Obstructive Jaundice does not Change the Population Pharmacokinetics of Etomidate in Patients who Underwent Bile Duct Surgery

Abstract

Background: Etomidate is commonly used in the induction of anesthesia. We have previously confirmed that etomidate requirements are significantly reduced in patients with obstructive jaundice and that etomidate anesthesia during Endoscopic Retrograde Cholangiopancreatography (ERCP) results in more stable hemodynamics compared to propofol. The aim of the present study is to investigate whether obstructive jaundice affects the pharmacokinetics of etomidate in patients who underwent bile duct surgery.

Methods: A total of 18 patients with obstructive jaundice and 12 non-jaundiced patients scheduled for bile duct surgery were enrolled in the study. Etomidate 0.333 mg/kg was administered by IV bolus for anesthetic induction. Arterial blood samples were drawn before, during, and up to 300 minutes after the bolus. Plasma etomidate concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A nonlinear mixed-effects population modeling approach was used to characterize etomidate pharmacokinetics. The covariates of age, gender, height, weight, Body Surface area (BSA), Body Mass Index (BMI), Lean Body Mass (LBM), Total Bilirubin (TBL), Alanine Aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), creatinine (CR), and blood urea nitrogen (BUN) were tested for significant effects on parameters using a multiple forward selection approach. Covariate effects were judged based on changes in the Objective Function Value (OFV).

Results: A three-compartment disposition model adequately described the pharmacokinetics of etomidate. The model was further improved when height was a covariate of total clearance [Cl1=1.30+0.0232(HT-162), ΔOFV=-7.33; P<0.01)]. The introduction of any other covariates, including bilirubin and total bile acids, did not improve the model significantly (P>0.01). For the height of 162cm, the final pharmacokinetic parameter values were as follows: V1=1.42 (95% CI, 1.01-1.83, L), V2=5.52 (95% CI, 4.07-6.97, L), V3=63.9 (95% CI, 41.95-85.85, L),Cl1= 1.30 (95% CI, 1.19-1.41, L/min), Cl2= 1.21 (95%CI, 0.95-1.47, L/min), and Cl3=0.584 (95%CI, 0.95-1.21, L/min), respectively.

Conclusion: A 3-compartment open model might best describe the concentration profile of etomidate after bolus infusion for anesthesia induction. The pharmacokinetics of etomidate did not change by the presence of obstructive jaundice.

Keywords: Population pharmacokinetics; bile duct; etomidate; nonlinear mixed-effect population model; obstructive jaundice; threecompartment model.