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Safety and Efficacy of Tranexamic Acid Compared With Aprotinin in Thoracic Aortic Surgery With Deep Hypothermic Circulatory Arrest
Safety and Efficacy of Tranexamic Acid Compared With Aprotinin in Thoracic Aortic Surgery With Deep Hypothermic Circulatory Arrest Ramona Nicolau-Raducu, MD, PhD,* Kathirvel Subramaniam, MD,† Jose Marquez, MD,† Cynthia Wells, MD,† Ibtesam Hilmi, MD, MBChB, FRCA,† and Erin Sullivan, MD† Objectives: This study was conducted to evaluate the safety and efficacy of high-dose tranexamic acid (TA) compared with aprotinin in patients who underwent thoracic aortic surgery with deep hypothermic circulatory arrest (DHCA). Design: A retrospective study. Participants: Eighty-four patients underwent thoracic aortic surgery with DHCA arrest between July 2006 and December 2007. Antifibrinolytic efficacy and perioperative outcomes were compared between the groups by appropriate statistical tests. Measurements and Main Results: Demographic data, comorbid conditions, aortic pathology, surgical procedures, and operative data were comparable between groups. The use of blood products tended to be more in the TA group, despite the fact that the aprotinin group had longer CPB duration. Thirty-day mortality was 5 of 48 (10.4%) in the aprotinin group versus 5 of 36 (13.9%) in the TA group (p ⴝ 0.44). Neurologic, cardiac, and respiratory dysfunctions were comparable as well as intensive care unit and hospital stay.
Serum creatinine increased significantly postoperatively in both groups, with more patients in the aprotinin group developing stage 1 postoperative renal dysfunction based on Acute Kidney Insufficiency Network criteria. Multivariate logistic regression analysis identified risk factors for postoperative renal dysfunction including preoperative creatinine clearance, blood transfusion, and sepsis. Throughout the study, both drugs were available for use, allowing selective bias for providers. Conclusions: Aprotinin appeared more effective in reducing blood product use after thoracic aortic surgery in this limited cohort. Aprotinin use also appeared to be associated with postoperative renal dysfunction. The choice of antifibrinolytic appeared to not be associated with cardiac, neurologic, or respiratory outcomes or survival after thoracic aortic surgery requiring DHCA. © 2010 Elsevier Inc. All rights reserved.
T
results of the BART study,3 the authors stopped using aprotinin in all cardiac surgical patients. The time distribution of antifibrinolytic use is shown in Table 1. Nine surgeons and 9 attending anesthesiologists were involved in taking care of the patients. Standard American Society of Anesthesiologists monitoring was used in all patients along with invasive arterial pressure monitoring, pulmonary artery catheter, and transesophageal echocardiography. Aprotinin, 2 ⫻ 106 KIU loading dose, was followed by a continuous infusion of 5 ⫻ 105 KIU/h until the end of surgery. In addition, aprotinin, 2 ⫻ 106 KIU, was added to the cardiopulmonary bypass (CPB) circuit prime. TA, 30 mg/kg loading dose, was followed by a continuous infusion of 15 mg/kg/h until the end of surgery. In addition, TA, 2 mg/kg, was added to the CPB circuit prime. Aprotinin administration was started after anesthesia induction and before surgical incision, and TA was given after heparinization. Anticoagulation for CPB was provided with heparin, 300 to 500 U/kg, to achieve an activated coagulation time (ACT) greater than 400 seconds in the TA group and an ACT greater than 500 seconds (kaolin ACT method) in the aprotinin group. Hepcon (Medtronic, Minneapolis, MN) was used to monitor heparin blood concentrations in the aprotinin group. Cannulation sites varied and were determined by surgeons based on the extent of aortic disease and patient factors (redo, emergency).
HORACIC AORTIC SURGERY is associated with significant perioperative bleeding. In addition to the surgical dissection and the effects of cardiopulmonary bypass (CPB) on hemostasis, the use of deep hypothermic circulatory arrest (DHCA) places patients at a very high risk for bleeding in the postbypass and postoperative periods. In the past, aprotinin was used in all high-risk cardiac surgical patients as the antifibrinolytic agent to reduce surgical blood loss because of its superior efficacy compared with epsilon-aminocaproic acid (EACA) and tranexamic acid (TA).1 In a prospective, observational study, Mangano et al2 described that aprotinin was associated with increased mortality and an increased risk of cardiac and renal events in patients undergoing coronary artery revascularization. Aprotinin was subsequently withdrawn from the market because of patient safety concerns pointed out in Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), a recent prospective clinical trial.3 TA is being used currently as the replacement for aprotinin in high-risk cardiac surgery at some institutions. So far, there is no study in the literature comparing TA and aprotinin in thoracic aortic surgery. This retrospective study was conducted to evaluate the safety and efficacy of the current practice of using TA compared with aprotinin in patients who underwent thoracic aortic surgical procedures (ascending aorta and aortic arch) with DHCA. METHODS
The institutional review board approved this project. All patients’ records who underwent thoracic aortic surgery with DHCA via sternotomy between July 2006 and December 2007 were reviewed. After Mangano et al’s study2 was published questioning the safety of aprotinin in cardiac surgical patients, the Department of Anesthesiology and Cardiac Surgery instituted a protocol (June 2006) that restricted the use of aprotinin in situations in which the benefits of using aprotinin outweighed the risks. These risks were clearly explained to the patients. In October 2007, after the publication of the preliminary
KEY WORDS: thoracic aortic surgery, deep hypothermic circulatory arrest, aprotinin, tranexamic acid
From the *University of Illinois Medical Center at Chicago, Chicago, IL; and †University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, PA. Presented at the International Cardiothoracic and Vascular Anesthesiology Meeting, Berlin, Germany, September 14-18, 2008, and the Annual Meeting of American Society of Anesthesiologists, Orlando, FL, October 13-17, 2008. Address reprint requests to Ramona Nicolau-Raducu, MD, PhD, Department of Anesthesiology (M-C515), University of Illinois Medical Center at Chicago, 1740 West Taylor Street, Chicago, IL 60612-7239. E-mail: [email protected] © 2010 Elsevier Inc. All rights reserved. 1053-0770/10/2401-0014$36.00/0 doi:10.1053/j.jvca.2009.06.010
Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 1 (February), 2010: pp 73-79
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Table 1. Time Distribution and Antifibrinolytic Used
July-December 2006 January-June 2007 July-December 2007
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
25 20 3
3 15 18
NOTE. Values indicate number of patients.
The CPB circuit was primed with a balanced crystalloid, colloid, and mannitol solution. Nonpulsatile flow was established with a roller pump, and oxygenation was achieved by using a hollow-fiber membrane oxygenator. Myocardial protection during aortic cross-clamping was achieved with cold blood cardioplegia. During DHCA, retrograde or antegrade cerebral perfusion was used based on the duration of DHCA and the preference of the surgeon. Heads of the patients were covered with ice packs. A bispectral index monitor was used to monitor cerebral activity. During CPB, blood from pump suction was filtered and returned to the venous reservoir. Blood, nasopharyngeal, and bladder temperatures were monitored. For DHCA, the target core temperature was 15°C, and the duration of DHCA was noted. After completion of the distal anastomosis, CPB was restarted for the completion of the procedure. Gradual rewarming to a bladder temperature of 36°C was done before the termination of CPB. Anticoagulation was reversed with protamine sulfate, 1 mg/100 U of heparin. Blood from the operative field was salvaged, processed and reinfused using a cell-saver circuit. Preoperative data included demographic variables, comorbid conditions (smoking and respiratory disease, history of recent myocardial infarction (⬍3 months), congestive cardiac failure, history of significant cardiac arrhythmias (atrial fibrillation, ventricular tachycardia and fibrillation, hypertension, diabetes mellitus, peripheral vascular disease, renal dysfunction, and cerebrovascular disease), laboratory data (hematocrit, creatinine, platelet count, prothrombin time [PT], partial thromboplastin time [PTT]), and preoperative echocardiographic evaluation findings (eg, ventricular function and aortic