Design of a pharmacokinetic/pharmacodynamic model for administration of low dose peripheral norepinephrine during general anaesthesia.

Autor: Joachim J; Université Paris Cité, Paris, France.; Department of Anaesthesiology, Burn and Critical Care, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Cartailler J; Université Paris Cité, Paris, France.; Department of Anaesthesiology, Burn and Critical Care, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Vallee F; Université Paris Cité, Paris, France.; Department of Anaesthesiology, Burn and Critical Care, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Lefevre T; Department of Anaesthesiology, Burn and Critical Care, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Callebert J; Université Paris Cité, Paris, France.; Service of Biochemistry and Molecular Biology, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Gayat E; Université Paris Cité, Paris, France.; Department of Anaesthesiology, Burn and Critical Care, St-Louis-Lariboisière-Fernand Widal University Hospitals, Paris, France., Lavielle M; Inria & CMAP, Ecole Polytechnique, CNRS, Institut Polytechnique de Paris, Paris, France.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2024 Nov; Vol. 90 (11), pp. 2861-2869. Date of Electronic Publication: 2024 Jul 22.
DOI: 10.1111/bcp.16180
Abstrakt: Aims: Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low-dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP).
Methods: From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex.
Results: We included 29 patients (age 52 [46-64] years, 69% female). NOR median time to peak effect on MAP was 74 [53-94] s. After bolus administration, MAP increased by 24% (15-31%). A 2-comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters.
Conclusion: We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target-controlled infusion.
(© 2024 British Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: