Red Blood Cell Transfusion Is Associated With Troponin Release After Elective Off-Pump Coronary Artery Bypass Surgery

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1 CARDIOTHORACIC ANESTHESIOLOGY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Red Blood Cell Transfusion Is Associated With Troponin Release After Elective Off-Pump Coronary Artery Bypass Surgery Fausto Biancari, MD, PhD, and Eeva-Maija Kinnunen, MS Department of Surgery, Oulu University Hospital, Oulu, Finland Background. Increased troponin levels after coronary artery bypass surgery are associated with increased risk of early and late mortality. We hypothesized that perioperative blood transfusion is associated with increased postoperative troponin release. Methods. Complete data on perioperative blood transfusion and troponin I were available for 140 patients who underwent isolated, elective off-pump coronary artery bypass graft surgery. Results. Linear regression analysis showed that red blood cell (RBC) transfusion (p 0.007) was an independent predictor of troponin I levels on the first postoperative day. The RBC transfusion was associated with a high risk of type V myocardial infarction as indicated by troponin I levels greater than 6.6 g/l on the first postoperative day (9 of 58 patients [15.5%] versus 1 of 82 patients [1.2%], p 0.002; adjusted analysis odds ratio , 95% confidence interval: to ). This finding did not change when hemoglobin and hematocrit nadirs were included in the analysis. Repeated-measure test showed that any blood product transfusion (p 0.040), any blood product transfusion on the operation day (p 0.025), any RBC transfusion (p 0.014), and RBC transfusion on the operation day (p 0.026) were associated with increased postoperative troponin I release. These findings persisted even after adjusting for hemoglobin and hematocrit nadirs. Conclusions. Red blood cell transfusion is associated with increased troponin I release after elective off-pump coronary artery bypass graft surgery independently of hemoglobin and hematocrit nadirs. These findings suggest that prevention of major bleeding requiring blood transfusion may be cardioprotective during coronary surgery. Further studies are needed to verify whether troponin release is affected simply by RBC transfusion or by unstable hemodynamic conditions in presence of mild and severe anemia. (Ann Thorac Surg 2012;94:1901 7) 2012 by The Society of Thoracic Surgeons Accepted for publication May 11, Address correspondence to Dr Biancari, Department of Surgery, Oulu University Hospital, PL 21, Oulu 90029, Finland; faustobiancari@yahoo.it. Anumber of studies have shown that myocardial injury after coronary artery bypass graft surgery (CABG) as measured by cardiac biomarkers is associated with a significantly higher risk of early and late mortality [1]. In particular, cardiac troponin I (TnI) seems to be the most accurate biomarker of myocardial injury after cardiac surgery [2, 3]. Recent findings suggest that TnI, at an appropriate threshold, is adequate to detect type V myocardial infarction after CABG independently of supplementary evidence [2]. A number of studies have shown that red blood cell (RBC) transfusion may have a negative impact on early and late outcome of patients with acute coronary syndrome [4 6] and patients undergoing cardiac surgery [7 10]. Of particular concern is the impact of RBC transfusion on the risk of cardiac events after CABG [9]. We hypothesized that RBC transfusion may be associated with myocardial injury after cardiac surgery and therefore with postoperative release of TnI. This issue has been investigated in this study by including only patients who recently underwent isolated, elective OPCABG, therefore excluding any potential impact of unstable angina pectoris, recent myocardial infarction, and cardioplegic cardiac arrest on TnI release. Material and Methods The present study includes a consecutive series of 140 patients who underwent isolated, elective OPCABG for stable angina pectoris from October 2009 to December 2011 at the Oulu University Hospital, Finland. The study plan was approved by the Institutional Review Board of the Oulu University Hospital. During the study period, 869 patients underwent isolated CABG with or without the Maze procedure. The OPCABG was performed in 458 of them (52.7%), of whom 140 patients underwent elective OPCABG. We excluded from this analysis patients who undergo on-pump CABG, any Maze procedure, with recent myocardial infarction, any preoperative increase of TnI