valve). Preoperative coagulopathy was defined as the intake of antiplatelet (clopidogrel) or anticoagulant medications (warfarin sodium) at the time of surgery or laboratory evidence of a coagulopathy including prolonged PTT and/or PT with an international normalized ratio (INR) ⬎1.4, platelet count ⬍100,000/mm3, or an abnormal baseline thromboelastography performed after the induction of anesthesia. Recorded surgical factors included redo sternotomy, elective versus emergent procedure, type of aortic and aortic valve procedure, duration of anesthesia and surgery, CPB duration, aortic cross-clamp time, DHCA duration, and the use of blood products (packed red cells [PRBCs], fresh frozen plasma [FFP], platelets [PLTS], and cryoprecipitate [CRYO]). Intraoperative transfusion was guided by hematocrit, thromboelastography, functional platelet count using Collagen Plateletworks (Helena Laboratories, Beaumont, TX), and other coagulation studies such as PTT/PT/INR. The Plateletworks methodology is an adaptation of platelet aggregometry, and the reference range is 70% to 100% of the baseline platelet count. Postoperative transfusion was guided by clinical bleeding, hematocrit and coagulation studies. PRBCs and PLTS were transfused to maintain the hematocrit above 27% and the platelet count above 100,000/mm3, respectively. FFP was given to maintain the INR below 1.4, and CRYO was administered for blood fibrinogen levels below 150 mg/dL. The transfusions were recorded as units as follows: 1 U of PRBC ⫽ 300 mL, 1 U of FFP ⫽ 250 mL, 1 U of PLTS (6 pools) ⫽ 300 mL, and 1 U of CRYO (5 pools) ⫽ 50 mL. Desmopressin acetate was administered in the postbypass period to patients with pre-existing renal dysfunction. Recombinant factor VII was considered for severe coagulopathy that did not respond to conventional therapy. Recombinant factor, 20 g/kg, was given in the
postbypass period, and the dose was repeated postoperatively as needed. All blood products given intraoperatively and during the first 24 hours were recorded. The chest tube drainage was also recorded for the first 24 hours. Surgical re-exploration of the mediastinum was considered when bleeding in the first 2 hours was greater than 300 mL/h or greater than 200 mL/h for 4 consecutive hours despite adequate replacement with blood products and normal coagulation studies. Re-exploration was also done in patients with hemodynamic instability or cardiac tamponade. The surgical re-exploration rate was noted for both groups. Outcome parameters included: postoperative 30-day mortality; cardiac, neurologic, and renal morbidities; deep venous thrombosis (DVT); serious infections; and prolonged ventilatory support. Cardiac morbidity consisted of low-cardiac-output syndrome (cardiac index ⬍1.8 L/min/m2 despite high-dose inotropic support and requirement of inotropic support beyond 48 hours), postoperative myocardial infarction, arrhythmias requiring treatment or the need for postoperative mechanical circulatory support with an intra-aortic balloon pump, or extracorporeal membrane oxygenator. Neurologic morbidity included a new-onset focal neurologic deficit or death without awakening. Altered mental status was defined as any alteration from normal sensorium (depression or delirium) in the postoperative period. DVT was diagnosed by ultrasound Doppler of the leg when DVT was suspected clinically (swelling and/or tenderness of calf muscle and unexplained postoperative hypoxemia). Serious infections consisted of sepsis or mediastinitis. In addition, the diagnosis of sepsis included organisms isolated from cultures along with elevated temperature and white blood cell counts. Prolonged ventilatory support was defined as the need for mechanical ventilatory support longer than 72 hours postoperatively. The duration of intensive care unit (ICU) and hospital stay and readmissions were recorded. Creatinine clearance (CrCl) was calculated to evaluate preoperative renal function using the Cockcroft and Gault formula as follows: for men, CrCl ⫽ ([140 ⫺ age] ⫻ weight ⫻ 1.2)/serum creatinine and, for women, CrCl ⫽ ([140 ⫺ age] ⫻ weight)/serum creatinine, where age is in years, weight is in kilograms, and serum creatinine is in micromoles per liter (mg/L ⫻ 88.4).4 Preoperative renal dysfunction was defined as CrCl ⬍60 mL/min. Postoperative renal dysfunction was defined according to Acute Kidney Injury Network (AKIN) classification.5 Although the diagnosis of acute kidney injury is based on changes over the course of 48 hours, staging occurs over a slightly longer time frame. One week was proposed by the Acute Dialysis Quality Initiative group in the original RIFLE criteria.6 Based on this any change in creatinine according to AKIN classification within the first postoperative week was considered AKI and was staged accordingly. Patients who received renal replacement therapy (RRT) were considered to have met the criteria for stage 3 irrespective of the stage they were in at the time of RRT. RRT was used whenever there was a persistent decrease in urine output with significant elevation of serum creatinine (at the discretion of the nephrologist) and clinical evidence of uremia (encephalopathy, acidosis, hyperkalemia, pericardial effusion). To test the normality of the distribution of the continuous variables, the Kolmogorov-Smirnov test was performed. The normally distributed data were compared between the groups by using an unpaired Student t test, and the results were expressed as mean ⫾ standard deviation. Categoric data were analyzed with a chi-square test or Fisher exact test wherever appropriate. Binary logistic regression analysis for the development of postoperative renal dysfunction was performed, and an odds ratio was calculated. Variables with p values ⬍0.1 were examined in a multivariable logistic regression model to assess the impact of those risk factors on postoperative renal dysfunction. A stepwise procedure was used, and a p value of less than 0.05 was used to enter or eliminate a variable. The Kaplan-Meier method was used to analyze the survival rate between the 2 groups. For overall comparison, a log-rank test
TRANEXAMIC ACID VERSUS APROTININ
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Table 2. Patient Characteristics
Age (y)* Sex (M/F) Body surface area (m2)* Smoking (%) Sleep apnea (%) Chronic obstructive pulmonary disease (%) Preoperative respiratory failure (%) Atrial fibrillation (%) Left ventricular ejection fraction ⬍40% (%) Myocardial infarction (%) Congestive heart failure (%) Hypertension (%) Diabetes mellitus (%) Peripheral vascular disease (%) Cerebrovascular disease (%) Preoperative renal dysfunction (%) Coagulopathy (%)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
62 ⫾ 15 31/17 1.98 ⫾ 0.2 8 (16.7) 3 (6.3)
58 ⫾ 19 24/12 2.0 ⫾ 0.3 6 (16.7) 2 (5.6)
0.28 0.52 0.92 0.62 0.64
13 (27.1) 4 (8.3) 8 (16.7)
11 (30.6) 1 (2.8) 2 (5.6)
0.46 0.28 0.11
4 (8.3) 2 (4.2) 8 (16.7) 43 (89.6) 5 (10.4) 22 (45.8) 6 (12.5) 19 (39.6) 4 (8.3)
2 (5.6) 2 (5.6) 4 (11.1) 31 (86.1) 7 (19.4) 10 (27.8) 5 (13.9) 12 (33.3) 2 (5.7)
0.48 0.58 0.35 0.44 0.20 0.07 0.55 0.36 0.50
NOTE. All values expressed as n (%) unless indicated. *Values expressed as mean ⫾ standard deviation.
(Mantel-Cox) was used. Data were analyzed with the SPSS 15.0 statistical package (SPSS Inc, Chicago, IL). RESULTS
Demographic data (age, sex, and body surface area) and comorbid conditions were similar between the 2 groups (Table 2). Aortic pathology, surgical procedures, and operative data
Intraoperative Transfusion*
PRBC (U) FFP (U) Platelets (U) Cryoprecipitate (U) Cell-saver blood (mL) DDAVP (%) Factor VII (%) Heparin (mg) Protamine (mg) Transfusion 1st 24 hours postoperatively* PRBC1st 24 h (U) FFP1st 24 h (U) Platelets1st 24 h (U) Cryoprecipitate1st 24 h (U) Total intra- and postoperative blood products transfused* Total RBC (U) Total FFP (U) Total platelets (U) Total cryoprecipitate (U) Re-exploration within 1st 24 hours (%) Surgical bleeding Diffuse oozing Other surgical causes Re-exploration within 1st week (%) Surgical bleeding Other surgical causes Bleeding complications after 1 week (%)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
2.3 ⫾ 3.2 3.9 ⫾ 4.5 2.1 ⫾ 2.4 3.6 ⫾ 4.1 1.5 ⫾ 1.0 2.1 ⫾ 2.1 0.1 ⫾ 0.5 0.5 ⫾ 1.0 836 ⫾ 424 984 ⫾ 779 7 (14.6) 2 (5.6) 2 (4.2) 2 (5.6) 392 ⫾ 208 376 ⫾ 192 347 ⫾ 123 307 ⫾ 73
0.06 0.07 0.16 0.08 0.27 0.17 0.58 0.73 0.17
0.9 ⫾ 1.2 0.5 ⫾ 1.2 0.1 ⫾ 0.4 0.1 ⫾ 0.4
0.6 ⫾ 1.0 0.7 ⫾ 1.2 0.2 ⫾ 0.3 0.1 ⫾ 0.3
0.35 0.46 0.55 0.70
1.7 ⫾ 2.6 1.5 ⫾ 2.1 0.9 ⫾ 1.1 0.2 ⫾ 0.5
2.4 ⫾ 3.7 2.3 ⫾ 3.4 1.2 ⫾ 1.8 0.3 ⫾ 0.8
0.19 0.06 0.22 0.17
7 (15.2) 0 2 (4.3) 5 (10.9) 2 (4.3) 1 (2.2) 1 (2.2)
7 (19.4) 3 (8.3) 2 (5.6) 2 (5.6) 1 (2.8) 0 1 (2.8)
0.41 0.08 0.59 0.33 0.59 0.56 0.68
5 (10.9)
3 (8.8)
0.54
*Values expressed as mean ⫾ standard deviation and others as n (%).
