Yingxue Li (1), Jeroen V. Koomen (1,2), Douglas J. Eleveld (1), Johannes P. van den Berg (1), Jaap Jan Vos (1), Ilonka N. de Keijzer (1), Michel M. R. F. Struys (1), Pieter J. Colin (1)
(1) University of Groningen, University Medical Center Groningen, The Netherlands. (2) CBG-MEB, The Netherlands
Objectives: Intraoperation hypotension (IOH) is frequently seen in patients undergoing surgery under general anesthesia (GA) and is largely induced by the usage of anesthetics [1-4]. The occurrence of adverse outcome increases even for a brief episodes of IOH[3, 4]. To reduce the risk, blood pressure is closely monitored during GA, and norepinephrine (NE) is often administered upon detecting hypotension. NE is a vasopressor that is routinely used during general anesthesia to treat arterial hypotension as it can quickly restore vascular tone and blood pressure[5, 6]. Despite its routine application, the dose-exposure-response relationship of NE remains poorly understood, and initial dosing is largely reliant on clinical experience. Moreover, quantification of the influence of GA on the pharmacokinetics (PK) of NE is lacking. In this study, we aimed to describe NE pharmacokinetics in healthy volunteers and the influence of GA on its PK.
Methods: A single center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.08, 0.12, 0.16 and 0.20 mcg-1 kg-1 min-1) in firstly awake state and then under GA. GA was administered using propofol/remifentanil Eleveld TCI[7,8]. During GA, a 30 second electrical stimulus was applied as surrogate for surgical incision to the volunteers. Blood samples were collected before the initial dosing, after each dosing step, following the cessation of the stimulus, and during the washout phase. Plasma NE concentrations were subsequently determined. A population PK model was developed by non-linear mixed effects modelling. Effect of GA on NE PK were assessed through covariate analysis and the cause of the effect was investigated examining relevant hemodynamic and anesthetic variables. Simulations were performed to predict the plasma NE concentration in patients at different measured propofol concentrations.
Results: A total of 1219 samples were analyzed from 36 volunteers. The data were well characterized by a two compartment model with a first-order elimination. Weight, age, and session effect (awake vs. GA) were identified as relevant covariates on the clearance (CL) of NE. A reduction of 10% in NE CL was identified following GA induction as indicated by the session effect parameter. This observed variation between sessions is more effectively accounted for by the measured concentration of propofol, rather than the anticipated influence of cardiac output[9-11]. The estimated post-stimulation NE concentration is 0.66 nmol L-1 [95% CI 0.06 – 1.20 nmol L-1] lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g. 6 mcg mL-1) exhibited higher NE concentrations [95% PI 18.10 – 43.89 nmol L-1] than patients at a lower measured propofol concentration (e.g. 3 mcg mL-1) [95% PI 16.81 – 38.91 nmol L-1].
Conclusions: The NE PK is well described with a two compartment model with a first-order elimination. NE CL exhibited a 10% decrease under GA, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under GA is very limited.
References:
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Reference: PAGE 32 (2024) Abstr 11012 [www.page-meeting.org/?abstract=11012]
Poster: Drug/Disease Modelling - Other Topics