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Ann Thorac Surg 2005;79:837-845
© 2005 The Society of Thoracic Surgeons
a Cardiac Surgery Unit, University Magna Graecia, Catanzaro
b Department of Cardiothoracic Surgery, Second University of Naples, Naples, Italy
Accepted for publication July 23, 2004.
* Address reprint requests to Dr Onorati, Viale dei Pini, 28, 80131 Napoli, Italy (E-mail: frankono{at}libero.it).
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Abstract |
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METHODS: Data of 776 consecutive patients undergoing CABG between January 2002 and January 2004 were prospectively exposed to univariate and multivariate analysis. We evaluated the prognosis of patients with all the ECG, echocardiographic, and biochemical criteria for acute myocardial infarction and that of patients with only TnI elevation. Twelve-month follow-up survival and freedom from cardiac events (FCE) were accomplished.
RESULTS: Troponin I greater than 3.1 µg/L at 12 hours was detected in 6.9% of the population, and correlated with lower in-hospital (p < 0.001) and follow-up survival (p = 0.00001), and lower FCE (p = 0.0009). Twenty-one (38.8%) of these fulfilled ECG-echocardiographic criteria (p = 0.05), demonstrating higher TnI values at 12 (p = 0.001), 24 (p = 0.01), 48 (p = 0.01), and 72 (p = 0.04) hours, prolonged ventilation time (p = 0.001), higher in hospital mortality (p = 0.003), lower follow-up survival (p = 0.023), and lower FCE (p = 0.0084). A EuroSCORE greater than 6, ongoing unstable angina, aortic cross-clamp time greater than 90 minutes, cardiopulmonary bypass time greater than 180 minutes, incomplete revascularization, and intraoperative intraaortic balloon pump were independent predictors of myocardial damage (MD) at multivariate analysis. Combined antegrade and retrograde cardioplegia and postoperative enoximone infusion were associated with a lower TnI elevation.
CONCLUSIONS: Troponin I greater than 3.1 µg/L at 12 hours defines perioperative MD. Associated ECG-echocardiographic criteria indicate acute myocardial infarction and anticipate a worse outcome. Identification of predictors for MD is important to develop preventative strategies, as antegrade plus retrograde cardioplegia and enoximone infusion.
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Introduction |
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Despite attempts to improve the detection of perioperative myocardial necrosis, new Q waves on the electrocardiograph (ECG) and elevated blood levels of the MB isoenzyme of creatine kinase are still used to establish the diagnosis. Moreover, although new Q waves on the ECG suggest transmural infarction, minimal necrosis and damage are not recognized with this approach [3, 4].
Recently cardiac troponin I (TnI) has been shown to be a specific marker of myocardial damage (MD) with a higher sensitivity and specificity and a wider diagnostic window as compared to conventional biochemical enzymes such as creatine kinase, MB isoenzyme, and myoglobin. It is widely accepted that TnI should be able to detect even minor differences of myocardial ischemia, and that TnI greater than 3.1 µg/L at 12 hours also defined perioperative MD in cases without ECG or echocardiographic findings [5]. Moreover, recent reports have defined postoperative TnI as a sensible marker of the quality of myocardial protection and of prognostic value for cardiovascular events at follow-up [6].
During the past few decades, perioperative MD has been the focus of a number of studies, which differed with respect to the time period examined, the surgical strategies, the data elements compared, and the patient population. In fact, the variation in demographic data and in the distribution of risk factors among different ethnic groups, races, and geographical locations has to be considered [7]. Moreover, there have also been tremendous efforts to develop risk stratification models to provide a more accurate risk prediction. Finally, the changing profile of patients undergoing cardiac surgery operations necessitates continuous updating and revision of risk models [1, 2].
However, the prediction of outcome after CABG is still of significant interest to the scientific community. It was the aim of our study to evaluate determinants of perioperative myocardial damage, as defined by TnI elevation, in a double-center population undergoing primary isolated CABG in the last two years.
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Material and Methods |
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Of preoperative variables, number and type of diseased vessels were determined based on the angiography of the patient. The left anterior descending, left circumflex, right coronary artery, or posterior descending artery were considered to be diseased only if the stenosis was equal to or greater than 60% of the luminal diameter. The left main coronary artery was classified as diseased if any stenosis equal to or greater than 50% of luminal diameter was reported. Left main disease was also dichotomized in two groups: greater than 50% and less than 75%, and greater than 75%.