Table 3. Operative Data
Emergency surgery (%) Redo sternotomy (%) Aorta and valve pathology (%) Aneurysms Dissections Severe aortic incompetence Severe aortic stenosis Aortic surgery (%) Ascending aortic aneurysm repair Hemiarch repair Complete arch repair Surgery on aortic valve (%) Aortic valve replacement Bentall repair Resuspension/aortic valve repair Coronary artery bypass surgery (%) Duration of anesthesia* (min) Duration of surgery* (min) Cardiopulmonary bypass duration* (min) Aortic cross-clamp time* (min) DHCA duration* (min)
Table 4. Intra-, Postoperative and Total Transfusion Data and Postoperative Re-exploration Data
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
13 (27.1) 12 (25)
11 (30.6) 6 (16.7)
0.46 0.26
27 (56.3) 21 (43.8) 15 (31.3) 4 (8.3)
17 (47.2) 20 (52.8) 10 (27.8) 2 (5.6)
0.27 0.27 0.46 0.48
7 (14.6) 39 (81.3) 2 (4.2)
1 (2.8) 32 (88.9) 3 (8.3)
0.06 0.26 0.36
7 (14.6) 11 (22.9) 9 (18.8) 13 (27.1) 534 ⫾ 100 421 ⫾ 82
1 (2.8) 8 (22.9) 12 (33.3) 12 (33.3) 535 ⫾ 137 416 ⫾ 132
0.07 0.60 0.10 0.35 0.97 0.83
234 ⫾ 80 123 ⫾ 46 31 ⫾ 21
199 ⫾ 60 136 ⫾ 50 28 ⫾ 15
0.04 0.25 0.37
*Duration expressed as mean ⫾ standard deviation and others as n (%).
were comparable except for CPB duration, which was significantly higher in the aprotinin group (Table 3). Intraoperative and postoperative transfusion data are presented in Table 4. There was a general trend toward less overall and intraoperative blood product transfusions (RBC, FFP, PLTS, CRYO, and cell saver) in the aprotinin group; however, no statistical significance was reached. There was no significant difference in the use of DDAVP and factor VII between the 2 groups. Re-exploration rate was similar in both the groups (Table 4). Rebleeding after 1 week presented as late-onset pericardial effusion or cardiac tamponade. This occurred during ICU stay, after discharge from the ICU to a regular floor or after discharge from the hospital. Five of the patients presented with cardiac tamponade in the aprotinin group, 2 patients in the TA group had exploration for the left hemothorax, and another bleeding complication in the TA group was related to rectal pathology. Possible reasons include hypertensive episodes, strain on the suture related with coughing, and sepsis. Chest tube drainage in the first 24 hours was 964 ⫾ 477 mL in the aprotinin group versus 763 ⫾ 490 mL in the TA group (p ⫽ 0.11). Functional platelet counts decreased significantly (p ⬍ 0.001) in both groups after CPB (181 ⫾ 67 pre-CPB v 55 ⫾ 28 post-CPB in the aprotinin group and 140 ⫾ 63 pre-CPB v 61 ⫾ 48
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post-CPB in the TA group) with no difference between the 2 groups either before or after CPB. Preoperative renal dysfunction, expressed as CrCl preoperative, was similar between the groups. There was a significant increase in creatinine on postoperative day 1 (p ⫽ 0.01) and postoperative day 7 (p ⫽ 0.02) compared with preoperative creatinine in the aprotinin group. Such an increase in creatinine was detected in the TA group on postoperative day 1 (p ⫽ 0.004) or postoperative day 7 (p ⫽ 0.07) compared with baseline. According to the AKIN definition, 13 patients from the aprotinin group developed new-onset renal dysfunction (stage 1) compared with 3 patients in the TA group (p ⫽ 0.02). No differences between the 2 groups were noted for stage 2 and 3 of the AKIN classification (Table 5). Multivariate logistic regression identified preoperative CrCl, PRBC transfusion, and sepsis as risk factors for development of postoperative renal dysfunction (Table 6). All other complications (neurologic, cardiac, respiratory, and infective) were similar between the 2 groups (Table 7). The duration of ICU and hospital stay were comparable. Overall survival was 86.9%. Three patients died in the operating room (2 patients died of severe uncontrolled bleeding from the aortic suture catheter, and another died of severe refractory biventricular dysfunction). The reasons for mortality of the remaining patients included multiorgan failure (3 patients), a cerebrovascular event (3 patients), and sudden cardiac death (ventricular fibrillation/cardiac arrest in 2 patients). Survival was similar at the point of data collection (February 2008) (89.6% in the aprotinin group v 83.3% in the TA group, p ⫽ 0.42; Fig 1). Thirty-day mortality in the aprotinin group was 5 of 48 (10.4%) compared with 5 of 36 (13.9%) in the TA group (p ⫽ 0.44).
DISCUSSION
Patients who undergo thoracic aortic surgery with DHCA have a higher risk for bleeding compared with other cardiac
Table 6. Predictors of Postoperative Renal Dysfunction Predictor
Odds Ratio
Confidence Interval
p Value
RBC transfusion Sepsis Preoperative CrCl
0.712 0.054 0.978
0.544–0.934 0.004–0.751 0.960–0.995
0.014 0.030 0.013
surgical procedures with CPB. The effects of hypothermia on coagulation and DHCA were published in many articles.7-11 Hypothermia alters platelet morphology, depresses enzyme function, and causes platelet sequestration in the hepatic sinusoids. Thrombin generation during hypothermia stimulates protein C production and tissue plasminogen activator release, both of which promote fibrinolysis.12 Aprotinin, a serine protease inhibitor, has been advocated for the preservation of hemostatic function in cardiac surgery patients at high risk for bleeding including patients undergoing aortic surgery with DHCA. Aprotinin inhibits activation of the kallikrein-kinin system and the plasmin fibrinolysis system, preserves platelet function, and partially inhibits neutrophil activation during CPB.12 The safety and hemostatic efficacy of aprotinin in patients undergoing aortic surgery with DHCA are still matters of debate. In early studies of DHCA and aprotinin, Sundt et al13 and Westaby et al14 showed that aprotinin was ineffective and even potentially harmful. The prolongation of celite ACT used in their study has been proposed as the mechanism for inadequate heparinization and increased thrombotic complications associated with aprotinin. Parolari et al,15 in a retrospective study of 39 patients undergoing DHCA with aprotinin, noticed increased postoperative morbid events with no blood-sparing effects even when appropriate amounts of heparin were administered to maintain celite ACT ⬎800. Lowdose aprotinin has been shown to decrease bleeding without
Table 7. Postoperative Outcome Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
2 (4.3) 4 (8.7) 0 21 (45.7)
2 (5.6) 2 (5.6) 2 (5.6) 12 (33.3)
0.59 0.47 0.19 0.18
5 (10.9) 7 (15.2)
4 (11.1) 3 (8.3)
0.62 0.27
31 (67.4) 20 (43.5) 7 (15.2) 5⫾7
28 (80) 11 (31.4) 4 (11.4) 3⫾6
0.15 0.19 0.44 0.33
8 (17.4) 6 (13) 14 (29.8) 6 (13) 6 (13) 7⫾7 12 ⫾ 7
7 (20) 4 (11.4) 8 (22.9) 2 (5.7) 3 (8.6) 7⫾9 12 ⫾ 13
0.49 0.55 0.33 0.24 0.39 0.82 0.99
Table 5. Serum Creatinine and AKIN Classification
CrClpreop ⬍60 mL/min (%) Serum creatininepreop (mg/dL)* Serum creatinine1st 24 h (mg/dL)* Serum creatinine1st week (mg/dL)* AKIN stage 1† (%) AKIN stage 2‡ (%) AKIN stage 3§储 (%) Renal replacement therapy (RRT)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
19 (39.6) 1.2 ⫾ 0.5 1.4 ⫾ 0.7 1.3 ⫾ 0.6 13 (27.1) 4 (8.3) 2 (4.1) 2 (4.1)
12 (33.3) 1.2 ⫾ 0.4 1.3 ⫾ 0.5 1.3 ⫾ 0.9 3 (8.3) 1 (2.7) 3 (8.3) 3 (8.3)
0.36 0.98 0.38 0.98 0.02 0.27 0.37 0.37
*Data expressed as mean ⫾ SD and others as n (%). †Increase in serum creatinine of more than or equal to 0.3 mg/dL (ⱖ26.4 mol/L) or increase to more than or equal to 150% to 200% (1.5- to 2-fold) from baseline. ‡Increase in serum creatinine to more than 200% to 300% (⬎2- to 3-fold) from baseline. §Increase in serum creatinine to more than 300% (⬎ 3-fold) from baseline (or serum creatinine of more than or equal to 4.0 mg/dL [ⱖ 354 mol/L] with an acute increase of at least 0.5 mg/dl [44 mol/l]). 储Patients who received RRT were considered to have met the criteria for stage 3 irrespective of the stage they were in at the time of RRT.
Cardiac morbidity (%) Myocardial infarction Postoperative IABP ECMO Rhythm irregularities Low cardiac index requiring inotropes RV dysfunction Respiratory morbidity (%) Extubation ⬍72 hours Respiratory failure Tracheostomy Days on ventilator* Neurologic morbidity (%) Stroke Mental status changes Sepsis Deep vein thrombosis ICU readmission ICU stay (d)* Hospital stay (d)*
*Data expressed as mean ⫾ SD and others as n (%).
