Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy

Abstract

Background: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations.

Methods: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses.

Results: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h-1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h-1. Based on Monte Carlo simulation results, an infusion of 17.5 μg h-1 seems to reach target sufentanil concentration (0.3-0.6 μg L-1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low.

Conclusions: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery.

Trial registration: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Keywords: Anaesthetics, intravenous; Extracorporeal membrane oxygenation; Pharmacokinetics; Sufentanil; Temperature.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Goodness-of-fit plots of the final population pharmacokinetic model. Log of observed sufentanil concentrations versus log of population predicted concentrations (a) and versus log of individual predicted concentrations (b), and conditional weighted residuals (CWRES) versus population predicted concentrations (c) and versus time (d)

Fig. 2

Prediction-corrected visual predictive checks (pc-VPCs) of the final population pharmacokinetic model. Open circles, observed sufentanil concentrations; solid line, median; lower and upper dashed lines, 5th and 95th percentiles of the simulated data, respectively; shaded areas, 95% confidence intervals for simulated predicted median, 5th percentile, and 95th percentile constructed from 1000 simulated datasets of individuals from the original dataset

Fig. 3

Simulated mean sufentanil concentrations for 120-h sufentanil infusion in patients. Patients were stratified for body temperature (a, c) or total plasma protein (b, d). a 12.5 μg h−1 infusion in patients with total plasma protein levels of 4.5 g dL−1. b 12.5 μg h−1 infusion in patients with body temperatures of 36.9 °C. c 17.5 μg h−1 infusion in patients with total plasma protein levels of 4.5 g dL−1. d 17.5 μg h−1 infusion in patients with body temperatures of 36.9 °C