Of intraoperative variables, aortic cross-clamp time was categorized as more or less than 90 minutes; similarly, cardiopulmonary bypass time was dichotomized in more or less than 180 minutes. Inotropic support was defined as low dose when enoximone or dobutamine were administered at dosages lower than 5 µg · Kg · min. A medium dose of inotropic agents was considered when dobutamine or dopamine were at dosages between 5 and 10 µg · Kg · min for greater than 6 hours postoperatively. A high dose was defined when epinephrine was added to dobutamine or dopamine infusion greater than 10 µg · Kg · min.
Of postoperative variables and complications, arrhythmias were considered to be a complication only if they were life-threatening or needed medical treatment; postoperative respiratory failure was defined as the need for mechanical ventilator support for greater than 48 hours; acute renal failure as the need for continuous veno-venous hemofiltration or dialysis.
Patient Population and Surgery
Of the patients, 226 (29.1%) were female; 211 (27.2%) had unstable angina with endovenous infusion of nitrates on hospital admission; 187 (24.1%) had left main stem disease (LMSD) as indication of CABG. Forty-five (5.8%) patients demonstrated severe left ventricular dysfunction (ejection fraction < 30%) on hospital admission; 264 (34%) suffered from diabetes mellitus with oral drugs or insulin therapy; 338 (43.8%) had hypertension with ecochardiographic finding of ventricular hypertrophy; 299 (38.5%) were dyslipidemic.
Surgery was always performed by the same group of surgeons (No. 4) and always through a median sternotomy. One hundred and thirty-three (17.2%) patients underwent off-pump surgery, whereas 643 patients (82.8%) underwent conventional CABG with cardiopulmonary bypass and warm blood cardioplegia; in 369 (57.4%) of these blood cardioplegia was administered only antegrade and in 274 (42.6%) intermittent retrograde delivery was added. One hundred and seventy (21.9%) patients underwent total arterial grafting.
Electrocardiography
Twelve-lead electrocardiographic recordings were performed preoperatively, on admission to the intensive therapy unit postoperatively, and then daily thereafter until hospital discharge or whenever judged necessary. All patients had continuous electrocardiogram monitoring for the first 48 hours postoperatively. The incidence of dysrhythmias, both atrial and ventricular, were recorded together with transient ischemic events (ST segment elevation > 1 mm). The ECG diagnostic criteria for perioperative AMI were new Q waves of greater than 0.04 ms, and/or a reduction in R waves greater than 25% in at least two leads.
Echocardiography
All studies were performed using a transthoracic Acuson Sequoia C256 echocardiography system (Acuson Corporation, Mountain View, CA) with probe 3V2C, always by the same two physicians in a blind manner, preoperatively, at the time of hospital admission, and before hospital discharge. Left ventricular ejection fraction (LVEF), wall motion score index, and indexed left ventricular mass (ILVM) were recorded. A value of ILVM greater than 125 g/m2 was considered as a marker of left ventricular hypertrophy.
Biochemical Analysis
Blood samples were always collected from the central venous line; the tip of the cannula was located in the lower part of the right atrium as confirmed by chest roentgenogram postoperative control. Determination of blood concentration of cardiac TnI was conducted preoperatively before anesthetic induction, and postoperatively at 12, 24, 48, and 72 hours postoperatively. The assays were carried out using diagnostic kits provided by Beckman Coulter for TnI (Access Immunoassay System - AccuTnI).
Definitions of MD and AMI
Perioperative MD was defined when TnI peaked at 3.1 µg/L at 12 hours [5]. Perioperative AMI was defined when new Q waves of greater than 0.04 ms, and/or a reduction in R waves greater than 25% in at least two leads were detected, new akinetic-dyskinetic segment was identified at echocardiography, and TnI peaked at 3.1 µg/L at 12 hours.
Data Collection
Data were recorded prospectively using the institutional databases. All variables analyzed were entered in a prospective fashion by physicians involved in the daily care of patients, resulting in a complete data set for each patient. The quality of the data were routinely assessed when used to generate text documents that became the patient's chart while in hospital, resulting in meticulous confirmation of the entered data. In order to avoid bias in the interpretation of the results, the physicians involved in the analysis of ECG and echocardiography were blinded toward the biochemical results.
Follow-up data (survival and cardiac events; ie, myocardial infarction, recurrence of angina, heart failure, cardiac-related readmission to hospitals) were collected by the database of our outpatient clinic for the majority of patients. About 20% of the follow-up data were completed by telephone interview or by correspondence with the patient's own general physicians.