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Fig 1. Survival data for TA- and aprotinintreated patients. (Color version of figure is available online.)
increasing side effects in at least 3 clinical trials.16-18 Mora Mangano et al,19 in a retrospective study, found no beneficial effects of using aprotinin for patients undergoing thoracic aortic surgery. No increase in renal dysfunction was reported in their study.19 No definitive conclusions could be drawn from these studies reporting a varying degree of efficacy and safety of aprotinin in DHCA. The synthetic antifibrinolytic TA is a potent inhibitor of plasminogen and appears to be an effective antifibrinolytic when used for coronary artery bypass surgery. Casati et al20 used a low-dose TA protocol in a prospective, randomized, double-blinded and placebo-controlled study (1-g loading dose followed by 400 mg/h and 500 mg in the pump) for elective thoracic aortic surgery. They found a significant reduction in perioperative bleeding and the transfusion of allogeneic blood in the TA group. There was no significant increase in the occurrence of thrombotic complications such as renal failure, stroke, myocardial infarction, or survival. This study was limited by the small number of patients who underwent thoracic aortic surgery with DHCA (total of 6 patients). Shimamura et al,21 in a study of patients with acute aortic dissection, found that TA (7 g prebypass with additional 3 g after bypass) was effective in reducing blood loss and transfusion requirements compared with placebo and was associated with reduced morbidity and mortality. Eaton and Deeb,22 in a study comparing aprotinin and EACA, reported equal efficacy for both of these drugs, but only EACA was associated with renal dysfunction. TA has replaced aprotinin as the primary antifibrinolytic in high-risk cardiac surgery at some institutions. Very few clinical trials have compared TA with aprotinin in high-risk cardiac surgery. Wong et al,23 in a prospective, randomized study of 80 patients, reported superior efficacy of aprotinin compared with TA in patients with long CPB duration. TA was used as a single dose at induction. High-risk patients on anticoagulants and patients who underwent DHCA were excluded from this study.
Karkouti et al,24 in a propensity-matched case-control study, compared aprotinin and TA in high transfusion risk cardiac surgery and found similar hemostatic effectiveness for both of these drugs. Only aprotinin was associated with renal dysfunction. TA was used as a single dose (50-100 mg/kg) after induction. A subgroup analysis of patients who had DHCA time ⬎15 minutes revealed comparable transfusion rates for TA and aprotinin. A recently published prospective, randomized study (BART study) by Fergusson et al3 found increased 30-day mortality for patients treated with aprotinin compared with lysine analog drugs in high-risk cardiac surgery patients. In the present study, patients received a similar dose of aprotinin and TA but involved only patients requiring DHCA for aortic surgery. Emergency surgery also was included in the analysis unlike prospective studies. Aprotinin was not associated with increased adverse events in this study compared with TA-treated patients. The timing of the administration of the 2 drugs was different in the present study. TA was administered after heparinization. This institutional practice was based on the case reports of graft and native coronary artery thrombosis when TA/EACA was given before heparin administration.25,26 The dose of TA used in the present study was based on Dowd et al’s pharmacokinetic study of TA during cardiopulmonary bypass.27 A single dose is unlikely to maintain the concentrations required for hemostasis during long CPB cases such as aortic surgery. The present authors used the dose that would provide the highest possible and stable concentration (800 mol/L) to produce 98% to 100% reduction of tissue activator activity. In the postaprotinin era, there is a need for evidence-based recommendations for the 2 available lysine analog antifibrinolytics, TA and EACA, regarding dose, efficacy, timing of administration, and adverse events in thoracic aortic surgery. Most institutions use one of them based on their experience and
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consider them to be more helpful than placebo in reducing transfusion requirements and re-explorations. Prospective, randomized, and comparative clinical trials are recommended in this area. The authors used the AKIN criteria to define renal dysfunction and failure. It can be inferred from the present results that aprotinin may be associated with increased renal dysfunction as measured by an increase in serum creatinine but did not increase the incidence of serious renal failure requiring RRT. The incidence of other postoperative complications and the 30-day mortality were similar in both groups. This can be interpreted in different ways. Aprotinin may be as safe as TA; however, because the drug is off the market, this way of interpreting the results may not impact the current practice. The other way of interpreting the results is concerning because TA could produce the same number of side effects as aprotinin, which needs further evaluation. Another way of reasoning is that the patients undergoing complex aortic surgery with DHCA are at a higher risk for developing perioperative complications, and the antifibrinolytic used may not be a significant factor influencing the outcome. The authors used FVII in 4 patients (2 in each group) for refractory bleeding, and 3 of those patients (2 in the TA group and 1 in the aprotinin group) developed stroke within the first 24 hours, so FVII could have promoted thrombus formation,28 but it might have happened irrespective of the antifibrinolytic used. However, in the study by Tripepe et al,29 when FVII was used, there was no increase in thromboembolic complications after acute aortic dissection surgery with DHCA. Although other factors such as embolism could play a role in the development of postoperative stroke, FVII should be used with caution.
LIMITATIONS
The observational nature of this study indicates that data may imply only association not causation. Because this is a retrospective study, various unmeasured variables could have influenced the results. For example, there could be variations in the surgical techniques between different surgeons to account for the bleeding. Although the scientific guidelines had been followed in general for the transfusion of blood products, there could be variation from protocols in individual patients based on the clinical status. The use of blood products tends to be more in the TA group despite the fact that the aprotinin group had higher CPB duration. This may indicate better antifibrinolytic efficacy of aprotinin, which cannot be proven by this retrospective study of limited sample size. Aprotinin group patients had numerically higher preoperative arrhythmias, peripheral vascular disease, redo sternotomy, and higher CPB duration. Only CPB duration reached statistical significance. It is possible that aprotinin patients were sicker preoperatively, and the groups were not matched perfectly. It is possible that sicker patients received aprotinin inducing a selective bias during the time period when both antifibrinolytics were available for use. Small sample size prevented the authors from performing statistical matching such as propensity matching. In conclusion, aprotinin appeared to be more effective in reducing blood product transfusion after thoracic aortic surgery with DHCA compared with tranexamic acid. However, this could not be proven with this retrospective study of 84 patients. The choice of antifibrinolytic appeared not to be associated with cardiac, neurologic, and respiratory outcomes and survival after thoracic aortic surgery requiring DHCA. However, aprotinin use appeared to be associated with increased postoperative renal dysfunction.
REFERENCES 1. Umscheid CA, Kohl BA, Williams K: Antifibrinolytic use in adult cardiac surgery. Curr Opin Hematol 14:455-467, 2007 2. Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation: The risk associated with aprotinin in cardiac surgery. N Engl J Med 354:353-365, 2006 3. Fergusson DA, Hebert PC, Mazer CD, et al: (BART study). A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358:2319-2331, 2008 4. Chukwuemeka A, Weisel A, Mangani M, et al: Renal dysfunction in high-risk patients after on-pump and off-pump coronary artery bypass surgery: A propensity score analysis. Ann Thorac Surg 80: 2148-2154, 2005 5. Mehta RL, Kellum JA, Shah SV, et al: Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31, 2007 6. Kellum JA, Mehta RL, Angus DC, et al: The first international consensus conference on continuous renal replacement therapy. Kidney Int 62:1855-1863, 2002 7. Mossad EB, Machado S, Apostolakis J: Bleeding following deep hypothermia and circulatory arrest in children. Semin Cardiothorac Vasc Anesth 11:34-46, 2007 8. Krause KR, Howells GA, Buhs CL, et al: Hypothermia-induced coagulopathy during hemorrhagic shock. Am Surg 66:348-354, 2000 9. Kirkpatrick AW, Chun R, Brown R, et al: Hypothermia and the trauma patient. Can J Surg 42:333-343, 1999
10. Westaby S: Coagulation disturbance in profound hypothermia: The influence of anti-fibrinolytic therapy. Semin Thorac Cardiovasc Surg 9:246-256, 1997 11. Wilde JT: Hematological consequences of profound hypothermic circulatory arrest and aortic dissection. J Card Surg 12:201-206, 1997 (suppl) 12. Westaby S: Anti-fibrinolytic therapy in thoracic aortic surgery. Ann Thorac Surg 67:1983-1985, 1999 13. Stundt TM, Kouchoukos NT, Saffitz JE, et al: Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 55:1418-1424, 1993 14. Westaby S, Forni A, Dunning J, et al: Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 8:82-86, 1994 15. Parolari A, Antona C, Alamanni F, et al: Aprotinin and deep hypothermic circulatory arrest: There are no benefits even when appropriate amounts of heparin are given. Eur J Cardiothorac Surg 11:149-156, 1997 16. Goldstein DJ, DeRosa CM, Mongero LB, et al: Safety and efficacy of aprotinin under conditions of deep hypothermia and circulatory arrest. J Thorac Cardiovasc Surg 110:1615-1622, 1995 17. Seigne PW, Shorten GD, Johnson RG, et al: The effects of aprotinin on blood product transfusion associated with thoracic aortic surgery requiring deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 14:676-681, 2000
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18. Ehrlich M, Grabenwöger M, Cartes-Zumelzu F, et al: Operations on the thoracic aorta and hypothermic circulatory arrest: Is aprotinin safe? J Thorac Cardiovasc Surg 115:220-225, 1998 19. Mora Mangano CT, Neville MJ, Hsu PH, et al: Aprotinin, blood loss, and renal dysfunction in deep hypothermic circulatory arrest. Circulation 104:I276-I281, 2001 (suppl 1) 20. Casati V, Sandreli L, Speziali G, et al: Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: A prospective, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 123:1084-1091, 2002 21. Shimamura Y, Nakajima M, Hirayama T, et al: The effect of intraoperative high-dose tranexamic acid on blood loss after operation for acute aortic dissection. J Thorac Cardiovasc Surg 46:616-621, 1998 22. Eaton MP, Deeb GM: Aprotinin versus epsilon-aminocaproic acid for aortic surgery using deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 12:548-552, 1998 23. Wong BI, McLean RF, Fremes SE, et al: Aprotinin and tranexamic acid for high transfusion risk cardiac surgery. Ann Thorac Surg 69:808-816, 2000
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24. Karkouti K, Beattie WS, Dattilo KM, et al: A propensity score case-control comparison of aprotinin and tranexamic acid in hightransfusion-risk cardiac surgery. Transfusion 46:327-338, 2006 25. Shaw AD, Stafford-Smith M, White WD, et al: The effects of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 358:784-793, 2008 26. Schneeweiss S, Seeger JD, Landon J, et al: Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 358:771-783, 2008 27. Dowd NP, Karski JM, Cheng DC, et al: Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2:390399, 2002 28. O’Connell KA, Wood JJ, Wise RP, et al: Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 295:293-298, 2006 29. Tripepe L, De Santis V, Vitale D, et al: Recombinant activated factor VII for refractory bleeding after acute aortic dissection surgery: A propensity score analysis. Crit Care Med 35:1685-1690, 2007
Serum creatinine increased significantly postoperatively in both groups, with more patients in the aprotinin group developing stage 1 postoperative renal dysfunction based on Acute Kidney Insufficiency Network criteria. Multivariate logistic regression analysis identified risk factors for postoperative renal dysfunction including preoperative creatinine clearance, blood transfusion, and sepsis. Throughout the study, both drugs were available for use, allowing selective bias for providers. Conclusions: Aprotinin appeared more effective in reducing blood product use after thoracic aortic surgery in this limited cohort. Aprotinin use also appeared to be associated with postoperative renal dysfunction. The choice of antifibrinolytic appeared to not be associated with cardiac, neurologic, or respiratory outcomes or survival after thoracic aortic surgery requiring DHCA. © 2010 Elsevier Inc. All rights reserved.
