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Anesthesia and analgesia 07/2010; 111(1):74-5. · 3.08 Impact Factor
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Journal of cardiothoracic and vascular anesthesia 11/2009; 24(3):467-8. · 1.06 Impact Factor
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ABSTRACT: Until recently, aprotinin was the only antifibrinolytic drug with a licensed indication in cardiac surgery in the United States. The most popular alternative, epsilon-aminocaproic acid (EACA), has not been adequately compared with aprotinin. We undertook this study to test the hypothesis that EACA, when dosed appropriately, is not inferior to aprotinin at reducing fibrinolysis and blood loss.
Seventy-eight patients scheduled for primary, isolated coronary artery bypass graft surgery were randomly assigned to receive "full Hammersmith" dose aprotinin, high dose EACA (100 mg/kg initial loading dose, 5 g in the pump prime solution, 30 mg x kg(-1) x h(-1) maintenance infusion) or equal volumes of a saline-placebo in a double-blind trial. Reductions in peak D-dimer formation (a measure of fibrinolysis) and 24-h chest tube drainage (CTD) were the primary end points by which noninferiority of EACA was tested. The noninferiority limit was set at a 30% increase in peak D-dimer formation (a difference of 250 microg/mL) and 24-h CTD (a difference of 350 mL) relative to aprotinin.
The between-group differences (EACA versus aprotinin) in peak D-dimer formation (-3.58 microg/L, 95% CI -203 to 195 microg/L) and 24-h CTD (67 mL, 95% CI -90 to 230 mL) were within the predetermined noninferiority margins (250 microg/mL and 350 mL, respectively) and satisfied the criteria for noninferiority. Compared with saline, significant between-group reductions in peak D-dimer formation were observed using EACA (589 microg/L, 95% CI 399-788 microg/L; P < 0.0001) and aprotinin (585 microg/L, 95% CI 393-778 microg/L; P < 0.0001). Similar reductions in 24 h CTD were also seen using EACA (239 mL, 95% CI 50-415 mL; P < 0.05) and aprotinin (323 mL, 95% CI 105-485 mL; P < 0.05) compared with saline. Plasma EACA levels were maintained well above a target of 260 microg/mL.
When dosed in a pharmacologically guided manner, EACA is not inferior to aprotinin in reducing fibrinolysis and blood loss in patients undergoing primary, isolated coronary artery bypass surgery.
Anesthesia and analgesia 07/2009; 109(1):15-24. · 3.08 Impact Factor
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Anesthesia and analgesia 11/2008; 107(4):1155-7. · 3.08 Impact Factor
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ABSTRACT: The use of established heparin protocols when heparin-induced thrombocytopenia (HIT) antibodies are negative is currently recommended for the management of patients with previous HIT who require cardiac surgery. Routine preoperative testing for HIT antibodies using an anti-PF4/heparin enzyme-linked immunosorbent assay (ELISA) introduces the problem of detecting nonpathogenic HIT antibodies, which can lead to a false diagnosis of the presence of platelet-activating antibodies. Our case report demonstrates the clinical utility of a newer confirmatory procedure performed using high dose heparin. We use this procedure in situations in which pretest probability is low (remote HIT) and the anti-PF4/heparin ELISA test results are weak to moderately positive (absorbance 0.4-1.0).
Anesthesia and analgesia 08/2008; 107(2):379-81. · 3.08 Impact Factor
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ABSTRACT: Monocyte activation plays a key role in amplifying both inflammatory and coagulopathic sequelae in patients undergoing on-pump coronary artery bypass graft (CABG) surgery. Off-pump CABG diminishes, but does not eliminate, the systemic inflammatory response and its influence on monocyte activation remains unclear. This study was performed to determine if off-pump CABG suppresses all features of monocyte activation.
Prospective, controlled, clinical study.
University-affiliated veterans affairs hospital and laboratory.
Twenty-two patients scheduled to undergo primary CABG surgery (11 on-pump and 11 off-pump).
On-pump and off-pump CABG surgery was performed via median sternotomy. Anticoagulation and heparin reversal were identical. Moderate hypothermia (28 degrees-30 degrees C) was used for on-pump CABG surgery, whereas temperature was maintained above 35.5 degrees C for off-pump CABG. No antifibrinolytic agents were used.
