Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation

Seungwon Yang,Jiseon Kim,Jongsung Hahn,Taegon Hong,Kyoung Lok Min,Jin Wi,Min Jung Chang,Hayeon Noh,Min Soo Park,Soo Kyung Bae,Byung Hak Jin

doi:10.1038/s41598-017-16358-6

Abstract

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.

Highlights

Extracorporeal membrane oxygenation (ECMO) has been increasingly used over the last decade to augment gas exchange and hemodynamic support in critically ill patients with refractory cardiac or respiratory failure[1,2]
(1) For female patients: pump speed 1700–2000 RPM, ≥0.42 mg/h; 2000–2900 RPM, ≥0.63 mg/h (2) For male patients: pump speed 1700–2000 RPM, ≥0.21 mg/h; 2000–2900 RPM, ≥0.42 mg/h. In this prospective cohort study, we investigated the population PK of remifentanil in adult patients on venoartrial extracorporeal membrane oxygenation (VA-ECMO)
We found that remifentanil V and CL were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO, and we identified two significant determinants that affected remifentanil concentrations: sex and ECMO pump speed

Summary

Introduction

Extracorporeal membrane oxygenation (ECMO) has been increasingly used over the last decade to augment gas exchange and hemodynamic support in critically ill patients with refractory cardiac or respiratory failure[1,2]. With more patients being treated with ECMO, there is an increasing requirement to understand the complicated alterations in drug pharmacokinetics (PK) associated with the introduction of the ECMO system. The presence of ECMO increases the PK variability of these drugs owing to additional extracorporeal circulation[3]. With these dramatic PK alterations, which can lead to changes in drug concentrations, the provision of optimal pharmacotherapy to patients on ECMO remains a considerable challenge in clinical settings. Current knowledge regarding PK alterations of drugs in patients on ECMO is limited, making it difficult to provide optimal dosing regimens of drugs to this patient population. Population PK analysis is a pragmatic approach to describe the drug PK, identify patient-related and clinical PK variability, and recommend appropriate dosing regimens based on model simulations

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Conclusion