Statistical Analysis
Continuous variables are expressed as mean ± standard deviation, and categorical data as proportions. Comparisons of continuous variables were made with the Student's unpaired t test and categorical variables were compared with the 
2 test or Fisher exact test. Univariate analyses of risk factors were performed calculating odds ratio (OR) with 95% confidence interval (CI). Variables with a p value less than 0.05 were consecutively subjected to a multivariate logistic regression model to assess the independent impact of each risk factor on perioperative acute MD. A stepwise procedure (backward Wald) was used with a p value of less than 0.05 to enter and eliminate variables.
Estimates of survival and freedom from postoperative cardiac events in patients with postoperative myocardial infarction, postoperative myocardial damage, or with uncomplicated course were determined with the method of Kaplan-Meier life-table analysis. The log-rank test was performed to ascertain differences between the two groups. All statistical analyses were performed using the SPSS statistical package 10.0.
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Results |
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No differences were found in terms of off-pump procedures between the patients with, and those without, postoperative TnI greater than 3.1 µg/L (11 of 54 to 20.4% vs 122 of 722 to 16.9%; p = 0.311). However, all but one patient of those undergoing on-pump procedures and demonstrating TnI greater than 3.1 µg/L underwent isolated antegrade cardioplegia delivery, compared with patients without TnI elevation (42 of 43 to 97.6% vs 327 of 600 to 54.5%; p = 0.01).
Patients with TnI greater than 3.1 µg/L demonstrated more prolonged ventilatory support (58.2 ± 27.3 hours vs 11.2 ± 7.7 hours; p = 0.03), had a significantly longer intensive care stay (5.1 ± 6.4 vs 2.2 ± 2.9 days, respectively; p < 0.001) and were also more prone to have postoperative high inotropic support (59.3% vs 7.7%; p < 0.001) and intraaortic balloon pump (IABP) support (72.2% vs 2.9%; p < 0.001). On the other side, patients with TnI less than 3.1 µg/L, had a statistically higher incidence of no postoperative inotropic support (29.2% vs 0%; p < 0.001).
Moreover, postoperative echocardiography showed a significant left ventricular recovery in patients with TnI less than 3.1 µg/L, either for LVEF (preoperative: 48.4 ± 10.1 – postoperative: 61.2 ± 8.9; p = 0.001) and wall motion score index (WMSI) (preoperative: 1.46 ± 0.36 – postoperative: 1.14 ± 0.17; p = 0.001). Such recovery did not result in patients with isolated TnI elevation greater than 3.1 µg/L (LVEF: preoperative 42.9 ± 12.3 – postoperative 44.1 ± 8.2, p = 0.381; WMSI: preoperative: 1.56 ± 0.56 – postoperative: 1.49 ± 0.21; p = 0.175), whereas patients with associated ECG/echocardiographic criteria for AMI showed a worse LVEF (preoperative: 40.1 ± 5.3 – postoperative: 34.1 ± 10.3; p = 0.03) and WMSI (preoperative: 1.61 ± 0.67 – postoperative: 1.82 ± 0.88; p = 0.001).
Univariate analysis revealed that 33 of 58 recorded variables had a significant (p < 0.05) association with postoperative TnI elevation (see Appendix). Stepwise logistic regression analysis revealed six variables as independent predictors of AMI (Table 1): EuroSCORE greater than 6, ongoing unstable angina with ECG changes, cross-clamp time greater than 90 minutes, cardiopulmonary bypass time greater than 180 minutes, incomplete revascularization, and need for intraoperative intraaortic balloon pumping. Combined antegrade and retrograde cardioplegia and postoperative enoximone infusion were the only variables associated with lower TnI values in this multivariable analysis (OR 0.12 and 0.53, respectively [see Table 1]). Follow-up (mean: 12.4 ± 4.9 months; min 1 month–max 24 months) was 100% completed.
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Comment |
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Several studies have demonstrated that perioperative significant MD ranged from 1% to 6% of patients undergoing isolated CABG. In the current series the incidence of TnI elevation greater than 3.1 µg/L was 6.9%. For the purpose of this study, we included all patients with TnI greater than 3.1 µg/L in our univariate and multivariate analysis, in contrast to previous studies that have generally focused on electrocardiographic, echocardiographic, or conventional biochemical findings. Our definition of damage may therefore have led to a slight overestimation of its incidence.
