Yingxue Li1, Dr Jeroen Koomen1,2, Prof. Dr Douglas Eleveld1, Dr Johannes van den Berg1, Dr Jaap Jan Vos1, Dr Ilonka de Keijzer1, Prof. Dr Michel Struys1, Prof. Dr Pieter Colin1
1University of Groningen, University Medical Center Groningen, The Netherlands, 2CBG-MEB, The Netherlands
Background: Intraoperation hypotension (IOH) is a common complication of general anesthesia (GA) in patients undergoing surgery [1-4]. The probability of developing adverse events increases even during brief episodes of IOH[3, 4]. To reduce this risk, blood pressure is closely monitored during GA. Norepinephrine (NE), a vasopressor, can be administered upon detection of hypotension to quickly reverse arterial hypotension by restoring vascular tone and blood pressure[5, 6]. Despite the routine use of NE, the dose-exposure-response relationship of NE is not well quantified, and dosing relies largely on clinical experience. In particular, little is known regarding NE pharmacokinetics and pharmacodynamics (PKPD) in the general adult population undergoing elective surgery under general anesthesia. Objective: In this study, we aimed to evaluate whether a previously-developed mechanism-based model for the hemodynamic effects of GA (i.e. propofol and remifentanil) is suitable for characterizing the hemodynamic effects of norepinephrine. Methods: A single-center, cross-over study was conducted in 36 healthy volunteers using a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 µg-1 kg-1 min-1). Hemodynamic variables, including mean arterial pressure (MAP), heart rate (HR) and pulse pressure (PP) were collected. The mechanism-based model of Su [7] was used as a foundation. The data were analyzed using the first-order conditional estimation method with interaction (FOCE-I) algorithm in NONMEM. Information from the Su model was incorporated into the current model by using a “frequentist prior” approach[8], which involves adding a penalty function based on the prior distribution to the objective function value (OFV) derived from the current data. Results: The mechanistic model consisted of three turnover equations representing total peripheral resistance (TPR), stroke volume (SV), and HR. PP serves as a surrogate for SV, with an assumed SV/PP ratio of 1.5 as SV was not measured. MAP is represented as the product of cardiac output (CO) and TPR, with CO derived from HR and SV. NE plasma concentration positively affected the production rate of TPR and SV while negatively affecting the elimination rate of HR. These effects were best described by a linear model. A shared kout was estimated for the turnover equations for TPR, SV, and HR. To account for the observed undershoot phenomenon in MAP and SV during the washout phase, a tolerance-rebound model was incorporated on the TPR and SV. For each 1 nmol·L?¹ increase in norepinephrine concentration, TPR and SV increased by 1.61%, and HR increased by 0.52%. Goodness-of-fit plots and prediction-corrected visual predictive check plots showed good predictive performance of the model. Conclusion: The previously developed mechanism-based pharmacodynamic model was able to characterize the effects of norepinephrine on MAP, HR, PP in healthy volunteers. Future studies should aim at combining NE and GA hemodynamic drug effects before the model can be used to enhance the management of IOH in clinical practice.
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Reference: PAGE 33 (2025) Abstr 11538 [www.page-meeting.org/?abstract=11538]
Poster: Drug/Disease Modelling - Other Topics