Perioperative monocyte changes were assessed by using cellular (CD11b, monocyte-platelet conjugates) and secreted markers (plasma IL-6, IL-8, and IL-10) measured at 6 time points before, during, and after CABG surgery. Off-pump CABG surgery completely blocked the increases in monocyte CD11b expression (p < 0.001) and monocyte-platelet conjugate formation (p < 0.001) observed in the on-pump group. In contrast, plasma interleukin levels were significantly elevated in both groups, although off-pump CABG surgery resulted in lower levels (p < 0.001) and a delayed time course.
Off-pump CABG surgery attenuates monocyte secreted cytokines and completely suppresses activation-dependent monocyte cell-surface changes (CD11b, monocyte-platelet conjugate formation). Whether these pathophysiologic differences in monocyte activation translate into a reduction in adverse events after CABG surgery warrants a larger, randomized, outcomes study.
Journal of cardiothoracic and vascular anesthesia 06/2008; 22(3):361-8. · 1.06 Impact Factor
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Philip E Greilich
The Annals of thoracic surgery 04/2008; 85(3):852-3. · 3.74 Impact Factor
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ABSTRACT: Recombinant hirudin (r-hirudin) is being used increasingly for therapeutic anticoagulation in patients with heparin-induced thrombocytopenia undergoing cardiovascular surgery. Although multiple laboratory methods are available for measuring r-hirudin, the ecarin clotting time (ECT) is the most commonly used for this purpose. Ecarin (extracted from snake venom) converts prothrombin to meizothrombin, which promotes clot formation. Direct thrombin inhibitors, like r-hirudin, bind meizothrombin and yield a linear, dose-dependent prolongation of ECT. Low levels of prothrombin and fibrinogen in plasma samples can lead to higher ECT; suggesting falsely elevated r-hirudin levels. A modified ECT assay with prothrombin and fibrinogen in excess was optimized using an orthogonal array method to eliminate the variations in patients' plasma prothrombin and/or fibrinogen levels for accurate determinations of plasma r-hirudin levels. By using the modified ECT assay, falsely elevated r-hirudin levels can be avoided in patients undergoing cardiopulmonary bypass, thus providing reliable and accurate r-hirudin monitoring in this clinical setting.
American Journal of Clinical Pathology 03/2006; 125(2):290-5. · 2.60 Impact Factor
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ABSTRACT: We investigated poly(L-lactic acid) (PLLA) fibers and coils, simulating stents and the influence of impregnation with curcumin, a non-steroidal anti-inflammatory drug, intended to reduce the pro-inflammatory property of these implants. Fibers obtained by melt extrusion of 137 kDa PLLA resin containing 10% curcumin (C-PLLA) exhibited a stable curcumin release rate for periods up to 36 days. Curcumin increased the fiber tensile strength at break and decreased embrittlement vs. controls in 36 day 37 degrees C saline incubation. A mouse peritoneal phagocyte model was employed to test the anti-inflammatory properties of C-PLLA fibers in vitro. Myeloperoxidase and non-specific esterase activity assays were performed for adherent cells (polymorphonuclear leukocytes (PMN) and macrophages (MPhi), respectively). PMN and MPhi adhesion to C-PLLA fibers were significantly reduced compared to control PLLA fibers (2.6 +/- 0.91) x 10(5) vs. (5.6 +/- 0.67) x 10(5) PMN/cm2 and (3.9 +/- 0.23) x 10(3) vs. (9.1 +/- 0.7) x 10(3) MPhi/cm2 (P < 0.05), respectively. In addition, superoxide release in the phagocyte pool contacting C-PLLA fibers was 97% less than that for PLLA controls. A fresh human whole blood recirculation system was employed to analyze cell adhesion under flow conditions, employing scanning electron microscopy (SEM). Reduced adhesion of cells on C-PLLA fiber coils vs. controls was observed. These in vitro studies demonstrate that bulk curcumin impregnation can reduce the inflammatory response to bioresorbable PLLA fibers, whilst improving mechanical properties, thereby suggesting curcumin loading may benefit PLLA-based implants.
