Background
A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA) has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remain unexplored. Accordingly, the present study developed a fluorogenic-microdialysis system to measure in-vivo dynamic changes in PLact following TXA administration in a large animal model.
Methods
Pigs (25–35kg) were randomly assigned to receive TXA (30mg/kg, diluted into 50cc normal saline; n=9) or vehicle (50cc normal saline; n=7) in which microdialysis probes were placed in the liver, myocardium, kidney and quadricep muscle compartments. The microdialysate infusion contained a validated plasmin specific fluorogenic peptide. The fluorescence emission (Standard Fluorogenic Units; SFU) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline, 30, 60, 90 and 120 minutes following TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach.
Results
With respect to vehicle values, TXA reduced plasma PLact at 30 minutes post infusion by more than 110 SFU (p<0.05). Specifically, there was a decrease in liver PLact at 90 and 120 minutes post TXA infusion of greater than 150 (p<0.05) and 175 (p<0.05) SFU, respectively. The decline in liver PLact occurred 60 minutes after the maximal decline in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 minutes.
Conclusions
Using a large animal model and in-vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.
Background-Epsilon aminocaproic acid (EACA) is used in cardiac surgery to modulate plasmin activity (PLact). The present study developed a fluorogenic-microdialysis system to measure invivo region specific temporal changes in PLact following EACA administration.
Background-Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis following cardiac surgery. However, aprotinin was empirically dosed, and while the pharmacological target was the inhibition of plasmin activity (PLact) this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic-microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact.
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