Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes.

BACKGROUND: Inappropriate activation of hemostasis and inflammation may contribute to postoperative morbidity and mortality. The serine protease inhibitor, aprotinin, has been shown to prevent tissue and organ injury in laboratory and animal studies. In this retrospective analysis, we evaluated the relationship of aprotinin therapy with organ dysfunction in humans undergoing coronary artery bypass graft surgery (CABG). METHODS: Data from prospective randomized, double-blind, placebo-controlled studies evaluating the safety and efficacy of full-dose aprotinin (2 million KIU load, 2 million KIU pump prime, and 0.5 million KIU/h continuous infusion) to reduce blood loss and transfusion requirements in patients undergoing CABG (placebo, n = 861; aprotinin, n = 862) were examined retrospectively. Primary end-points were death, adverse cerebrovascular outcome, myocardial infarction (MI), and pharmacological interventions (inotropic drugs, vasopressors, and antiarrhythmics). RESULTS: Univariate analysis showed that relative to placebo, full-dose aprotinin therapy was associated with significant effects on the incidence of adverse cerebrovascular outcome (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.19-0.93; P = 0.03) and use of inotropic drugs (OR 0.79, 95% CI 0.65-0.97; P = 0.02), vasopressors (OR 0.74, 95% CI 0.61-0.90; P < 0.01), and antiarrhythmics (OR 0.79, 95% CI 0.65-0.96; P = 0.02), but not death (OR = 1.00, 95% CI 0.54-1.85; P = 1.0) or MI (OR 0.92, 95% CI 0.64-1.31; P = 0.6). Multivariate analysis confirmed results of univariate analysis. CONCLUSIONS: This retrospective analysis of data collected from prospective, randomized, placebo-controlled studies in CABG shows that full-dose aprotinin use was associated with a lower risk of adverse cerebrovascular outcomes and a reduced need for use of vasoactive drugs; the risk of death and perioperative MI was not affected by aprotinin therapy.

Increased creatine kinase MB level predicts postoperative mortality after cardiac surgery independent of new Q waves.

BACKGROUND: Recent consensus statements recommend cardiac enzyme release as the essential criterion for diagnosing myocardial infarction. However, the outcome implications of cardiac enzyme release in patients undergoing coronary artery bypass grafting are controversial. METHODS: Eight hundred patients were followed for 30 days after elective on-pump coronary artery bypass grafting in a multicenter, prospective, randomized trial of the anti-C5 complement antibody pexelizumab. Data from centralized electrocardiography and creatine kinase MB analyses were examined for any association with death or severe left ventricular dysfunction. RESULTS: More than half of the 800 patients had peak creatine kinase MB levels of more than 5 times the upper limit of 5 ng/mL set by the core laboratory. The median peak value was 29 ng/mL. The incidence of the combined outcome (death or severe left ventricular dysfunction) was 1.7% if the peak creatine kinase MB level was less than 25 ng/mL and 18.0% if 100 ng/mL or greater (P < .01). Similarly, the incidence of new Q-wave myocardial infarction was 3.9% if the peak creatine kinase MB level was less than 25 ng/mL and 30.6% if 100 ng/mL or greater (P < .01). In a multivariate analysis that included preoperative and intraoperative factors, as well as peak enzyme release and Q-wave myocardial infarction, the strongest predictor of the combined outcome was a peak creatine kinase MB level of 100 ng/mL or greater. New Q-wave myocardial infarction did not significantly predict the combined outcome. CONCLUSIONS: Increased postoperative peak creatine kinase MB level, especially when 20 times or more of the upper limit of normal, indicates increased risk of severe postoperative left ventricular dysfunction and mortality within 30 days of coronary artery bypass grafting. High peak enzyme level is a stronger predictor of adverse outcomes than is postoperative Q-wave myocardial infarction in this population.

Preliminary report of the effects of complement suppression with pexelizumab on neurocognitive decline after coronary artery bypass graft surgery.

