The influence of antithrombin substitution on heparin sensitivity and activation of hemostasis during coronary artery bypass graft surgery: a dose-finding study.

BACKGROUND: Cardiopulmonary bypass is associated with a high degree of hemostatic system activation. Supplementation of antithrombin (AT) may attenuate this activation and increase a patient's susceptibility to heparin. However, the appropriate dosage of AT has not been defined. We sought to determine the dosage of AT concentrate necessary to achieve >100% AT activity at the end of cardiac surgery and the influence of AT on heparin sensitivity. METHODS: Forty-one patients were included. Thirty consecutive patients undergoing primary coronary artery bypass graft surgery with cardiopulmonary bypass were assigned to 3 groups of increasing dosages of AT concentrate. Eleven additional patients served as controls. AT activity and molecular markers of thrombin generation were determined, and heparin sensitivity was calculated. RESULTS: A median amount of 36.5 U (19.0; 42.8), 47.0 U (41.3; 61.6), and 50.0 U (47.4; 66.6) AT concentrate/kilogram body weight in the low, medium, and high AT group, respectively, was administered. At the end of surgery, AT activity with substitution was 84% (77; 111), 110% (92; 120), and 104% (97; 120) (median [25th; 75th percentile]), respectively, compared with 63% (49; 79) in controls (P < 0.05 all substitution groups versus control). Heparin sensitivity increased from 1.29 (1.17; 1.66) s/U heparin/kg in the control group to 2.02 (1.43; 3.65), 2.56 (1.52; 3.64), 1.72 (1.24; 2.66) s/U heparin/kg in the groups with substitution (P < 0.05 all substitution groups versus control). Compared with preoperative values, AT activity decreased during the postoperative period in all patients with a nadir on postoperative day 3 (P < 0.05 compared with baseline except for the medium AT group). Corresponding to this decrease, an increase in prothrombin fragment 1+2 and d-dimer could be observed postoperatively. DISCUSSION: High dosages of AT were required to preserve physiologic AT activity during coronary artery bypass graft surgery and to significantly enhance heparin sensitivity, respectively. However, a significant decrease in AT activity, accompanied by high levels of thrombin generation, was encountered up to 5 days postoperatively.

Enhanced thrombin generation after cardiopulmonary bypass surgery.

BACKGROUND: Thrombin generation has a key role in the pathophysiology of hemostasis. Research has focused on the intraoperative course of hemostasis, while little is known about postoperative hemostatic activation. Thrombin generation assays quantify the potential for thrombin generation ex vivo and may be useful for determining hypercoagulability. The thrombin dynamics test (TDT) assesses the initial kinetics of thrombin formation. We hypothesized that there would be an increase in thrombin generation as well as thrombin capacity after cardiac surgery. METHODS: Two hundred twenty patients undergoing primary coronary artery bypass grafting or aortic valve replacement (AVR) surgery were prospectively enrolled. Patients undergoing AVR received warfarin beginning on the second postoperative day. In addition to prothrombin fragment (F(1+2)), TDT, d-dimer, and troponin T were assessed. Blood samples were obtained preoperatively, at the end of the operation, 4 hours postoperatively, and the morning of postoperative days (PODs) 1, 3, and 5. The primary end point was the change of thrombin dynamics on POD 1. RESULTS: In all patients, F(1+2) peaked at the end of the operation and remained significantly elevated until POD 5. Compared with baseline and after an initial decrease, TDT was found to be significantly elevated on POD 1. After coronary artery bypass graft, TDT remained significantly elevated, whereas in AVR patients with warfarin treatment, TDT was significantly reduced on PODs 3 and 5. CONCLUSIONS: After cardiac surgery, thrombin generation continues, accompanied by a high thrombin-generating capacity and elevated fibrinogen levels. This constellation suggests a marked procoagulopathic state in the postoperative period with the potential to aggravate the risk of thromboembolic complications. Warfarin treatment after AVR significantly reduced thrombin-generating capacity.

Tranexamic acid and aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic acid or aprotinin.

