. Base MAP (typ) and E max_PP (typ) are the population typical values of baseline MAP and the maximal effect of propofol on PP. Age was a significant covariate on Base MAP (Δ objective function value=–13.3) and E max_PP (Δ objective function value=–15.2), with Base MAP and E max_PP increasing with age according to equations ( (4), (5)). The time-dependent effect in equations ( (2), (3)) was significant for MAP (Δ objective function value=–91.0) and HR (Δ objective function value=–16.9), and resulted in a temporary increase in MAP by 6 mm Hg and HR by 3 beats min −1 with a half-life for attenuation of 14.74 and 5.46 min, respectively. The estimated half-lives for the MAP, HR, and PP models were 3.15, 7.79, and 5.78 min, respectively, indicating that MAP changed first followed by PP and HR. We found that E max_PP negatively correlated with baseline PP (Base PP, ρ=–0.72), meaning that individuals with higher than typical baseline PP were more likely to have a lower than typical E max_PP (ρ is the correlation coefficient). For PP, the estimated maximum effect of PP ( E max_PP) was –8.9% with individual estimates ranging from –116.8% to 54.9%. Estimated E max values for MAP and HR were –40.0% and 26.0%, respectively. The E max functions characterise the relationship between the predicted propofol plasma concentrations and MAP, HR, and PP. Effect-site concentration targets were set at 0.5, 1, 1.5, 2.5, 3.5, 4.5, 6, and 7.5 μg ml −1 using a three-compartment pharmacokinetic model with an effect compartment developed by Schnider and colleagues. After 2 min of baseline measurements, a ‘staircase’ step-up followed by step-down infusion of propofol was initiated. RUGLOOPII software (Demed, Temse, Belgium) was used to control infusion rates between ml h −1 via an RS-232 interface. Braun, Melsungen, Germany) was administered via the same intravenous line using a Fresenius Base Primea docking station (Fresenius-Kabi, Bad Homburg, Germany) carrying two Fresenius Module DPS pumps. Each volunteer received an arterial line for blood sampling and an intravenous line for the administration of crystalloids (2 ml kg −1 h −1). After written informed consent was obtained, volunteers were stratified by age and sex ( Online Supplementary 2, Table 2–1). In brief, 36 healthy volunteers with ASA physical status 1 were enrolled. The study was approved by the Institutional Review Board of the University Medical Center Groningen (NL43238.042.13) and was registered at (NCT02043938). Special Issue on Memory and Awareness in Anesthesia (PDF)Īs shown in Online Supplementary 1 Figure 1-1.Special Issue on Mass Casualty Medicine and Anaesthesia: Science and Clinical Practice (JPG).
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