Population Pharmacokinetics of Etomidate isnotchangedin Patients with Obstructive Jaundice : an observational study

Background: Etomidate is a commonly used in induction of anesthesia. We have previously confirmed that etomidate requirements are significantly reduced in patients with obstructive jaundice and that etomidate anesthesia during ERCP results in more stable hemodynamics when compared with propofol. The aim of the present study is to investigate the pharmacokinetics of etomidate in patientswith and without obstructive jaundice. Method: 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 bolus. Plasma etomidate concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed-effects modeling approach was used to characterize etomidate pharmacokinetics. Thecovariates 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), blood urea nitrogen(BUN)were tested for significant effects on parametersusing a multiple forward selection approach. Covariate effects were judged based onchanges in the objective function value (OFV). Results: A three-compartment disposition model adequately described the further when


Background
Etomidate is a commonly used ininduction of anesthesia. The mechanism of etomidate's hypnotic effect involves binding to γ aminobutyric acid (GABA)type A receptors in the central nerve system and potentiating the effect of GABA [1,2]. In healthy volunteers, etomidate is approximately 76% protein bound and has a high solubility in fat [2]. Thus, etomidate is characterized by a large apparent volume of distribution. The major metabolic pathway of etomidate is hydrolysis by carboxylesterase in liver and plasma, with a total clearance rate of 15-20 ml/kg/min [3].
There aresignificant alterations in pharmacokinetic parametersof etomidate in the cirrhotic patients [4].We have confirmed that the etomidate requirement in anesthesia induction was significantly reduced in patients with obstructive jaundice [5], and etomidate anesthesia during ERCP is associated withmore stable haemodynamic responses compared with propofol [6].However, pharmacokinetics of etomidate inpatients with obstructive jaundice have not been determined.We hypothesized that the pharmacokinetics of etomidatewould be affected by obstructive jaundice. This study was designed to investigatethe etomidate pharmacokinetics in patients with and without obstructive jaundice.

Clinical trail
This study was approved by the Ethics Committee of Eastern Hepatobiliary Surgery Hospital (EHBHKY2013-002-003), and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (ChiCTR-IPR-15007574, Principal investigator: Jin-chao Song, Date of registration: 2015-12-10).Participants were patients scheduled for elective bile duct surgery in 2016, were 18 to 70 years of age, and weighed 50 to 80 kg. Exclusion criteria were 1) ASA > 3, 2) severe cardiac, pulmonary, renal, or metabolic disease, 3) analgesic or neuromodulating medication in the past month. A total of 30 patients were recruited into this study. Eighteen of them had obstructive jaundice secondary to malignant disease. Twelve patients without jaundice serviced as a control group.
Written informed consent were obtained from each individual prior to the surgery.
The patients were fasted overnight. A radial artery catheter (20G, BL BRUN B.) was also inserted under local anesthesia for invasive monitoring of blood pressure and blood sampling, and a cannula (CV-501-20, Central Venous Catheter, Ltd, Singapore) was inserted into an internal jugular vein for drug administration, fluid infusion and CVP measuring. Other monitors including: noninvasive blood pressure, heart rate, ECG, pulse oximetry, and end-tidal carbon dioxide continuously throughout the surgery.

Pharmacokinetic Analysis
The pharmacokinetic analysis was performed using nonlinear mixed-effect population model (NONMEM) (6).Models were run using the first-order conditional estimation with interaction method, one-, 2-or 3-compartment models were investigated. Models

Results
The demographic details of the two groups are presented in Table 1 Approximately 76% of etomidate is bound to plasma albumin, mainly hydrolyzed by esterase in the liver and plasma and then metabolized to carboxylic acids. The carboxylate metabolite is excreted mostly in urine (85%) and bile (13%). Etomidate has a high liver clearance rate of 18-25 ml / (kg.min), a liver uptake rate of 0.5 to 0.9 [15], and its metabolic clearance is approximately equal to the hepatic blood flow. Of note, numerous evidences have identified altered hepatic blood flow in obstructive jaundice.
Kands et al. [16] used a real-time ultrasound flow meter to measure portal blood flow and hepatic arterial blood flow in dogs with obstructive jaundice, and found that the hepatic arterial blood flow was significantly higher than that before obstruction while Several limitations of this study should be mentioned. First of all,our study may have an unclear risk of bias due to the small sample sizeof a rather homogenous population with complicated physical conditions.Therefore, any relationship with the covariates might be difficult to discern.Second, the covariates of age, weight as well as obstructive associated factors provided no improvement in the objective function of the model, while height significantly affects the estimated value of systematic clearance rate. This is an interesting result as previous evidence suggested that height also affects the pharmacokinetic model of other sedative anesthetics [18,19]. However, current data are insufficient to verify and explain this phenomenon.It is clearthat the current study will provide a framework to design future studies.