BACKGROUND: Antifibrinolytics are widely used in cardiac surgery to reduce bleeding. Allogeneic blood transfusion, even in primary cardiac operations with low blood loss, is still high. In the present study we evaluated the impact of tranexamic acid compared to aprotinin on the transfusion incidence in cardiac surgical patients with low risk of bleeding. METHODS: This prospective, randomized, double-blind study included 220 patients undergoing primary coronary artery revascularization (coronary artery bypass grafting [CABG]) or aortic valve replacement (AVR). Randomized in blocks of 20, patients received either tranexamic acid (approximately 6 g) or full-dose aprotinin (approximately 5-6 x 10(6) Kallikrein Inhibiting Units). Transfusion was guided by a strict transfusion algorithm. Molecular markers of hemostasis were determined to assess differences in the mode of action of the two drugs. Primary end-points were the incidence of allogeneic red cell transfusion and 24-h postoperative blood loss. Data were analyzed according to the intention-to-treat principle and compared using the chi(2) and Mann-Whitney U-test. RESULTS: Two-hundred-twenty patients were enrolled (CABG: 134, AVR: 86). In the aprotinin Group 47% of patients received allogeneic blood during the hospital stay as compared to 61% in the tranexamic acid group (P = 0.036). Aprotinin conferred a 23% reduction in allogeneic transfusion risk (RR 0.77, 95% CI 0.53-0.88). Overall, no significant difference in postoperative bleeding was observed, although 24-h blood loss was reduced in aprotinin-treated CABG patients (500, 350-750 mL vs 650, 475-875 mL (median, 25th-75th percentile); P = 0.039). Despite the lower transfusion rate, the hemoglobin concentration on the first postoperative day was higher in the aprotinin group (11.3, 9.9-12.1 vs 10.6, 9.9-11.6 mg/dL; P = 0.023). The fibrinolytic activity at the end of operation determined by D-Dimer was comparable in both groups. (0.15, 0.11-0.17 mg/L [aprotinin] versus 0.18, 0.12-0.24 mg/L [tranexamic acid]). The activated partial thromboplastin time was prolonged up to 4 h postoperatively in the aprotinin group, while the heparin requirement was reduced: 19% of the patients in the aprotinin group and 45% in the tranexamic acid group received at least one additional bolus heparin during cardiopulmonary bypass (P < 0.001). Troponin T levels postoperatively and on postoperative day 1 were significantly higher in the tranexamic acid group (P = 0.017). No differences in renal, cardiac, or mortality outcomes were observed. CONCLUSION: Considering the rate of transfusion of red blood cells, tranexamic acid was slightly inferior in patients undergoing CABG, but there was no difference in patients receiving AVR. Tranexamic acid seems to be less effective in operations with increased bleeding such as CABG. Clinical benefit depends on specific patient and institution characteristics (ClinicalTrials.gov NCT00396760).

Effects of aprotinin dosage on renal function: an analysis of 8,548 cardiac surgical patients treated with different dosages of aprotinin.

BACKGROUND: The nonspecific serine protease inhibitor aprotinin is widely used in cardiac surgery to limit bleeding. Recently, concerns about the safety of this drug were raised, especially regarding impaired renal outcome. This event rate was supposed to be dose dependent. METHODS: In this observational study, the authors analyzed prospectively collected data of a single-center cardiac-anesthetic database. Adult patients treated with various dosages of aprotinin were evaluated. Logistic regression analysis identified independent predictors of renal outcome. The primary endpoint was a composite of novel postoperative renal failure requiring hemodialysis, an increased postoperative creatinine plasma concentration of 2 mg/dl or greater, or a difference between maximal postoperative and preoperative plasma creatinine of 0.7 mg/dl or greater. RESULTS: The study analyzed 8,548 patients. Multiple logistic regression (c index = 0.861) did not show a significant association between aprotinin dosage and renal outcome, as did the bootstrap procedure (odds ratio, 0.98; confidence interval, 0.90-1.07). The most relevant predictor was a preoperatively elevated creatinine concentration (odds ratio, 11.4; confidence interval, 9.05-14.3). Patients with postoperative renal impairment or failure were at higher preoperative risk and/or underwent more complex procedures. In subgroups of patients with preoperatively impaired renal function (creatinine > or =1.5 mg/dl) (n = 1,075), complex procedures (n = 1,920), or insulin-dependent diabetes (n = 650) or patients undergoing isolated myocardial revascularization (n = 4,901), no association between aprotinin dosage and adverse renal outcome was observed. CONCLUSION: In the current analysis, aprotinin dosage was not associated with increased adverse renal outcome. In regard to renal outcome, this analysis did not demonstrate an essential detrimental influence of aprotinin dosage on renal function.

Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery.

