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Direct Thrombin Inhibition With Bivalirudin For Cardiopulmonary Bypass Causes A Decrease In The Inflammatory Response In comparison To Indirect Inhibition With Heparin
S. M. Eldaif, K. A. Tanaka, J. Deneve, C. J. Mutrie, N. Wang, F. Szlam, S. L. Schmarkey, S. Katzmark, R. Jiang, Z. Zhao, R. A. Guyton, J. Vinten-Johansen. Emory University, Atlanta, GA,
BACKGROUND:Cardiopulmonary bypass(CPB)is associated with marked thrombin generation which stimulates circulating pro-inflammatory mediators. Thrombin is also a potent activator of endothelium and neutrophil (PMN) recruitment. Heparin, the gold standard anticoagulant for CPB, has some inherent anti-inflammatory properties. While achieving anticoagulation by activating antithrombin III (AT-III), heparin may also block AT-III innate anti-inflammatory effect. This lead to question whether direct thrombin inhibitors, such as bivalirudin, may be more effective at attenuating thrombin-mediated inflammation as their anti-inflammatory profile is unknown. The purpose of this study was to determine whether bivalirudin reduces the inflammatory response during CPB compared to heparin.
METHODS:Using a porcine model of moderate hypothermic (28°C) CPB, 9 pigs (20 - 25 kg) were randomized to two groups: 1) indirect thrombin inhibitor group using heparin (n=5), and 2) direct thrombin inhibitor group using bivalirudin (n=4). Generation of the inflammatory markers tumor necrosis factor alpha(TNF-α) and interleukin 6(IL-6), were compared at baseline, the end of 90 minutes of CPB and 60 minutes after discontinuation of CPB. Left ventricular (LV) P-selectin (immunohistochemistry) and PMN counts in subendocardial and subepicardial regions of LV myocardium were also compared as markers of tissue activation. Results are presented as mean ± standard error of the mean.
RESULTS:All baseline variables were comparable between groups. Plasma TNF-α was significantly lower in the bivalirudin group compared to the heparin group during CPB(1706.5±344.9 vs. 12778.2±2363.7 pg/mL, P= 0.005) and after CPB (1073±524.6 vs. 8482.2±2487.7 pg/mL, P=0.036). Plasma IL-6 levels were also significantly lower post CPB in the bivalirudin group(2132.7±739.6 vs. 7043±1037.1 pg/mL, P=0.008). PMN accumulation in LV myocardium was less in the bivalirudin group compared to the heparin group both in the subendocardium(39.0 ± 0.6 vs. 54.3 ± 1.3cells/8 high powered fields, P<0.001) and subepicardium(69.25 ± 1.9 vs. 78.5 ± 1.7 cells/8 high powered fields, P<0.01). P-selectin expression was less in the bivalirudin group compared to the heparin group looking at the percentage of positive peroxidase brown reaction product of 50 vessels per slide in 4 hearts per group(53±2.6 vs. 43.3±2.4%, P=0.049).
CONCLUSIONS:The inflammatory response to CPB is significantly attenuated when the direct thrombin inhibitor bivalirudin is used in comparison to heparin. This suggests that bivalirudin may be an anticoagulant with better anti-inflammatory profile than heparin and may be useful in more than patients with HIT undergoing CPB.
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