The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing ab
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ORIGINAL PAPER
The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing abdominal aortic surgery Agnieszka Bienert1 • Paweł Sobczyn´ski2 • Katarzyna Młodawska1 • Roma Hartmann-Sobczyn´ska3 Edmund Grzes´kowiak1 • Paweł Wiczling4
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Received: 12 February 2020 / Accepted: 13 August 2020 The Author(s) 2020
Abstract Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2–3 lg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients‘ age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient’s responses to both drugs. Keywords Propofol Fentanyl Cardiac output Pharmacokinetics Pharmacodynamics
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09712-1) contains supplementary material, which is available to authorized users.
Providing an adequate level of anaesthesia is challenging and requires careful monitoring and dose titration. Especially in the light of recent studies which have suggested 3
Department of Experimental Anaesthesiology, Poznan University of Medical Sciences, Sw. Marii Magdaleny 14 Street, 61-861 Poznan, Poland
4
Department of Biopharmacy and Pharmacodynamics, Medical University of Gdansk, Hallera 107 Street, 80-416 Gdansk, Poland
& Agnieszka Bienert [email protected] 1
Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Sw. Marii Magdaleny 14 Street, 61-861 Poznan, Poland
2
Departmen
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