Intravenous Lipid Emulsion Does Not Reverse Dabigatran‐induced Anticoagulation in a Rat Model

Abstract

The anticoagulant dabigatran has no reversal agent and may cause life-threatening bleeding in patients with trauma or closed-space hemorrhage. Intravenous lipid emulsion (ILE) is thought to create a lipid compartment in serum that sequesters lipophilic drugs. Dabigatran is lipophilic, and its anticoagulant effects are concentration dependent. The study objective was to determine if ILE therapy reverses dabigatran's anticoagulant effects. Twenty rats were selected at random, 10 in the ILE group and 10 in a normal saline (NS) control group. Animals had a baseline tail bleeding time (T0), followed by oral dabigatran administration (15mg/kg). At 45minutes (T45), a second tail bleed time measurement was performed, followed by a 7-minute infusion of 15mL/kg ILE or NS. A final 60-minute (T60) bleed time measurement was obtained. An ILE-only group of five animals had bleeding times assessed prior to (T0) and 15minutes after (T15) ILE therapy. A mixed-effect repeated-measures analysis of variance modeling the effect of time, group, and the interaction of group and time on bleed times was conducted. There was a significant within-subject change in bleeding time across the assessment points (F(2,36)=33; p<0.001), but there were no effect of group (F(1,18)=1.42, p=0.25) or an interaction between group and assessment point on mean bleeding time (F(2,36)=0.59, p=56). Between T0 and T45, average bleeding times increased from 109.5seconds (95% confidence interval [CI]=94 to 125seconds) to 231.8seconds (95% CI=193 to 271seconds; p<0.0001) for both the ILE group and the NS control group. Between T45 and T60, bleeding times in the ILE group decreased by 31.5seconds (95% CI=-77 to 14seconds) and by 6seconds (95% CI=-67 to 55seconds) in the NS group (p=0.46). In the five ILE-only animals, the average bleeding time at T0 was 114seconds (95% CI=62 to 166seconds), which increased significantly at T15 to 237seconds (95% CI=161 to 313seconds; p=0.02). The anticoagulant effects of dabigatran are not reversed with ILE therapy. Although ILE itself significantly prolonged bleeding times, when administered to dabigatran-anticoagulated rats, bleeding times did not change significantly. There may be a complex interaction of ILE with dabigatran that this study was not able to elucidate.