BACKGROUND AND PURPOSE: Pharmacological modulation of complement activation recently has been postulated as a therapeutic target in the treatment of neurological injury. We hypothesized that pexelizumab, a humanized scFv monoclonal antibody directed against the C5 complement component, would limit deficits in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. METHODS: The Phase II Pexelizumab study was a 914-patient, double-blind, placebo-controlled, 65-center study of patients undergoing coronary artery bypass graft surgery. Patients were randomized to pexelizumab bolus, bolus plus infusion, or placebo. Neurological and neurocognitive functions were assessed as secondary endpoints at baseline and on postoperative days (POD) 4 and 30. Cognitive deficits were assessed with multivariable tests accounting for baseline cognition, age, diabetes, years of education, sex, elevated creatinine, history of myocardial infarction, neurological disorder or congestive heart failure, and cardiopulmonary bypass time. RESULTS: Pexelizumab had no statistically significant effect on the primary composite endpoint or on overall cognition. When domain specific effects were examined, a decline of at least 10% in the visuo-spatial domain was observed on POD 4 in 56% of patients receiving placebo compared with 40% receiving pexelizumab by bolus and infusion (P=0.003). Similarly, on POD 30, a 10% decline was present in 21% of patients in the placebo group versus only 12% of the drug bolus plus infusion group (P=0.016). No differences were seen between treatment groups in any of the other domains. CONCLUSIONS: Pexelizumab administration for 24 hours perioperatively had no effect on global measures of cognition but may reduce dysfunction in the visuo-spatial domain.

Segmental vascular resistance after mild controlled cortical impact injury in the rat.

In an effort to localize the site at which increased resistance occurs after brain trauma, pial arteriole diameter and pressure were assessed after mild controlled cortical impact (CCI) injury in rats using an open cranial window technique. The authors tested the hypothesis that an increase in resistance accompanied by vasoconstriction occurs at the level of the pial arterioles within the injured cortex of the brain. At 1 hour after mild CCI injury, ipsilateral cerebral blood flow was significantly reduced by 42% compared with sham injury (n = 4; < 0.05). Pial arteriole diameter and pressure remained unchanged. Resistance in the larger arteries (proximal resistance), however, was significantly greater after CCI injury (1.87 +/- 0.26 mm Hg/[mL. 100 g. min]) compared with sham injury (0.91 +/- 0.21 mm Hg/[mL. 100 g. min]; < 0.0001). Resistance in small vessels, arterioles, and venules (distal resistance) was also significantly greater after CCI injury (1.13 +/- 0.05 mm Hg/[mL. 100 g. min]) compared with sham injury (0.74 +/- 0.13 mm Hg/[mL. 100 g. min]; = 0.0001). The authors conclude that, at 1 hour after mild CCI injury, changes in vascular resistance comprise a 53% increase in the resistance distal to the area of injury and, surprisingly, a 105% increase in resistance in the arteries proximal to the injury site.

Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass.

BACKGROUND: During cardiac surgery requiring cardiopulmonary bypass, pro-inflammatory complement pathways are activated by exposure of blood to bio-incompatible surfaces of the extracorporeal circuit and reperfusion of ischemic organs. Complement activation promotes the generation of additional inflammatory mediators thereby exacerbating tissue injury. We examined the safety and efficacy of a C5 complement inhibitor for attenuating inflammation-mediated cardiovascular dysfunction in cardiac surgical patients undergoing cardiopulmonary bypass. METHODS: Pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a recombinant, single-chain, anti-C5 monoclonal antibody, was evaluated in a randomized, double-blinded, placebo-controlled, multicenter trial that involved 914 patients undergoing coronary artery bypass grafting with or without valve surgery requiring cardiopulmonary bypass. RESULTS: Pexelizumab was administered intravenously as a bolus (2.0 mg/kg) or bolus plus infusion (2.0 mg/kg plus 0.05 mg/kg/h for 24 hours), and inhibited complement activation. There were no statistically significant differences between placebo-treated and pexelizumab-treated patients in the primary endpoint (composite of death, or new Q-wave, or non-Q-wave [myocardial-specific isoform of creatine kinase > 60 ng/mL] myocardial infarction, or left ventricular dysfunction, or new central nervous system deficit). However, post hoc analysis revealed a reduction in the composite of death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) for the isolated coronary artery bypass grafting, bolus plus infusion subgroup on POD 4 (p = 0.007) and on POD 30 (p = 0.004). CONCLUSIONS: Pexelizumab had no statistically significant effect on the primary endpoint. However, the reduction in death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) as revealed in the post hoc analysis in the isolated coronary artery bypass grafting bolus plus infusion subpopulation, suggests that further investigation of anti-C5 therapy for ameliorating complement-mediated inflammation and myocardial injury is warranted.

Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation.

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin-dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications.

Pharmacologic C5-complement suppression reduces blood loss during on-pump cardiac surgery.