level, or unstable angina pectoris. Complete data on the periop by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 1902 BIANCARI AND KINNUNEN Ann Thorac Surg BLOOD TRANSFUSION AND TROPONIN RELEASE 2012;94: Table 1. Baseline Characteristics and Operative Data on 140 Patients With Stable Angina Pectoris Who Underwent Elective Off-Pump Coronary Artery Bypass Surgery Characteristics and Operative Data No. of Patients (%) Univariate Analysis Multivariate Analysis Baseline characteristics Age, years Female 28 (20.0) Preoperative statin 129 (92.1) Preoperative aspirin 131 (93.6) Preoperative warfarin 11 (7.9) Hemoglobin, g/l Hematocrit egfr, a ml min m Dialysis 0 (0) Left main stenosis 75 (53.6) Three-vessel disease 108 (77.1) Pulmonary disease 14 (10.0) Diabetes mellitus 45 (32.1) Atrial fibrillation 11 (7.9) Stroke 1 (0.7) Neurologic dysfunction 1 (0.7) Extracardiac arteriopathy 11 (7.9) Previous PCI 1 (0.7) Previous cardiac surgery 1 (0.7) Recent myocardial infarction 0 (0) LVEF 50% 23 (16.4) Systolic pulmonary pressure 60 mm Hg 1 (0.7) Additive EuroSCORE Operative data Intraoperative use of tranexamic acid 12 (8.6) Number of distal anastomoses Length of the operation, minutes Results of univariable and multivariable analysis for prediction of serum level of troponin I on the first postoperative day are also reported. Continuous variables are reported as mean SD; dichotomous variable are reported as counts and percentages. a Estimated glomerular filtration rate (egfr) according to Modification of Diet in Renal Disease formula [29]. EuroSCORE European System for Cardiac Operative Risk Evaluation; LVEF left ventricular ejection fraction; PCI percutaneous coronary intervention. erative use of blood products such as RBCs, platelets, and solvent/detergent-treated plasma (Octaplas; Octapharma AG, Lachen, Switzerland) as well as on TnI, hemoglobin, and hematocrit levels were available in all these patients as retrieved from electronic patients records. Baseline and operative data were provided by a local institutional clinical registry, which prospectively collects information in computerized databases. Operative risk was assessed by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk scoring method [11]. Patients characteristics are summarized in Table 1. Perioperative Antithrombotic Treatment, Blood Transfusion, and Resternotomy for Excessive Bleeding Aspirin, 100 mg orally, was discontinued preoperatively in 106 patients (75%), whereas 34 patients (25%) received aspirin within 3 days before surgery. Heparin (2.5 to 4.0 mg/kg) was administered intravenously after sternotomy to maintain an activated clotting time of more than 400 s, and it was neutralized at the end of the procedure by protamine sulphate (1.5 to 3.0 mg/kg). Further protamine was given in case of bleeding during closure of the chest or within the first hour after surgery according to activated coagulation time. Aprotinin was not used in any of these patients. Tranexamic acid was administered intraoperatively at discretion of the anesthesiologist. Packed leuko-reduced RBCs were transfused on the operation day if hemoglobin was lower than 90 g/l. Later, RBCs were transfused if hemoglobin was less than 80 g/l. Octaplas as well as platelets were transfused according to the amount of intraoperative and postoperative bleeding, international normalized ratio levels, and platelet count. Resternotomy was performed in case of excessive bleeding according to criteria previously described [12]. All blood lost during the operation was collected in the cell-saving reservoir and washed; salvaged RBCs were autotransfused during or at the completion of the operation. Mediastinal blood/fluid was collected after surgery in

3 Ann Thorac Surg BIANCARI AND KINNUNEN 2012;94: BLOOD TRANSFUSION AND TROPONIN RELEASE 1903 a sterile collection chamber connected to 15-cm H 2 O wall suction through an underwater seal and then discarded. Enoxaparin (40 to 80 mg once a day) was started on since the evening of the operation day in those patients without excessive bleeding ( 1,000 ml). Aspirin, 100 mg, was restarted on the first postoperative day. Warfarin was started on the first postoperative day in patients on chronic oral anticoagulation or started de novo in case of persistent atrial fibrillation. Clopidogrel was used postoperatively in these patients only in case of allergy to aspirin or recent percutaneous coronary intervention. Operative Techniques The OPCABG technique was used in all these patients. Epiaortic ultrasonography was