BACKGROUND: Hypersensitivity reactions to the nonspecific proteinase inhibitor aprotinin may occur. The present study evaluates the incidence of hypersensitivity reactions to aprotinin. METHODS: Data were prospectively collected as part of the institution's quality assurance program. The database was screened for anaphylactic reactions, especially those against aprotinin. The definition of an allergic reaction was predefined. A severe reaction was defined as hemodynamic instability of more than 10 minutes despite high dosages of vasopressors and inotropic medication. RESULTS: Of 13,315 cardiac operations, 12,403 were done with aprotinin, with 801 reexposures in 697 patients. Eleven reactions to aprotinin (11 of 11,602; 0.09%, 95% confidence interval: 0.05% to 0.16%) were recorded after primary exposure, of which none was severe, while 12 reactions (12 of 801; 1.5%; 95% confidence interval: 0.86% to 2.6%) occurred after reexposure, of which 5 were severe. All severe reactions were in patients reexposed to aprotinin within 6 months after previous exposure. There was no reaction observed in patients reexposed to aprotinin within 3 days after the last exposure (n = 42). The incidence of hypersensitivity reactions was 4.1%, 1.9%, and 0.4% in the less than 6 months, 6 to 12 months, and more than 12 months reexposure intervals, respectively. CONCLUSIONS: The risk of hypersensitivity reactions is low after primary exposure to aprotinin. This risk after reexposure reaches a maximum between the fourth day and the 30th day after previous exposure and declines considerably after 6 months. Consequently, application of aprotinin carries a high risk between the fourth and the 30th day after previous exposure, and cannot be recommended for the first 6 months, but is justifiable in previously aprotinin-exposed patients with a high risk of bleeding after this interval.

High-dose aprotinin in cardiac surgery: is high-dose high enough? An analysis of 8281 cardiac surgical patients treated with aprotinin.

In this retrospective analysis we tested the hypothesis that aprotinin doses of more than 6 x 10(6) kallikrein inhibiting units (KIU) per patient may be more effective in reducing bleeding compared with the high-dose regimen of 5-6 x 10(6) KIU aprotinin. The aprotinin doses administered for 8281 adult cardiac surgical patients were correlated to body weight and time of operation and calculated in KIU per kg body weight and minute of operation. Linear and logistic regression models were designed to detect potential associations between dose and postoperative bleeding, transfusion, and other covariates. The 6-h chest tube drainage in the lowest quartile dosing group was 447 +/- 319 mL (mean +/- sd) compared with 360 +/- 290 mL in the highest quartile dosing group (P < 0.001). The proportion of patients requiring allogeneic blood transfusion was reduced from 55% to 47% comparing the lowest with the highest dosing group (P < 0.01). Aprotinin dose was also an independent predictor for rethoracotomy for surgical hemostasis (1.9% in the highest quartile to 2.4% in the lowest dosing quartile; P < 0.01). The risk of renal failure requiring dialysis (2.3% in the highest dosing group vs 3.3% in the lowest dosing group; P < 0.01) or impairment of renal function (creatinine increase of >or=2 mg/dL postoperatively, 6.4% in the highest dosing group vs 10.0% in the lowest dosing group; P < 0.01) was lower with higher doses of aprotinin. Thus, there was no association between aprotinin dose and renal function. Our results support the hypothesis that a more individualized aprotinin regimen with potentially higher doses may optimize the effectiveness of aprotinin therapy in cardiac surgery.

Implantation of a prosthesis mounted inside a self-expandable stent in the pulmonary valvar area without use of cardiopulmonary bypass.

Patients with right ventricular outflow tract reconstruction often require redo operations with time. Unique surgical problems exist in this group of patients. We report an innovative method of implantation of a pulmonary valve without the use of cardiopulmonary bypass.

Autologous blood donation in cardiac surgery: reduction of allogeneic blood transfusion and cost-effectiveness.

OBJECTIVE: The purpose of this study was to assess transfusion requirements in patients undergoing cardiac surgery with and without autologous blood donation and to calculate the costs of predonation from the hospital perspective. DESIGN: Observational study. SETTING: Single university hospital. PARTICIPANTS: Four thousand three hundred twenty-five patients undergoing elective cardiac surgery with and without autologous blood donation. INTERVENTIONS: Eight hundred forty-nine patients (20%) underwent autologous blood donation, whereas 3,476 (80%) did not. Perioperative allogeneic blood transfusion was recorded as the primary endpoint. To avoid selection bias, patients were stratified according to their preoperative risk score. A decision model was derived from acquired data for the optimization of autologous blood donation. MEASUREMENTS AND MAIN RESULTS: Allogeneic blood transfusion rate was 13% in patients with predonation versus 48% without predonation (p < 0.05). This difference remained statistically significant even after risk stratification. The predonation of 1, 2, or 3 units reduced the probability of receiving allogeneic blood to 24%, 14%, and 9%, respectively. An efficient program of predonation within the department of anesthesiology allowed keeping the costs of predonation low. Decision-tree analysis revealed that predonation of 2 autologous units of blood saved the most allogeneic blood for the smallest increase in costs. Incremental cost for male patients predonating 2 units was dollars 33 (US), whereas for females predonation could be done at no extra cost in comparison to patients without predonation. CONCLUSION: Autologous blood donation significantly reduces allogeneic blood requirement in cardiac surgery. If adjusted for diagnosis and gender, autologous blood donation is a cost-effective alternative to reduce allogeneic blood consumption.