BACKGROUND: Inflammation contributes to morbidity following on-pump cardiac surgery. Complement activation during cardiopulmonary bypass has been associated with the postoperative bleeding and tissue injury. This study examines the pharmacology and impact on blood loss of complement C5 suppression with pexelizumab in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: Pexelizumab, a humanized monoclonal antibody single-chain fragment that binds to the human C5 complement component, was studied in a Phase II multicentered clinical trial. CABG (n = 800) and CABG with concomitant valve surgery (n = 114) patients were evaluated. Patients were randomized to either: pexelizumab bolus (2.0 mg/kg) + placebo infusion; pexelizumab bolus (2.0 mg/kg) + pexelizumab infusion (0.05 mg/kg/hour for 24 hours); or placebo bolus + placebo infusion. Pharmacology, chest tube drainage, and transfusion requirements were assessed. RESULTS: Mean maximum pexelizumab serum concentration was similar for bolus and bolus + infusion-treated patients. Complement-dependent serum hemolytic activity was completely suppressed within 1 hour following pexelizumab bolus, however, suppression was maintained for a longer duration in the bolus + infusion compared to the bolus-only treated patients. A reduction in chest tube drainage was observed for all pexelizumab-treated patients, although transfusion of blood products was similar across all study groups. CONCLUSION: Pexelizumab administration inhibits complement-dependent hemolytic activity and is associated with a reduction in postoperative chest tube drainage in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Further, clinical studies are needed to assess the value of complement attenuation in this setting.

Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes.

BACKGROUND: Platelet (PLT) transfusions are administered in cardiac surgery to prevent or treat bleeding, despite appreciation of the risks of blood component transfusion. The current analysis investigates the hypothesis that PLT transfusion is associated with adverse outcomes associated with coronary artery bypass graft surgery (CABG). STUDY DESIGN AND METHODS: Data originally collected during double-blind placebo-controlled phase III trials for licensure of Trasylol (aprotinin injection) were retrospectively analyzed. Adverse outcome data of patients (n = 1720) that received, and did not receive, perioperative PLT transfusion were compared. Logistic regression analysis was used to assess the association of perioperative adverse events with PLT transfusion. Propensity scoring analysis was used to verify results of the logistic regression. RESULTS: Patients receiving PLTs were more likely to have prolonged hospital stays, longer surgeries, more bleeding, re-operation for bleeding, and more RBC transfusions, and less likely to have full-dose aprotinin administration. Adverse events were statistically more frequent in patients that received one or more PLT transfusion. Logistic regression analysis showed that PLT transfusion was associated with infection, vasopressor use, respiratory medication use, stroke, and death. Propensity scoring analysis confirmed the risk of PLT transfusion. CONCLUSIONS: PLT transfusion in the perioperative period of CABG was associated with increased risk for serious adverse events. PLT transfusion may be a surrogate marker for sicker patients and have no causal role in the outcomes observed. However, a direct contribution to outcomes remains possible.

Transesophageal echocardiography interpretation: a comparative analysis between cardiac anesthesiologists and primary echocardiographers.

UNLABELLED: Diagnostic interpretation of intraoperative transesophageal echocardiography (TEE) examinations may vary, particularly when the echocardiographer is also the anesthesiologist. We therefore evaluated the concordance of TEE interpretation as part of a process of continuous quality improvement (CQI). Ten cardiac anesthesiologists participating in a CQI program conducted 154 comprehensive TEE examinations, each consisting of 16 major fields describing cardiac anatomy and function. These examinations were subsequently interpreted off-line by two primary echocardiographers (a radiologist and a cardiologist). Agreement was assessed using the kappa coefficient and percent agreement. Overall kappa and percent agreement were 0.58 and 83% for anesthesiologists versus radiologist, 0.57 and 80% for anesthesiologists versus cardiologist, and 0.60 and 82% for radiologist versus cardiologist. Anesthesiologists with longer than 5 yr of TEE experience had higher levels of agreement with the radiologist when assessing the aorta, right atrium, pulmonary vein flow, transmitral flow, and fractional area change. Cardiac anesthesiologists supported by a CQI program interpret TEE examinations at a level comparable with physicians whose primary practice is echocardiography. Thus, the anesthesiologist and the intraoperative echocardiographer need not be mutually exclusive. IMPLICATIONS: Interpretation of intraoperative transesophageal echocardiograms can be reliably performed by cardiac anesthesiologists.