T
results of the BART study,3 the authors stopped using aprotinin in all cardiac surgical patients. The time distribution of antifibrinolytic use is shown in Table 1. Nine surgeons and 9 attending anesthesiologists were involved in taking care of the patients. Standard American Society of Anesthesiologists monitoring was used in all patients along with invasive arterial pressure monitoring, pulmonary artery catheter, and transesophageal echocardiography. Aprotinin, 2 ⫻ 106 KIU loading dose, was followed by a continuous infusion of 5 ⫻ 105 KIU/h until the end of surgery. In addition, aprotinin, 2 ⫻ 106 KIU, was added to the cardiopulmonary bypass (CPB) circuit prime. TA, 30 mg/kg loading dose, was followed by a continuous infusion of 15 mg/kg/h until the end of surgery. In addition, TA, 2 mg/kg, was added to the CPB circuit prime. Aprotinin administration was started after anesthesia induction and before surgical incision, and TA was given after heparinization. Anticoagulation for CPB was provided with heparin, 300 to 500 U/kg, to achieve an activated coagulation time (ACT) greater than 400 seconds in the TA group and an ACT greater than 500 seconds (kaolin ACT method) in the aprotinin group. Hepcon (Medtronic, Minneapolis, MN) was used to monitor heparin blood concentrations in the aprotinin group. Cannulation sites varied and were determined by surgeons based on the extent of aortic disease and patient factors (redo, emergency).
HORACIC AORTIC SURGERY is associated with significant perioperative bleeding. In addition to the surgical dissection and the effects of cardiopulmonary bypass (CPB) on hemostasis, the use of deep hypothermic circulatory arrest (DHCA) places patients at a very high risk for bleeding in the postbypass and postoperative periods. In the past, aprotinin was used in all high-risk cardiac surgical patients as the antifibrinolytic agent to reduce surgical blood loss because of its superior efficacy compared with epsilon-aminocaproic acid (EACA) and tranexamic acid (TA).1 In a prospective, observational study, Mangano et al2 described that aprotinin was associated with increased mortality and an increased risk of cardiac and renal events in patients undergoing coronary artery revascularization. Aprotinin was subsequently withdrawn from the market because of patient safety concerns pointed out in Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), a recent prospective clinical trial.3 TA is being used currently as the replacement for aprotinin in high-risk cardiac surgery at some institutions. So far, there is no study in the literature comparing TA and aprotinin in thoracic aortic surgery. This retrospective study was conducted to evaluate the safety and efficacy of the current practice of using TA compared with aprotinin in patients who underwent thoracic aortic surgical procedures (ascending aorta and aortic arch) with DHCA. METHODS
The institutional review board approved this project. All patients’ records who underwent thoracic aortic surgery with DHCA via sternotomy between July 2006 and December 2007 were reviewed. After Mangano et al’s study2 was published questioning the safety of aprotinin in cardiac surgical patients, the Department of Anesthesiology and Cardiac Surgery instituted a protocol (June 2006) that restricted the use of aprotinin in situations in which the benefits of using aprotinin outweighed the risks. These risks were clearly explained to the patients. In October 2007, after the publication of the preliminary
KEY WORDS: thoracic aortic surgery, deep hypothermic circulatory arrest, aprotinin, tranexamic acid
From the *University of Illinois Medical Center at Chicago, Chicago, IL; and †University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, PA. Presented at the International Cardiothoracic and Vascular Anesthesiology Meeting, Berlin, Germany, September 14-18, 2008, and the Annual Meeting of American Society of Anesthesiologists, Orlando, FL, October 13-17, 2008. Address reprint requests to Ramona Nicolau-Raducu, MD, PhD, Department of Anesthesiology (M-C515), University of Illinois Medical Center at Chicago, 1740 West Taylor Street, Chicago, IL 60612-7239. E-mail: [email protected] © 2010 Elsevier Inc. All rights reserved. 1053-0770/10/2401-0014$36.00/0 doi:10.1053/j.jvca.2009.06.010
Journal of Cardiothoracic and Vascular Anesthesia, Vol 24, No 1 (February), 2010: pp 73-79
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Table 1. Time Distribution and Antifibrinolytic Used
July-December 2006 January-June 2007 July-December 2007
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
25 20 3
3 15 18
NOTE. Values indicate number of patients.
The CPB circuit was primed with a balanced crystalloid, colloid, and mannitol solution. Nonpulsatile flow was established with a roller pump, and oxygenation was achieved by using a hollow-fiber membrane oxygenator. Myocardial protection during aortic cross-clamping was achieved with cold blood cardioplegia. During DHCA, retrograde or antegrade cerebral perfusion was used based on the duration of DHCA and the preference of the surgeon. Heads of the patients were covered with ice packs. A bispectral index monitor was used to monitor cerebral activity. During CPB, blood from pump suction was filtered and returned to the venous reservoir. Blood, nasopharyngeal, and bladder temperatures were monitored. For DHCA, the target core temperature was 15°C, and the duration of DHCA was noted. After completion of the distal anastomosis, CPB was restarted for the completion of the procedure. Gradual rewarming to a bladder temperature of 36°C was done before the termination of CPB. Anticoagulation was reversed with protamine sulfate, 1 mg/100 U of heparin. Blood from the operative field was salvaged, processed and reinfused using a cell-saver circuit. Preoperative data included demographic variables, comorbid conditions (smoking and respiratory disease, history of recent myocardial infarction (⬍3 months), congestive cardiac failure, history of significant cardiac arrhythmias (atrial fibrillation, ventricular tachycardia and fibrillation, hypertension, diabetes mellitus, peripheral vascular disease, renal dysfunction, and cerebrovascular disease), laboratory data (hematocrit, creatinine, platelet count, prothrombin time [PT], partial thromboplastin time [PTT]), and preoperative echocardiographic evaluation findings (eg, ventricular function and aortic valve). Preoperative coagulopathy was defined as the intake of antiplatelet (clopidogrel) or anticoagulant medications (warfarin sodium) at the time of surgery or laboratory evidence of a coagulopathy including prolonged PTT and/or PT with an international normalized ratio (INR) ⬎1.4, platelet count ⬍100,000/mm3, or an abnormal baseline thromboelastography performed after the induction of anesthesia. Recorded surgical factors included redo sternotomy, elective versus emergent procedure, type of aortic and aortic valve procedure, duration of anesthesia and surgery, CPB duration, aortic cross-clamp time, DHCA duration, and the use of blood products (packed red cells [PRBCs], fresh frozen plasma [FFP], platelets [PLTS], and cryoprecipitate [CRYO]). Intraoperative transfusion was guided by hematocrit, thromboelastography, functional platelet count using Collagen Plateletworks (Helena Laboratories, Beaumont, TX), and other coagulation studies such as PTT/PT/INR. The Plateletworks methodology is an adaptation of platelet aggregometry, and the reference range is 70% to 100% of the baseline platelet count. Postoperative transfusion was guided by clinical bleeding, hematocrit and coagulation studies. PRBCs and PLTS were transfused to maintain the hematocrit above 27% and the platelet count above 100,000/mm3, respectively. FFP was given to maintain the INR below 1.4, and CRYO was administered for blood fibrinogen levels below 150 mg/dL. The transfusions were recorded as units as follows: 1 U of PRBC ⫽ 300 mL, 1 U of FFP ⫽ 250 mL, 1 U of PLTS (6 pools) ⫽ 300 mL, and 1 U of CRYO (5 pools) ⫽ 50 mL. Desmopressin acetate was administered in the postbypass period to patients with pre-existing renal dysfunction. Recombinant factor VII was considered for severe coagulopathy that did not respond to conventional therapy. Recombinant factor, 20 g/kg, was given in the