Journal of Biomaterials Science Polymer Edition 01/2005; 16(3):353-70. · 1.69 Impact Factor
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ABSTRACT: The administration of aprotinin during cardiopulmonary bypass (CPB) is hypothesized to decrease activation of leukocytes and platelets and possibly reduce their adhesion. Although epsilon-aminocaproic acid (EACA) shares the ability of aprotinin to inhibit excessive plasmin activity after CPB, its effect on leukocyte and platelet activation and leukocyte-platelet (heterotypic) adhesion is largely unknown. This study was performed to determine the relative effectiveness of the antifibrinolytics, aprotinin and EACA, at reducing leukocyte and platelet activation and leukocyte-platelet conjugate formation in patients undergoing CPB.
Thirty-six patients scheduled to undergo cardiac surgery with CPB were randomized in a double-blind fashion to receive EACA, aprotinin, or saline (placebo). Markers of plasmin activity (D-dimer concentrations), platelet activation (CD62P), leukocyte activation (CD11b), and leukocyte-platelet adhesion (monocyte- and neutrophil-platelet conjugates) were measured before, during, and after CPB.
Platelet CD62P (P-selectin), monocyte CD11b, and monocyte-platelet conjugates were all significantly increased (compared with baseline) in the saline group during and after CPB. Despite equivalent reductions in D-dimer formation in patients receiving EACA (P < 0.0001) and aprotinin (P < 0.0001), decreases in platelet CD62P and monocyte CD11b expression were incomplete (not significantly different from saline control). In contrast, peak monocyte-platelet conjugate formation was significantly reduced by both EACA (P = 0.026) and aprotinin (P = 0.039) immediately after CPB.
EACA seems to be as effective as aprotinin at reducing peak monocyte-platelet adhesion after CPB. Furthermore, inhibition of excessive plasmin activity seems to influence monocyte-platelet adhesion. The findings suggest that monocyte-platelet conjugate formation may be a useful marker of monocyte and platelet activation in this clinical setting.
Anesthesiology 03/2004; 100(2):225-33. · 5.36 Impact Factor
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ABSTRACT: Background: The administration of aprotinin during cardiopulmonary bypass (CPB) is hypothesized to decrease activation of leukocytes and platelets and possibly reduce their adhesion. Although ε-aminocaproic acid (EACA) shares the ability of aprotinin to inhibit excessive plasmin activity after CPB, its effect on leukocyte and platelet activation and leukocyte–platelet (heterotypic) adhesion is largely unknown. This study was performed to determine the relative effectiveness of the antifibrinolytics, aprotinin and EACA, at reducing leukocyte and platelet activation and leukocyte–platelet conjugate formation in patients undergoing CPB.
Anesthesiology 01/2004; 100(2):225-233. · 5.36 Impact Factor
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ABSTRACT: Aprotinin is a broad-spectrum serine protease inhibitor that has been shown to attenuate the systemic inflammatory response in patients undergoing cardiac surgery with cardiopulmonary bypass. Although epsilon-aminocaproic acid is similar to aprotinin in its ability to inhibit excessive fibrinolysis (ie, plasmin activity and D-dimer formation), its ability to influence proinflammatory cytokine production remains unclear. This study was designed to compare the effects of epsilon-aminocaproic acid and aprotinin on plasma levels of interleukin-6 and interleukin-8 during and after cardiopulmonary bypass.
Sixty patients were randomized in a double-blind fashion to receive epsilon-aminocaproic acid, aprotinin, or saline (placebo) in similar dosing regimens (loading dose, pump prime, and infusion). Arterial blood samples were collected before, during, and after cardiopulmonary bypass, and plasma levels of D-dimer, interleukin-6, and interleukin-8 were measured. Data were analyzed using repeated measures analysis of variance.
Both epsilon-aminocaproic acid and aprotinin administration resulted in significant (P <.05) reductions in D-dimer and interleukin-8 levels compared with saline. These reductions in D-dimer and interleukin-8 levels did not differ between the 2 drug-treated groups. The effect of these two antifibrinolytic agents on interleukin-6 was qualitatively similar to that noted with interleukin-8 but did not reach statistical significance.
When dosed in a similar manner, epsilon-aminocaproic acid seems to be as effective as aprotinin at reducing interleukin-6 and interleukin-8 levels in patients undergoing primary coronary artery bypass graft surgery. These data indicate that suppression of excessive plasmin activity or D-dimer formation or both may play an important role in the generation of proinflammatory cytokines during and after cardiopulmonary bypass.
