The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing abdominal aortic surgery

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 E max 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.

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups - an Investigation using Physiologically based Pharmacokinetic Modelling

“…The propofol models used in this analysis were optimized from a published model (Michelet et al) [22], and satisfactorily recovered pharmacokinetic profiles and estimated clearance parameters reported for children and adults (Supplementary Materials, Figure S1 and Table S3) [27][28][29][30][31][32][33][34][35][36][37][38]. In adults, total propofol clearance has been reported with some variability with a clearance of 1.54, 2.2 or 2.64 L/min [20,41,42]. These are greater than hepatic perfusion (0.8-1.2 L/min) [43], and similar to the model predicted clearance in this analysis, implementing the Robert et al model [40] (1.66 ± 0.45 L/min; Supplementary Materials, Table S4).…”

“…Clinically, children are exposed to propofol in low CO conditions, such as neonatal asphyxia and TH, after cardiac surgery, or heart failure [5,6,7]. The effect of reduced CO on propofol pharmacokinetics has been described in adults [20], while the combined effect of age and low CO was not yet well explored.…”

“…While the result from this study provides valuable insight into the impact of reduced CO on clearance and dosing strategies of propofol across age groups, a limitation of the study was the inability to validate the model in patients with reduced CO. Though there are published studies showing the impact of reduced CO on propofol pharmacokinetics, the dosing methods used in these studies were target concentrated based making it impossible to simulate a particular dosing strategy as one would expect for manual infusions [20,49]. However, it does support the practices to be much more cautious and vigilant on propofol in low CO patients, making the collection of pharmacokinetic samples in pediatric studies even more challenging.…”

“…Since propofol is classified as high extraction drug and clearance is affected by alterations in CO in adults, it serves as a good model compound to explore the impact of both physiology and pathophysiology on its pharmacokinetics across age groups [5,7,20]. The aim of this study was therefore to (i) assess the impact of reduced CO in low CO settings, like asphyxia and TH in neonates, on the propofol clearance capacity and (ii) how this affects safe and therapeutic concentration attainment across age groups to explore dosing optimization strategies under low CO conditions.…”

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling

“…Since propofol is classified as a high extraction drug, with clearance therefore expected to be altered upon CO reduction in adults, it serves as a good model compound to explore the impact of both physiology and pathophysiology on its pharmacokinetics across age groups [5,7,20]. The aim of this study was therefore to (i) assess the impact of reduced CO, such as asphyxia and TH in neonates, on propofol clearance capacity and (ii) how this affects safe and therapeutic concentration attainment across age groups, to explore dosing optimization strategies under low CO conditions.…”