postbypass period, and the dose was repeated postoperatively as needed. All blood products given intraoperatively and during the first 24 hours were recorded. The chest tube drainage was also recorded for the first 24 hours. Surgical re-exploration of the mediastinum was considered when bleeding in the first 2 hours was greater than 300 mL/h or greater than 200 mL/h for 4 consecutive hours despite adequate replacement with blood products and normal coagulation studies. Re-exploration was also done in patients with hemodynamic instability or cardiac tamponade. The surgical re-exploration rate was noted for both groups. Outcome parameters included: postoperative 30-day mortality; cardiac, neurologic, and renal morbidities; deep venous thrombosis (DVT); serious infections; and prolonged ventilatory support. Cardiac morbidity consisted of low-cardiac-output syndrome (cardiac index ⬍1.8 L/min/m2 despite high-dose inotropic support and requirement of inotropic support beyond 48 hours), postoperative myocardial infarction, arrhythmias requiring treatment or the need for postoperative mechanical circulatory support with an intra-aortic balloon pump, or extracorporeal membrane oxygenator. Neurologic morbidity included a new-onset focal neurologic deficit or death without awakening. Altered mental status was defined as any alteration from normal sensorium (depression or delirium) in the postoperative period. DVT was diagnosed by ultrasound Doppler of the leg when DVT was suspected clinically (swelling and/or tenderness of calf muscle and unexplained postoperative hypoxemia). Serious infections consisted of sepsis or mediastinitis. In addition, the diagnosis of sepsis included organisms isolated from cultures along with elevated temperature and white blood cell counts. Prolonged ventilatory support was defined as the need for mechanical ventilatory support longer than 72 hours postoperatively. The duration of intensive care unit (ICU) and hospital stay and readmissions were recorded. Creatinine clearance (CrCl) was calculated to evaluate preoperative renal function using the Cockcroft and Gault formula as follows: for men, CrCl ⫽ ([140 ⫺ age] ⫻ weight ⫻ 1.2)/serum creatinine and, for women, CrCl ⫽ ([140 ⫺ age] ⫻ weight)/serum creatinine, where age is in years, weight is in kilograms, and serum creatinine is in micromoles per liter (mg/L ⫻ 88.4).4 Preoperative renal dysfunction was defined as CrCl ⬍60 mL/min. Postoperative renal dysfunction was defined according to Acute Kidney Injury Network (AKIN) classification.5 Although the diagnosis of acute kidney injury is based on changes over the course of 48 hours, staging occurs over a slightly longer time frame. One week was proposed by the Acute Dialysis Quality Initiative group in the original RIFLE criteria.6 Based on this any change in creatinine according to AKIN classification within the first postoperative week was considered AKI and was staged accordingly. Patients who received renal replacement therapy (RRT) were considered to have met the criteria for stage 3 irrespective of the stage they were in at the time of RRT. RRT was used whenever there was a persistent decrease in urine output with significant elevation of serum creatinine (at the discretion of the nephrologist) and clinical evidence of uremia (encephalopathy, acidosis, hyperkalemia, pericardial effusion). To test the normality of the distribution of the continuous variables, the Kolmogorov-Smirnov test was performed. The normally distributed data were compared between the groups by using an unpaired Student t test, and the results were expressed as mean ⫾ standard deviation. Categoric data were analyzed with a chi-square test or Fisher exact test wherever appropriate. Binary logistic regression analysis for the development of postoperative renal dysfunction was performed, and an odds ratio was calculated. Variables with p values ⬍0.1 were examined in a multivariable logistic regression model to assess the impact of those risk factors on postoperative renal dysfunction. A stepwise procedure was used, and a p value of less than 0.05 was used to enter or eliminate a variable. The Kaplan-Meier method was used to analyze the survival rate between the 2 groups. For overall comparison, a log-rank test
TRANEXAMIC ACID VERSUS APROTININ
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Table 2. Patient Characteristics
Age (y)* Sex (M/F) Body surface area (m2)* Smoking (%) Sleep apnea (%) Chronic obstructive pulmonary disease (%) Preoperative respiratory failure (%) Atrial fibrillation (%) Left ventricular ejection fraction ⬍40% (%) Myocardial infarction (%) Congestive heart failure (%) Hypertension (%) Diabetes mellitus (%) Peripheral vascular disease (%) Cerebrovascular disease (%) Preoperative renal dysfunction (%) Coagulopathy (%)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
62 ⫾ 15 31/17 1.98 ⫾ 0.2 8 (16.7) 3 (6.3)
58 ⫾ 19 24/12 2.0 ⫾ 0.3 6 (16.7) 2 (5.6)
0.28 0.52 0.92 0.62 0.64
13 (27.1) 4 (8.3) 8 (16.7)
11 (30.6) 1 (2.8) 2 (5.6)
0.46 0.28 0.11
4 (8.3) 2 (4.2) 8 (16.7) 43 (89.6) 5 (10.4) 22 (45.8) 6 (12.5) 19 (39.6) 4 (8.3)
2 (5.6) 2 (5.6) 4 (11.1) 31 (86.1) 7 (19.4) 10 (27.8) 5 (13.9) 12 (33.3) 2 (5.7)
0.48 0.58 0.35 0.44 0.20 0.07 0.55 0.36 0.50
NOTE. All values expressed as n (%) unless indicated. *Values expressed as mean ⫾ standard deviation.
(Mantel-Cox) was used. Data were analyzed with the SPSS 15.0 statistical package (SPSS Inc, Chicago, IL). RESULTS
Demographic data (age, sex, and body surface area) and comorbid conditions were similar between the 2 groups (Table 2). Aortic pathology, surgical procedures, and operative data
Intraoperative Transfusion*
PRBC (U) FFP (U) Platelets (U) Cryoprecipitate (U) Cell-saver blood (mL) DDAVP (%) Factor VII (%) Heparin (mg) Protamine (mg) Transfusion 1st 24 hours postoperatively* PRBC1st 24 h (U) FFP1st 24 h (U) Platelets1st 24 h (U) Cryoprecipitate1st 24 h (U) Total intra- and postoperative blood products transfused* Total RBC (U) Total FFP (U) Total platelets (U) Total cryoprecipitate (U) Re-exploration within 1st 24 hours (%) Surgical bleeding Diffuse oozing Other surgical causes Re-exploration within 1st week (%) Surgical bleeding Other surgical causes Bleeding complications after 1 week (%)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
2.3 ⫾ 3.2 3.9 ⫾ 4.5 2.1 ⫾ 2.4 3.6 ⫾ 4.1 1.5 ⫾ 1.0 2.1 ⫾ 2.1 0.1 ⫾ 0.5 0.5 ⫾ 1.0 836 ⫾ 424 984 ⫾ 779 7 (14.6) 2 (5.6) 2 (4.2) 2 (5.6) 392 ⫾ 208 376 ⫾ 192 347 ⫾ 123 307 ⫾ 73
0.06 0.07 0.16 0.08 0.27 0.17 0.58 0.73 0.17
0.9 ⫾ 1.2 0.5 ⫾ 1.2 0.1 ⫾ 0.4 0.1 ⫾ 0.4
0.6 ⫾ 1.0 0.7 ⫾ 1.2 0.2 ⫾ 0.3 0.1 ⫾ 0.3
0.35 0.46 0.55 0.70
1.7 ⫾ 2.6 1.5 ⫾ 2.1 0.9 ⫾ 1.1 0.2 ⫾ 0.5
2.4 ⫾ 3.7 2.3 ⫾ 3.4 1.2 ⫾ 1.8 0.3 ⫾ 0.8
0.19 0.06 0.22 0.17
7 (15.2) 0 2 (4.3) 5 (10.9) 2 (4.3) 1 (2.2) 1 (2.2)
7 (19.4) 3 (8.3) 2 (5.6) 2 (5.6) 1 (2.8) 0 1 (2.8)
0.41 0.08 0.59 0.33 0.59 0.56 0.68
5 (10.9)
3 (8.8)
0.54
*Values expressed as mean ⫾ standard deviation and others as n (%).
Table 3. Operative Data
Emergency surgery (%) Redo sternotomy (%) Aorta and valve pathology (%) Aneurysms Dissections Severe aortic incompetence Severe aortic stenosis Aortic surgery (%) Ascending aortic aneurysm repair Hemiarch repair Complete arch repair Surgery on aortic valve (%) Aortic valve replacement Bentall repair Resuspension/aortic valve repair Coronary artery bypass surgery (%) Duration of anesthesia* (min) Duration of surgery* (min) Cardiopulmonary bypass duration* (min) Aortic cross-clamp time* (min) DHCA duration* (min)
Table 4. Intra-, Postoperative and Total Transfusion Data and Postoperative Re-exploration Data
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
13 (27.1) 12 (25)
11 (30.6) 6 (16.7)
0.46 0.26
27 (56.3) 21 (43.8) 15 (31.3) 4 (8.3)
17 (47.2) 20 (52.8) 10 (27.8) 2 (5.6)
0.27 0.27 0.46 0.48
7 (14.6) 39 (81.3) 2 (4.2)
1 (2.8) 32 (88.9) 3 (8.3)
0.06 0.26 0.36
7 (14.6) 11 (22.9) 9 (18.8) 13 (27.1) 534 ⫾ 100 421 ⫾ 82
1 (2.8) 8 (22.9) 12 (33.3) 12 (33.3) 535 ⫾ 137 416 ⫾ 132
0.07 0.60 0.10 0.35 0.97 0.83
234 ⫾ 80 123 ⫾ 46 31 ⫾ 21
199 ⫾ 60 136 ⫾ 50 28 ⫾ 15
0.04 0.25 0.37
*Duration expressed as mean ⫾ standard deviation and others as n (%).
