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.

Sedation and analgesia requirements during venovenous extracorporeal membrane oxygenation in acute respiratory distress syndrome patients

“…19,21 Body temperature and total plasma protein level were found to be positively correlated with systemic clearance and peripheral volume of distribution of sufentanil. 26 Furthermore, Yang et al 27 showed that remifentanil volume and clearance were increased in adult patients who received VA-ECMO than those who did not receive ECMO. Remifentanil concentrations were affected by patient gender and pump speed of ECMO.…”

Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

“…Median optimal sufentanil LD and MD were calculated based on observed PK data. To calculate the optimal doses, we used the range of 0.3–0.6 μg/L as the PK target for efficacious and safe analgesia [21], while higher levels have been described for anaesthetic effects in the literature [26]. Currently, the usual induction and maintenance doses of sufentanil are 0.25–2.0 and 0.5–1.5 μg/kg/h, respectively [11, 27-29].…”

“…Optimal LD were calculated for each patient based on individual values of Vd c using the following formula: LD (μg/kg) = Vd (L/kg) × C ss (μg/L), where C ss is 0.45 μg/L as a midpoint of the sufentanil target steady-state therapeutic range (0.3–0.6 μg/L). Optimal daily MD were calculated for each patient based on individual values of CL using the following formula: MD (μg/kg/h) = CL (L/kg/h) × C ss (μg/L), where C ss is 0.45 μg/L as a midpoint of the sufentanil target steady-state therapeutic range (0.3–0.6 μg/L) [21].…”

Evaluation of analgesic and sedative effects of remifentanil‐based fast‐track anesthesia in children undergoing transthoracic device closure of ventricular septal defects

“…Sufentanil has a strong affinity for opioid receptors, resulting in a more vigorous analgesic intensity and a longer duration of action than remifentanil. However, the metabolism of sufentanil is mainly dependent on liver blood flow 19,20 . Compared with sufentanil, a fast‐track protocol with a rapidly metabolized drug such as remifentanil may allow for better titration to keep patients within their therapeutic window and to minimize opioid‐induced side effects.…”

“…However, the metabolism of sufentanil is mainly dependent on liver blood flow. 19,20 Compared with sufentanil, a fast-track protocol with a rapidly metabolized drug such as remifentanil may allow for better titration to keep patients within their therapeutic window and to minimize opioid-induced side effects. Our hospital adopted remifentanil-based fast-track anesthesia and reported on the relevant experiences.…”