Chad F. Brouse

Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of ϵ-aminocaproic acid and aprotinin

OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

In vitro hemocompatibility studies of drug-loaded poly-(L-lactic acid) fibers

Our objective was to evaluate the hemocompatibility of biodegradable stent fibers, employing a closed-loop circulation system filled with human blood. We also investigated the effects of the anti-inflammatory and anti-proliferative drugs curcumin and paclitaxel, incorporated into stent fibers. Fresh whole blood was circulated in four parallel closed-loop systems: the empty tube circuit (control) and tubes containing either a PLLA fiber coil (PLLA), a curcumin-loaded PLLA coil (C-PLLA) or a paclitaxel-loaded PLLA coil (P-PLLA). The influence of PLLA fiber, alone or loaded with drug incorporated during melt-extrusion, on leukocyte and platelet adhesion and activation was determined by flow cytometry. The effects of blood flow and fiber properties on cell deposition were assessed by scanning electron microscopy (SEM). The flow cytometry results clearly demonstrated that PLLA triggers blood cell activation at the site of deployment, as shown by increases in CD11b, CD62P and leukocyte-platelet aggregates, compared to controls. Curcumin and paclitaxel treatments both significantly reduced leukocyte and platelet activation and adhesion to PLLA fibers, as shown by flow cytometry and SEM. Activated leukocytes and platelets revealed significantly lower CD11b and CD62P receptor binding for C-PLLA compared with PLLA alone, and slightly lower for P-PLLA. Reductions in platelet-leukocyte aggregates were observed as well. In addition, there was less leukocyte and platelet adhesion to C-PLLA, compared with PLLA fiber controls, as shown by SEM. A continuous linear thrombus, composed of platelets, leukocytes, red blood cells and fibrin was occasionally detected along the line of tangency between the coil and the tube wall. Flow separation and eddying, proximal and distal to the line of tangency of coil and tube, is thought to contribute to this deposit. Curcumin was more effective than paclitaxel in reducing leukocyte and platelet activation and adhesion to PLLA stent fibers in this setting. However there was evidence of paclitaxel degeneration during melt extrusion that may have inhibited its effectiveness. Incorporation of the anti-inflammatory and anti-proliferative drug curcumin into bioresorbable stent fibers is proposed to prevent thrombosis and in-stent restenosis.

Reductions in platelet contractile force correlate with duration of cardiopulmonary bypass and blood loss in patients undergoing cardiac surgery

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.

Effects of ε-Aminocaproic Acid and Aprotinin on Leukocyte–Platelet Adhesion in Patients Undergoing Cardiac Surgery

BackgroundThe administration of aprotinin during cardiopulmonary bypass (CPB) is hypothesized to decrease activation of leukocytes and platelets and possibly reduce their adhesion. Although &egr;-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. MethodsThirty-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. ResultsPlatelet 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. ConclusionsEACA 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.

Monocyte Activation in On-Pump Versus Off-Pump Coronary Artery Bypass Surgery

OBJECTIVE 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. DESIGN Prospective, controlled, clinical study. SETTING University-affiliated veterans affairs hospital and laboratory. PARTICIPANTS Twenty-two patients scheduled to undergo primary CABG surgery (11 on-pump and 11 off-pump). INTERVENTIONS 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. MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS 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.

Proximal Extremity Weakness and Altered Mental Status

History of Present Illness The patient presented initially to the emergency department (ED) 6 days prior to the current visit with the complaint of progressive weakness and swelling of both arms and upper legs. She stated that she had experienced a similar episode of weakness 1 year earlier that coincided with a “flare” of her polymyositis. Her primary care physician had recently tapered her prednisone to 5 mg/day 1 month earlier (which had previously been 40 mg/day). During this recent ED visit, notable proximal muscle weakness was noted, and she reported periodic difficulty talking because her tongue was numb. The patient was subsequently diagnosed with recurrent polymyositis, her prednisone dose was increased to 60 mg/day, and she was discharged to home. She was brought back to the ED by her family (this visit) with similar symptoms and altered mental status and was hospitalized.