were comparable except for CPB duration, which was significantly higher in the aprotinin group (Table 3). Intraoperative and postoperative transfusion data are presented in Table 4. There was a general trend toward less overall and intraoperative blood product transfusions (RBC, FFP, PLTS, CRYO, and cell saver) in the aprotinin group; however, no statistical significance was reached. There was no significant difference in the use of DDAVP and factor VII between the 2 groups. Re-exploration rate was similar in both the groups (Table 4). Rebleeding after 1 week presented as late-onset pericardial effusion or cardiac tamponade. This occurred during ICU stay, after discharge from the ICU to a regular floor or after discharge from the hospital. Five of the patients presented with cardiac tamponade in the aprotinin group, 2 patients in the TA group had exploration for the left hemothorax, and another bleeding complication in the TA group was related to rectal pathology. Possible reasons include hypertensive episodes, strain on the suture related with coughing, and sepsis. Chest tube drainage in the first 24 hours was 964 ⫾ 477 mL in the aprotinin group versus 763 ⫾ 490 mL in the TA group (p ⫽ 0.11). Functional platelet counts decreased significantly (p ⬍ 0.001) in both groups after CPB (181 ⫾ 67 pre-CPB v 55 ⫾ 28 post-CPB in the aprotinin group and 140 ⫾ 63 pre-CPB v 61 ⫾ 48
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post-CPB in the TA group) with no difference between the 2 groups either before or after CPB. Preoperative renal dysfunction, expressed as CrCl preoperative, was similar between the groups. There was a significant increase in creatinine on postoperative day 1 (p ⫽ 0.01) and postoperative day 7 (p ⫽ 0.02) compared with preoperative creatinine in the aprotinin group. Such an increase in creatinine was detected in the TA group on postoperative day 1 (p ⫽ 0.004) or postoperative day 7 (p ⫽ 0.07) compared with baseline. According to the AKIN definition, 13 patients from the aprotinin group developed new-onset renal dysfunction (stage 1) compared with 3 patients in the TA group (p ⫽ 0.02). No differences between the 2 groups were noted for stage 2 and 3 of the AKIN classification (Table 5). Multivariate logistic regression identified preoperative CrCl, PRBC transfusion, and sepsis as risk factors for development of postoperative renal dysfunction (Table 6). All other complications (neurologic, cardiac, respiratory, and infective) were similar between the 2 groups (Table 7). The duration of ICU and hospital stay were comparable. Overall survival was 86.9%. Three patients died in the operating room (2 patients died of severe uncontrolled bleeding from the aortic suture catheter, and another died of severe refractory biventricular dysfunction). The reasons for mortality of the remaining patients included multiorgan failure (3 patients), a cerebrovascular event (3 patients), and sudden cardiac death (ventricular fibrillation/cardiac arrest in 2 patients). Survival was similar at the point of data collection (February 2008) (89.6% in the aprotinin group v 83.3% in the TA group, p ⫽ 0.42; Fig 1). Thirty-day mortality in the aprotinin group was 5 of 48 (10.4%) compared with 5 of 36 (13.9%) in the TA group (p ⫽ 0.44).
DISCUSSION
Patients who undergo thoracic aortic surgery with DHCA have a higher risk for bleeding compared with other cardiac
Table 6. Predictors of Postoperative Renal Dysfunction Predictor
Odds Ratio
Confidence Interval
p Value
RBC transfusion Sepsis Preoperative CrCl
0.712 0.054 0.978
0.544–0.934 0.004–0.751 0.960–0.995
0.014 0.030 0.013
surgical procedures with CPB. The effects of hypothermia on coagulation and DHCA were published in many articles.7-11 Hypothermia alters platelet morphology, depresses enzyme function, and causes platelet sequestration in the hepatic sinusoids. Thrombin generation during hypothermia stimulates protein C production and tissue plasminogen activator release, both of which promote fibrinolysis.12 Aprotinin, a serine protease inhibitor, has been advocated for the preservation of hemostatic function in cardiac surgery patients at high risk for bleeding including patients undergoing aortic surgery with DHCA. Aprotinin inhibits activation of the kallikrein-kinin system and the plasmin fibrinolysis system, preserves platelet function, and partially inhibits neutrophil activation during CPB.12 The safety and hemostatic efficacy of aprotinin in patients undergoing aortic surgery with DHCA are still matters of debate. In early studies of DHCA and aprotinin, Sundt et al13 and Westaby et al14 showed that aprotinin was ineffective and even potentially harmful. The prolongation of celite ACT used in their study has been proposed as the mechanism for inadequate heparinization and increased thrombotic complications associated with aprotinin. Parolari et al,15 in a retrospective study of 39 patients undergoing DHCA with aprotinin, noticed increased postoperative morbid events with no blood-sparing effects even when appropriate amounts of heparin were administered to maintain celite ACT ⬎800. Lowdose aprotinin has been shown to decrease bleeding without
Table 7. Postoperative Outcome Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
2 (4.3) 4 (8.7) 0 21 (45.7)
2 (5.6) 2 (5.6) 2 (5.6) 12 (33.3)
0.59 0.47 0.19 0.18
5 (10.9) 7 (15.2)
4 (11.1) 3 (8.3)
0.62 0.27
31 (67.4) 20 (43.5) 7 (15.2) 5⫾7
28 (80) 11 (31.4) 4 (11.4) 3⫾6
0.15 0.19 0.44 0.33
8 (17.4) 6 (13) 14 (29.8) 6 (13) 6 (13) 7⫾7 12 ⫾ 7
7 (20) 4 (11.4) 8 (22.9) 2 (5.7) 3 (8.6) 7⫾9 12 ⫾ 13
0.49 0.55 0.33 0.24 0.39 0.82 0.99
Table 5. Serum Creatinine and AKIN Classification
CrClpreop ⬍60 mL/min (%) Serum creatininepreop (mg/dL)* Serum creatinine1st 24 h (mg/dL)* Serum creatinine1st week (mg/dL)* AKIN stage 1† (%) AKIN stage 2‡ (%) AKIN stage 3§储 (%) Renal replacement therapy (RRT)
Aprotinin (n ⫽ 48)
TA (n ⫽ 36)
p Value
19 (39.6) 1.2 ⫾ 0.5 1.4 ⫾ 0.7 1.3 ⫾ 0.6 13 (27.1) 4 (8.3) 2 (4.1) 2 (4.1)
12 (33.3) 1.2 ⫾ 0.4 1.3 ⫾ 0.5 1.3 ⫾ 0.9 3 (8.3) 1 (2.7) 3 (8.3) 3 (8.3)
0.36 0.98 0.38 0.98 0.02 0.27 0.37 0.37
*Data expressed as mean ⫾ SD and others as n (%). †Increase in serum creatinine of more than or equal to 0.3 mg/dL (ⱖ26.4 mol/L) or increase to more than or equal to 150% to 200% (1.5- to 2-fold) from baseline. ‡Increase in serum creatinine to more than 200% to 300% (⬎2- to 3-fold) from baseline. §Increase in serum creatinine to more than 300% (⬎ 3-fold) from baseline (or serum creatinine of more than or equal to 4.0 mg/dL [ⱖ 354 mol/L] with an acute increase of at least 0.5 mg/dl [44 mol/l]). 储Patients who received RRT were considered to have met the criteria for stage 3 irrespective of the stage they were in at the time of RRT.
Cardiac morbidity (%) Myocardial infarction Postoperative IABP ECMO Rhythm irregularities Low cardiac index requiring inotropes RV dysfunction Respiratory morbidity (%) Extubation ⬍72 hours Respiratory failure Tracheostomy Days on ventilator* Neurologic morbidity (%) Stroke Mental status changes Sepsis Deep vein thrombosis ICU readmission ICU stay (d)* Hospital stay (d)*
*Data expressed as mean ⫾ SD and others as n (%).
TRANEXAMIC ACID VERSUS APROTININ
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Fig 1. Survival data for TA- and aprotinintreated patients. (Color version of figure is available online.)
increasing side effects in at least 3 clinical trials.16-18 Mora Mangano et al,19 in a retrospective study, found no beneficial effects of using aprotinin for patients undergoing thoracic aortic surgery. No increase in renal dysfunction was reported in their study.19 No definitive conclusions could be drawn from these studies reporting a varying degree of efficacy and safety of aprotinin in DHCA. The synthetic antifibrinolytic TA is a potent inhibitor of plasminogen and appears to be an effective antifibrinolytic when used for coronary artery bypass surgery. Casati et al20 used a low-dose TA protocol in a prospective, randomized, double-blinded and placebo-controlled study (1-g loading dose followed by 400 mg/h and 500 mg in the pump) for elective thoracic aortic surgery. They found a significant reduction in perioperative bleeding and the transfusion of allogeneic blood in the TA group. There was no significant increase in the occurrence of thrombotic complications such as renal failure, stroke, myocardial infarction, or survival. This study was limited by the small number of patients who underwent thoracic aortic surgery with DHCA (total of 6 patients). Shimamura et al,21 in a study of patients with acute aortic dissection, found that TA (7 g prebypass with additional 3 g after bypass) was effective in reducing blood loss and transfusion requirements compared with placebo and was associated with reduced morbidity and mortality. Eaton and Deeb,22 in a study comparing aprotinin and EACA, reported equal efficacy for both of these drugs, but only EACA was associated with renal dysfunction. TA has replaced aprotinin as the primary antifibrinolytic in high-risk cardiac surgery at some institutions. Very few clinical trials have compared TA with aprotinin in high-risk cardiac surgery. Wong et al,23 in a prospective, randomized study of 80 patients, reported superior efficacy of aprotinin compared with TA in patients with long CPB duration. TA was used as a single dose at induction. High-risk patients on anticoagulants and patients who underwent DHCA were excluded from this study.