Journal of Thoracic and Cardiovascular Surgery 11/2003; 126(5):1498-503. · 3.41 Impact Factor
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ABSTRACT: Aprotinin interferes with heparin binding to platelets and decreases blood loss during cardiopulmonary bypass (CPB). Heparin abolishes platelet force during CPB, and the extent of platelet force recovery after protamine administration appears to correlate with blood loss. This study assessed the effect of aprotinin on heparin suppression of platelet force.
Platelet force was measured using the Hemodyne Hemostasis Analyzer. Clots were formed from platelet-rich plasma (PRP) by the addition of batroxobin and 10 mM CaCl(2). Clotting conditions included pH 7.4, ionic strength 0.15 M, fibrinogen level 1 mg/ml and 75,000 platelets/microl.
After 1200 s of clotting, force was reduced from 7110+/-1190 to 450+/-450 dyn by 0.2 U/ml of heparin. Platelet force in aprotinin [20 microg/ml (140 KIU/ml)] containing PRP was not suppressed by heparin addition (7480+/-2410 dyn). Aprotinin [40 microg/ml (280 KIU/ml)] addition to previously heparinized plasma counteracted heparin force suppression. Aprotinin (40 microg/ml) increased platelet force from 5630 to 11,138+/-562 in PRP devoid of heparin. Aprotinin did not affect thrombin activity, fibrin structure, platelet aggregation or secretion.
Aprotinin counteracts heparin suppression of platelet force and enhances platelet force in the absence of heparin. Aprotinin-heparin-platelet interactions may help explain aprotinin's ability to reduce blood loss during CPB.
Thrombosis Research 12/2002; 108(2-3):161-8. · 2.44 Impact Factor
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ABSTRACT: Blood loss secondary to platelet dysfunction is known to be increased when the duration of cardiopulmonary bypass (CPB) is prolonged. The ability to correlate alterations in platelet function with the duration of bypass and early postoperative blood loss, however, has remained elusive. Platelet contractile force, a novel measure of platelet-mediated clot retraction, is known to be reduced following cardiac surgery and blockade of platelet adhesion receptors. The aim of this study was to determine if alterations in platelet contractile force (measured using whole blood) correlated with the duration of CPB and early postoperative blood loss. Thirty patients were entered into a study designed to measure platelet function before, during, and after CPB. Platelet aggregometry and surface expression of CD42b and CD61 were also measured (using whole blood) in a subset of subjects (n=10) to further characterize the intrinsic structural and functional defects induced by CPB. Reductions in platelet contractile force had a significant correlation with duration of CPB (r=0.564; P=0.002) and early blood loss (r=0.545; P=0.003). Although decreases in platelet contractile force and aggregation both correlated with CPB time in the smaller subset of patients tested, only platelet contractile force correlated with decreases in CD42b, CD61 and blood loss. The results of this study suggest that prolongation of CPB is related to increasing degrees of platelet dysfunction and that reductions in platelet contractile force are related to decreases in platelet adhesion receptors and early postoperative blood loss.
Thrombosis Research 04/2002; 105(6):523-9. · 2.44 Impact Factor
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ABSTRACT: Point-of-care testing (POCT) of coagulation parameters can help optimize transfusion practice in cardiac surgery. Antifibrinolytic agents may interfere with the laboratory and/or POCT coagulation assays. This randomized controlled study compared coagulation parameters obtained from a whole blood POCT coagulation device with a typical laboratory instrument in cardiac surgery patients receiving aprotinin, epsilon-aminocaproic acid, or normal saline before undergoing cardiopulmonary bypass. Aliquots of arterial blood samples from 42 patients were collected perioperatively, and their prothrombin times (PTs) and activated partial thromboplastin times (aPTTs) were measured by POCT and laboratory instrumentation. Linear regression and error analyses were used for the method comparison. For PT, the POCT device compared favorably with the laboratory method. For aPTT, the POCT device did not compare well with the laboratory method. Treatment with antifibrinolytic agents does not interfere with determination of PT.
American Journal of Clinical Pathology 02/2002; 117(1):74-8. · 2.60 Impact Factor