performed according to the surgeon s preference. Ascending aorta was left untouched in case of grade III diseased aorta [13]. Proximal anastomoses were sutured to the ascending aorta during side bite clamping, when the latter was considered safe. Octopus stabilizer and intracoronary shunts of appropriate size (Medtronic, Minneapolis, MN) were routinely used. Hemoglobin and Hematocrit Levels Data on baseline hemoglobin and hematocrit as well as their nadir on the operation day as well as on the first and third postoperative day were retrospectively retrieved. Measurement of Troponin I Plasma samples were obtained in all patients the day before surgery, at midnight of the operation day, and on the morning of the first and third postoperative day. Automated chemiluminescent immunoassay techniques were used to quantify TnI on the Siemens ADVIA Centaur XP (Healthcare Diagnostics, Espoo, Finland). This assay has a 99th percentile upper reference limit of 0.04 g/l. Outcome Endpoints The primary outcome endpoint of this study was postoperative TnI release as measured at about 12 hours after surgery (7 patients underwent surgery in the afternoon, and TnI levels were measured approximately 6 hours after the end of surgery), and on the morning of the first and third postoperative day. Plasma concentration of TnI on the first postoperative day was considered the main outcome endpoint as this biomarker usually reaches the highest level 12 to 24 hours after surgery [14, 15]. Troponin I as measured on the first postoperative day was dichotomized according to its 75th percentiles (2.0 g/l). Furthermore, we adopted a cutoff of 6.6 g/l for diagnosis of type V myocardial infarction as identified in a recent study assessing the diagnostic accuracy of TnI in identified areas of myocardial necrosis [2]. We decided to adopt this cutoff value because herein we measured TnI level with the same tools employed by Pegg and colleagues [2]. Secondary outcome endpoints were in-hospital death, stroke, low cardiac output syndrome (postoperative cardiac index 2.0 L min 1 m 2 ), prolonged use of inotropics ( 12 hours), new onset renal failure requiring dialysis, reexploration for excessive bleeding, postoperative blood loss as measured on the morning of the first postoperative day, and use of blood products. Ethical Considerations The study protocol was approved by the Institutional Review Board of the Oulu University Hospitals. This study was not financially supported. Statistical Analysis Data were analyzed with the use of PASW version 18 statistical software (IBM SPSS Inc, Chicago, IL). Continuous variables are reported as the mean SD and nominal variables as counts and percentages. Pearson s 2 test, Fisher s exact test, and Mann-Whitney s U test were used for univariate analysis. Correlations between continuous variables were assessed by the Spearman s test. Linear and logistic regression, with the help of backward selection, were used for multivariable analysis. Variables with a p value less than 0.20 at univariate analysis were included in the regression models. A p value less than 0.05 was considered statistically significant. Results Immediate Postoperative Outcome None of these patients were converted to on-pump surgery. None of these patients died during the inhospital stay. Ten patients (7.1%) experienced low cardiac output syndrome, 21 (15.0%) received inotropics for more than 12 hours after surgery, 3 (2.1%) underwent reexploration for excessive bleeding, 1 (0.7%) underwent dialysis for acute renal failure, and 3 had postoperative stroke (2.1%). Postoperative blood loss was ml. Predictors of Red Blood Cell Transfusion Univariate analysis showed that advanced age (p 0.008), female sex (p ), low estimated glomerular filtration rate (p ), low preoperative hemoglobin (p ), and low preoperative hematocrit (p ) were associated with significantly higher risk of RBC transfusion after surgery. Logistic regression showed that female sex (p 0.043, odds ratio [OR] 2.928, 95% confidence interval [CI]: to 8.271), and preoperative hemoglobin (p 0.003, OR 0.948, 95% CI: to 0.982) were independent predictors of RBC transfusion. Troponin I Release Results of univariate analysis are summarized in Tables 1 and 2. Postoperative TnI levels did not correlate with either hemoglobin nadirs (mean g/l; range, 64 to 126; p to p 0.949) or hematocrit nadirs (mean ; range, 0.19 to 0.37; p to p 0.976) at any of the study intervals. Furthermore, female sex was not associated with significantly increased levels of TnI (p 0.348).