Karkouti et al,24 in a propensity-matched case-control study, compared aprotinin and TA in high transfusion risk cardiac surgery and found similar hemostatic effectiveness for both of these drugs. Only aprotinin was associated with renal dysfunction. TA was used as a single dose (50-100 mg/kg) after induction. A subgroup analysis of patients who had DHCA time ⬎15 minutes revealed comparable transfusion rates for TA and aprotinin. A recently published prospective, randomized study (BART study) by Fergusson et al3 found increased 30-day mortality for patients treated with aprotinin compared with lysine analog drugs in high-risk cardiac surgery patients. In the present study, patients received a similar dose of aprotinin and TA but involved only patients requiring DHCA for aortic surgery. Emergency surgery also was included in the analysis unlike prospective studies. Aprotinin was not associated with increased adverse events in this study compared with TA-treated patients. The timing of the administration of the 2 drugs was different in the present study. TA was administered after heparinization. This institutional practice was based on the case reports of graft and native coronary artery thrombosis when TA/EACA was given before heparin administration.25,26 The dose of TA used in the present study was based on Dowd et al’s pharmacokinetic study of TA during cardiopulmonary bypass.27 A single dose is unlikely to maintain the concentrations required for hemostasis during long CPB cases such as aortic surgery. The present authors used the dose that would provide the highest possible and stable concentration (800 mol/L) to produce 98% to 100% reduction of tissue activator activity. In the postaprotinin era, there is a need for evidence-based recommendations for the 2 available lysine analog antifibrinolytics, TA and EACA, regarding dose, efficacy, timing of administration, and adverse events in thoracic aortic surgery. Most institutions use one of them based on their experience and
78
NICOLAU-RADUCU ET AL
consider them to be more helpful than placebo in reducing transfusion requirements and re-explorations. Prospective, randomized, and comparative clinical trials are recommended in this area. The authors used the AKIN criteria to define renal dysfunction and failure. It can be inferred from the present results that aprotinin may be associated with increased renal dysfunction as measured by an increase in serum creatinine but did not increase the incidence of serious renal failure requiring RRT. The incidence of other postoperative complications and the 30-day mortality were similar in both groups. This can be interpreted in different ways. Aprotinin may be as safe as TA; however, because the drug is off the market, this way of interpreting the results may not impact the current practice. The other way of interpreting the results is concerning because TA could produce the same number of side effects as aprotinin, which needs further evaluation. Another way of reasoning is that the patients undergoing complex aortic surgery with DHCA are at a higher risk for developing perioperative complications, and the antifibrinolytic used may not be a significant factor influencing the outcome. The authors used FVII in 4 patients (2 in each group) for refractory bleeding, and 3 of those patients (2 in the TA group and 1 in the aprotinin group) developed stroke within the first 24 hours, so FVII could have promoted thrombus formation,28 but it might have happened irrespective of the antifibrinolytic used. However, in the study by Tripepe et al,29 when FVII was used, there was no increase in thromboembolic complications after acute aortic dissection surgery with DHCA. Although other factors such as embolism could play a role in the development of postoperative stroke, FVII should be used with caution.
LIMITATIONS
The observational nature of this study indicates that data may imply only association not causation. Because this is a retrospective study, various unmeasured variables could have influenced the results. For example, there could be variations in the surgical techniques between different surgeons to account for the bleeding. Although the scientific guidelines had been followed in general for the transfusion of blood products, there could be variation from protocols in individual patients based on the clinical status. The use of blood products tends to be more in the TA group despite the fact that the aprotinin group had higher CPB duration. This may indicate better antifibrinolytic efficacy of aprotinin, which cannot be proven by this retrospective study of limited sample size. Aprotinin group patients had numerically higher preoperative arrhythmias, peripheral vascular disease, redo sternotomy, and higher CPB duration. Only CPB duration reached statistical significance. It is possible that aprotinin patients were sicker preoperatively, and the groups were not matched perfectly. It is possible that sicker patients received aprotinin inducing a selective bias during the time period when both antifibrinolytics were available for use. Small sample size prevented the authors from performing statistical matching such as propensity matching. In conclusion, aprotinin appeared to be more effective in reducing blood product transfusion after thoracic aortic surgery with DHCA compared with tranexamic acid. However, this could not be proven with this retrospective study of 84 patients. The choice of antifibrinolytic appeared not to be associated with cardiac, neurologic, and respiratory outcomes and survival after thoracic aortic surgery requiring DHCA. However, aprotinin use appeared to be associated with increased postoperative renal dysfunction.
REFERENCES 1. Umscheid CA, Kohl BA, Williams K: Antifibrinolytic use in adult cardiac surgery. Curr Opin Hematol 14:455-467, 2007 2. Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation: The risk associated with aprotinin in cardiac surgery. N Engl J Med 354:353-365, 2006 3. Fergusson DA, Hebert PC, Mazer CD, et al: (BART study). A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358:2319-2331, 2008 4. Chukwuemeka A, Weisel A, Mangani M, et al: Renal dysfunction in high-risk patients after on-pump and off-pump coronary artery bypass surgery: A propensity score analysis. Ann Thorac Surg 80: 2148-2154, 2005 5. Mehta RL, Kellum JA, Shah SV, et al: Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31, 2007 6. Kellum JA, Mehta RL, Angus DC, et al: The first international consensus conference on continuous renal replacement therapy. Kidney Int 62:1855-1863, 2002 7. Mossad EB, Machado S, Apostolakis J: Bleeding following deep hypothermia and circulatory arrest in children. Semin Cardiothorac Vasc Anesth 11:34-46, 2007 8. Krause KR, Howells GA, Buhs CL, et al: Hypothermia-induced coagulopathy during hemorrhagic shock. Am Surg 66:348-354, 2000 9. Kirkpatrick AW, Chun R, Brown R, et al: Hypothermia and the trauma patient. Can J Surg 42:333-343, 1999
10. Westaby S: Coagulation disturbance in profound hypothermia: The influence of anti-fibrinolytic therapy. Semin Thorac Cardiovasc Surg 9:246-256, 1997 11. Wilde JT: Hematological consequences of profound hypothermic circulatory arrest and aortic dissection. J Card Surg 12:201-206, 1997 (suppl) 12. Westaby S: Anti-fibrinolytic therapy in thoracic aortic surgery. Ann Thorac Surg 67:1983-1985, 1999 13. Stundt TM, Kouchoukos NT, Saffitz JE, et al: Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 55:1418-1424, 1993 14. Westaby S, Forni A, Dunning J, et al: Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 8:82-86, 1994 15. Parolari A, Antona C, Alamanni F, et al: Aprotinin and deep hypothermic circulatory arrest: There are no benefits even when appropriate amounts of heparin are given. Eur J Cardiothorac Surg 11:149-156, 1997 16. Goldstein DJ, DeRosa CM, Mongero LB, et al: Safety and efficacy of aprotinin under conditions of deep hypothermia and circulatory arrest. J Thorac Cardiovasc Surg 110:1615-1622, 1995 17. Seigne PW, Shorten GD, Johnson RG, et al: The effects of aprotinin on blood product transfusion associated with thoracic aortic surgery requiring deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 14:676-681, 2000
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18. Ehrlich M, Grabenwöger M, Cartes-Zumelzu F, et al: Operations on the thoracic aorta and hypothermic circulatory arrest: Is aprotinin safe? J Thorac Cardiovasc Surg 115:220-225, 1998 19. Mora Mangano CT, Neville MJ, Hsu PH, et al: Aprotinin, blood loss, and renal dysfunction in deep hypothermic circulatory arrest. Circulation 104:I276-I281, 2001 (suppl 1) 20. Casati V, Sandreli L, Speziali G, et al: Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: A prospective, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 123:1084-1091, 2002 21. Shimamura Y, Nakajima M, Hirayama T, et al: The effect of intraoperative high-dose tranexamic acid on blood loss after operation for acute aortic dissection. J Thorac Cardiovasc Surg 46:616-621, 1998 22. Eaton MP, Deeb GM: Aprotinin versus epsilon-aminocaproic acid for aortic surgery using deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 12:548-552, 1998 23. Wong BI, McLean RF, Fremes SE, et al: Aprotinin and tranexamic acid for high transfusion risk cardiac surgery. Ann Thorac Surg 69:808-816, 2000
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24. Karkouti K, Beattie WS, Dattilo KM, et al: A propensity score case-control comparison of aprotinin and tranexamic acid in hightransfusion-risk cardiac surgery. Transfusion 46:327-338, 2006 25. Shaw AD, Stafford-Smith M, White WD, et al: The effects of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 358:784-793, 2008 26. Schneeweiss S, Seeger JD, Landon J, et al: Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 358:771-783, 2008 27. Dowd NP, Karski JM, Cheng DC, et al: Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2:390399, 2002 28. O’Connell KA, Wood JJ, Wise RP, et al: Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 295:293-298, 2006 29. Tripepe L, De Santis V, Vitale D, et al: Recombinant activated factor VII for refractory bleeding after acute aortic dissection surgery: A propensity score analysis. Crit Care Med 35:1685-1690, 2007