Recirculatory model of fentanyl disposition with the brain as the target organ  Upton R.N. , Grant C. , Martinez A.M. , Ludbrook G.L.   British Journal of Anaesthesia  Volume 93, Issue 5, Pages 687-697 (November 2004) DOI: 10.1093/bja/aeh261 Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 1 Models of organ kinetics. See Appendix for equations and parameter names. British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 2 Basic structure of the hybrid recirculatory model of fentanyl disposition used for both the sheep and dog data. The submodels of the brain and lungs are based on those fitted individually to the sheep or dog data by hybrid modelling as appropriate, and parameter names are unchanged (Tables 2 and 3). QCO and Qbrn are cardiac output and cerebral blood flow, respectively. British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 3 (a) Measured pulmonary artery, aortic and sagittal sinus concentrations of fentanyl for short-infusion studies in sheep. Data are mean (se); no error bar is shown if it is smaller than the symbol. (b) The time course of the arterio-sagittal sinus concentration difference (across the brain) for these studies and its 95% confidence interval. The solid line is the line of best fit for the membrane-limited model of Table 2. (c) Time course of the pulmonary artery–arterial concentration difference (across the lungs) for these studies and its 95% confidence interval. The solid line is the line of best fit for the ‘flow with loss’ model of Table 3. If the 95% confidence interval of the difference at a given time point does not include zero, then the concentration difference is statistically significant at that time. British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 4 (a) Measured arterial concentrations of fentanyl for the long-infusion studies in sheep with 95% confidence intervals. The solid line is the best-fit concentration for the recirculatory model for the parameter values shown in Table 4. (b) Measured sagittal sinus concentrations of fentanyl for the long-infusion studies with 95% confidence intervals. The solid line is the predicted concentration for the membrane-limited model of Table 2. The good agreement between the observed and predicted measurements validates the cerebral model for a different dataset (long infusion) than that from which model parameters were estimated (short infusion). British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 5 (a) The cerebral blood flow (CBF) (error bars indicate sd; no error bar is shown if it is smaller than the symbol) determined by fitting the dog brain fentanyl data compared with the measurements by McPherson and colleagues24 (dotted lines indicate 95% confidence intervals). The fitted cerebral blood flow was calculated from the rate constants of the best ‘tank in series’ model adjusted to give the same baseline values as the McPherson data. There was good agreement between the relative changes in the CBF estimated via kinetic modelling and the measurements made in dogs under hypo-, normo- and hypercarbic conditions. (b) The cardiac output (CO) (dotted lines indicate 95% confidence intervals) determined by fitting the dog brain and serum fentanyl data compared with the measurements by Carson and colleagues25 and Kontos and colleagues.26 The fitted cardiac output was calculated from the parameter values of the best recirculatory model fitted to the dog data (Table 6). There was good agreement between the cardiac output values predicted from kinetic modelling and the measurements made in dogs under hypo-, normo- and hypercarbic conditions. British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 6 The fit of the best recirculatory model to (a) serum and (b) brain concentrations for the dog data of Ainslie and colleagues.23 This figure shows the ability of the final recirculatory model (which incorporated the best cerebral kinetic model) to describe the serum and brain concentrations of fentanyl simultaneously. Symbols are the observed data, and the solid lines are the lines of best fit. British Journal of Anaesthesia 2004 93, 687-697DOI: (10.1093/bja/aeh261) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions