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Abstract

Introduction: While argatroban dosing requirements are generally reduced in patients with critical illness, there is substantial variability from patient to patient. Thus, achieving therapeutic anticoagulation quickly and safely remains a challenge. This project aims to identify clinically relevant factors that predict argatroban dose response (ADR) in patients admitted to a cardiothoracic surgery intensive care unit (CTICU). Methods: This retrospective, single-center study was IRB approved at the University of Pennsylvania. Patients admitted to the CTICU from July 2005 to July 2012 who received argatroban for > 24 hours and achieved steady state (SS) were included. SS was defined as the initial set of 3 consecutive aPTT values obtained while receiving a constant infusion rate, where each aPTT value was within 10% of the average of those 3 consecutive aPTT values. Potential predictors of ADR were: age, abnormal (>1.2 mg/dL) total bilirubin (tbili), left ventricular ejection fraction, mean arterial blood pressure (MAP), enteral vs. parenteral nutrition, vasoactive medication exposure (yes/no), and SOFA score. ADR was measured using a novel parameter: the dose response ratio (DRR), defined as the mean SS aPTT ÷ SS infusion rate, with units of seconds/mcg/kg/min. Univariate and multivariate linear regression was used to evaluate the relationship between predictor variables and the DRR. Results: 53 patients were included. Median SS aPTT was 54.9 seconds (range 40.2-80.0 seconds). Median argatroban SS infusion rate was 0.37 mcg/kg/min (range 0.08-4.5 mcg/kg/min). This corresponds to a median DRR of 144.4 seconds/mcg/kg/min (range 14.6-657.5). Predictors of DRR in univariate analysis were: age, tbili, treatment with milrinone, norepinephrine, dopamine, MAP >65 mmHg, and receipt of parenteral nutrition. Independent predictors in multivariate analysis (R²=0.32) were: tbili (ß=97.2, p=0.027), treatment with milrinone (ß= -97.3, p=0.035), and MAP >65 mmHg (ß= -109.7, p=0.014). Conclusions: In a CTICU population, argatroban infusion requirements are significantly lower in patients with abnormal tbili and significantly higher in patients treated with milrinone and those with MAP >65 mmHg.