4 1904 BIANCARI AND KINNUNEN Ann Thorac Surg BLOOD TRANSFUSION AND TROPONIN RELEASE 2012;94: Table 2. Data on Postoperative Bleeding, Hemoglobin and Hematocrit Levels, and Use of Blood Products in 140 Patients With Stable Angina Pectoris Who Underwent Elective Off-Pump Coronary Artery Bypass Graft Surgery Variables No. of Patients (%) Univariate Analysis Multivariate Analysis Postoperative blood loss, ml Nadir hemoglobin on operation day, g/l Nadir hematocrit on operation day Hemoglobin first postoperative day, g/l Hematocrit first postoperative day Any blood product transfusion on operation day 51 (36.4) Red blood cell transfusion on operation day 41 (29.3) Any blood product transfusion 67 (47.9) Red blood cell transfusion 58 (41.4) Red blood cell units transfused Octaplas transfusion 27 (19.3) Octaplas units transfused Platelet transfusion 22 (15.7) Platelet units transfused All three blood products transfused 11 (7.9) Results of univariable and multivariable analysis for prediction of serum level of troponin I on the first postoperative day are also reported. Continuous variables are reported as mean SD; dichotomous variable are reported as counts and percentages. Troponin I levels measured on the operation day and on the first postoperative day were not associated with either the occurrence of low cardiac output syndrome (p and p 0.388, respectively), prolonged use of inotropics (p and p 0.336, respectively), or any other major postoperative complication. Red blood cell transfusion on the operation day was not associated with either the occurrence of low cardiac output syndrome (p 0.157) or prolonged use of inotropics (p 0.336). Predictors of plasma concentration of TnI on the first postoperative day are summarized in Tables 1 and 2. Linear regression analysis including estimated glomerular filtration rate, number of distal anastomoses, preoperative hemoglobin level, female sex, and RBC transfusion, showed that only RBC transfusion (p 0.007) was an independent predictor of TnI levels on the first postoperative day. This finding was confirmed also by a regression model including hematocrit and hemoglobin nadirs on the operation day. Red blood cell transfusion (p 0.012) was a predictor of TnI levels on the first postoperative day even when the latter was logtransformed and additive EuroSCORE (p 0.004) was included in the regression model. The amount of packed RBCs transfused correlated with postoperative release of TnI (rho 0.188, p 0.026; Fig 1) and was the only independent predictor of TnI release at linear regression (p 0.001). Logistic regression analysis showed that RBC transfusion was also the only independent predictor of TnI greater than 2.0 g/l on the first postoperative day (p 0.011, OR 2.73, 95% CI: 1.26 to 5.90). Red blood cell transfusion was associated with a high risk of type V myocardial infarction as indicated by TnI greater than 6.6 g/l on the first postoperative day (9 of 58 patients [15.5%] versus 1 of 82 patients [1.2%], p 0.002, adjusted analysis OR , 95%CI: to ). This finding did not change when hemoglobin and hematocrit nadirs were included in the regression model. Among patients with TnI greater than 6.6 g/l, 3 patients had hemoglobin nadir less than 80 g/l at any study interval (hemoglobin lowest level, 64 g/l), whereas 4 patients had a hematocrit nadir less than 24% at any study interval (hematocrit lowest level 19%). Repeated-measure test showed that any blood product transfusion (p 0.040), any blood product transfusion on the operation day (p 0.025), any RBC transfusion (p Fig 1. Scatter plot showing a significant correlation between troponin I levels on the first postoperative day (shown in logarithmic scale) and the number of red blood cell (RBC) units transfused (rho: 0.188, p 0.026). Lines are cubic fit line and 95% confidence interval.

5 Ann Thorac Surg BIANCARI AND KINNUNEN 2012;94: BLOOD TRANSFUSION AND TROPONIN RELEASE 1905 Fig 2. Troponin I release after off-pump coronary artery bypass surgery in 58 patients who did and in 82 patients who did not receive red blood cell transfusion (repeated-measure test: p 0.014). Differences between study groups were significant also at each postoperative (postop) time interval (Mann-Whitney test: p 0.026, p 0.012, and p 0.004, respectively) ; Fig 2), and RBC transfusion on the operation day (p 0.026) were associated with postoperative TnI release. Neither Octaplas (p 0.628) nor platelet transfusion (p 0.137) was associated with postoperative ctni release. Comment An increasing burden of evidence exists on the association between irreversible myocardial injury as detected at cardiovascular magnetic resonance imaging and release of troponins after cardiac surgery [2, 3, 16]. This in turn translates into a significantly higher risk of early and late mortality in these patients [1]. Therefore, identification of risk factors associated with and prevention of marked troponin release are of clinical significance in patients undergoing coronary surgery. Postoperative release of TnI after OPCABG can be related to unstable angina pectoris or recent myocardial infarction, prolonged aortic cross-clamp time, intraoperative hemodynamic instability, as well as a number of technical factors (inappropriate heart manipulation/stabilization, technical errors at anastomosis site, shuntless anastomosis technique, or graft failure). However, clinical experience demonstrates that increased postoperative levels of TnI can be often observed in patients in absence of significant perioperative hemodynamic instability or any evident intraoperative technical problems or signs of graft failure. Indeed, causes of troponin release after OPCABG are largely unexplored, the use of intracoronary shunts being the only factor recognized to significantly reduce postoperative troponin release [17]. The present results suggest that perioperative RBC transfusion may be a major determinant of marked TnI release after OPCABG. Even if there are no prior data to confirm these findings, our results are in line with a number of studies that demonstrated a significantly higher risk of cardiac events and mortality in patients with acute coronary syndrome or undergoing cardiac surgery [4 6,9]. The reasons for such a negative impact on prognosis of transfused patients are still unclear, but the significant impact of RBC transfusion is substantiated by the poorer outcome particularly in patients without severe anemia who received RBC transfusion [4, 6]. Red blood cell transfusion is the only available treatment for anemia in the acute setting. This is of particular relevance in patients with acute coronary syndrome as the myocardium has a resting oxygen extraction ratio of 60% to 70% and has little capacity to further increase oxygen extraction [18]. That makes the myocardium particularly vulnerable to anemia, and RBC transfusion is used to promptly improve oxygen delivery in severe anemia to reduce its related risk of myocardial and systemic ischemic injury. However, these cardioprotective effects can be achieved only when fresh RBCs are transfused, as indicated by experimental studies [19, 20]. In fact, transfusion of stored blood can be ineffective at salvaging ischemic myocardium. Indeed, clinical studies indicate that RBC storage time may increase the risk of mortality [21, 22]. That may be due to reduced deformability of stored RBCs, which may result in occlusion of the microcirculation by nondeformable RBCs. Tsai and colleagues [20] have shown a reduction of microvascular blood flow and functional capillary density after RBC transfusion also in experimental normovolemic anemic conditions. These findings were not confirmed by a clinical study evaluating systemic (but not myocardial) microcirculation in patients with a mean hemoglobin nadir of 80 g/l [23]. Stored RBCs have lower adenosine triphosphate levels and impaired ability to release it in the microcirculation, therefore preventing the potent adenosine triphosphate related vasodilatory effect [19]. The high free hemoglobin concentrations measured in stored blood may further affect microcirculation because free hemoglobin has a potent nitric oxide scavenging ability, and this may induce vasoconstriction and worsen the ischemic injury [24]. These factors may significantly worsen the effect of anemia in patients with compromised coronary artery reserve. Therefore, restoring microvascular perfusion deficiency in anemia and hemorrhagic resuscitation can be considered as efficacious as restoring oxygen carrying capacity. This may potentially reduce the use of blood transfusion and its related possible complications [25]. The significant association between RBC transfusion and postoperative increased levels of TnI, in particular

6 1906 BIANCARI AND KINNUNEN Ann Thorac Surg BLOOD TRANSFUSION AND TROPONIN RELEASE 2012;94: TnI greater than 6.6 g/l as an indicator of type V myocardial infarction [2], is of clinical importance. In fact, such high TnI levels were independent of either hemoglobin or hematocrit nadirs, and therefore confirms the impact of blood transfusion on the occurrence of perioperative cardiovascular events after coronary surgery. We have recently showed that use of blood products in patients undergoing CABG was associated also with a particularly high risk stroke [26], which suggested a possible prothrombotic status or worsening of brain microcirculation induced by the use of blood products. It is worth noting that in clinical studies, RBCs are often transfused in patients with severe perioperative hemodynamic instability even in absence of severe anemia, and this may introduce a severe bias in the analysis of any clinical series. Even if there is large evidence on the harms related with its use, at this stage, RBC transfusion could be considered simply as a marker of unfavorable perioperative oxyhemodynamic conditions as anesthesiologists administer blood products in cases of excessive bleeding and unstable hemodynamic conditions. In fact, the recently reported vasoplegic effect of blood transfusion may simply reflect unstable conditions inducing the use of RBC transfusion to improve oxygen delivery [27]. Future studies should specifically address these unfavorable hemodynamic conditions to get more conclusive results on the real impact of blood transfusion in these patients. The retrospective nature of this study and the lack of perioperative hemodynamic data are important limitations of this study. Furthermore, the limited number of patients who received RBC transfusion did not allow the analysis of the impact of transfusion in patients with different degree of anemia, which may be of particular relevance in this setting. In fact, previous data indicate that RBC transfusion may be of benefit only in patients with critically low hemoglobin levels [4]. However, we attempted to investigate this issue in a patient population with a low risk of marked troponin release by including only patients with stable angina pectoris and normal baseline TnI levels undergoing elective, isolated OPCABG, therefore without the confounding effect of acute coronary syndrome, use of cardioplegic heart arrest, and of cardiopulmonary bypass [28]. In conclusion, the results of this retrospective study indicate that RBC transfusion in patients undergoing isolated, elective OPCABG is associated with increased TnI release. 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