The results of the study clearly demonstrated that postoperative troponin elevation, above the cut-off value suggested by Mair and associates [5], really indicate a perioperative significant myocardial damage. There were not only a worse in-hospital outcome, as demonstrated by the higher mortality, a prolonged ventilatory support and intensive care stay, a higher inotropic support or IABP need, and an absence of postoperative recovery of the ventricular function, but also a worse short-term follow-up outcome, as demonstrated by the lower survival and the higher incidence of cardiac events.
However, it is noteworthy that patients with associated ECG or echocardiographic criteria for perioperative AMI demonstrate the worst hospital and follow-up outcome of all, when compared to patients with only the biochemical criteria of MD. It therefore seems that the isolated TnI elevation may suggest the onset of a perioperative MD rather than postoperative AMI.
Multivariate analysis has demonstrated six factors as isolated determinants of TnI elevation above 3.1 µg/L. Some of these were preoperative, such as EuroSCORE greater than 6 and emergent operation-ongoing ischemia with ECG changes; the remainder were intraoperative, such as cross-clamp time greater than 90 minutes, cardiopulmonary bypass time greater than 180 minutes, incomplete revascularization, and the need for intraaortic balloon counterpulsation.
Our study demonstrated EuroSCORE greater than 6 as a strong predictor of perioperative MD (OR 5.81). The EuroSCORE was constructed to design a risk stratification system to help in the assessment of quality of cardiac surgical care. A study by Sergeant and associates [1, 9] recently investigated relationships between mortality and the EuroSCORE, demonstrating that with increasing risk according to the EuroSCORE, the difference between predicted and observed mortality also increases. Similarly, a recent study by Riha and associates [2] showed that patients with EuroSCORE greater than 5 had higher in-hospital mortality and morbidity, need for IABP, and postoperative arrhythmias. Our data seem consistent with these studies, demonstrating that high-risk patients were more prone to develop perioperative MD.
Ongoing unstable angina with ECG changes was also detected as a determinant of myocardial injury (OR 1.27). The unstable hemodynamic status of these patients reflects a severely impaired coronary circulation, with a well-established preoperative MD, which could be stopped by prompt and accurate revascularization. Surgery, however, could not resolve the consolidated necrosis. Moreover, our data correlated with those of other authors, all demonstrating a closed association of this condition with a high risk of perioperative MD, morbidity, and mortality [10, 11]. It has, moreover, been demonstrated that this condition is associated with a high thrombogenicity that may impair the efficacy of myocardial revascularization [12].
Cross-clamp time lasting greater than 90 minutes and cardiopulmonary bypass (CPB) time greater than 180 minutes were also demonstrated as independent predictors of MD in the present study (OR 2.31 and 7.12, respectively). Prolonged cross-clamp and CPB time often denoted technical difficulties in executing the planned operation. This could be due to unfavorable anatomy, unexpected intraoperative complications, or difficulties in weaning the patient from bypass, maybe due to residual ischemia or post-CPB myocardial stunning, all of which are factors responsible for TnI elevation. Moreover, it has been clearly demonstrated that TnI levels are directly proportional to cross-clamp and CPB time [13]. Finally it has to be considered that prolonged cross-clamp time requires repeated cardioplegia administration, another source of TnI leakage in the systemic circulation.
Incomplete revascularization was another predictor of perioperative MD (OR 6.04). Incomplete revascularization in our study is defined by the surgeon's intention to treat. Complete revascularization is a primary goal of conventional CABG. This goal derives from the nature of the disease because once a stenosis is present, progression of the coronary artery disease is likely. However, it may be argued that the natural history of the patients, especially the elderly, is such that they are unlikely to live long enough to reap this benefit, so incomplete revascularization with shorter myocardial ischemic and CPB time is preferred to complete revascularization [14]. Moreover, sometimes in clinical practice even high-degree stenoses are not necessarily considered for bypass grafting (especially small diagonal and marginal branches or peripheral parts of the right coronary system); sometimes the atherosclerotic disease is so advanced into the coronary tree that the vessel is not suitable for CABG. It has to be noted that the majority of patients in our study have been incompletely revascularized because of small and diffusely diseased vessels. As a number of previous studies have clearly demonstrated, completeness of coronary revascularization is fundamental in reducing cardiovascular events, morbidity, and mortality after CABG. Our study confirms that both early biochemical and clinical results of CABG are critically affected by incompleteness of revascularization [15].
Finally, our analysis demonstrated intraoperative IABP insertion as a strong predictor of MD (OR 3.55). As well as our results, a number of previous studies [16, 17] have identified IABP insertion as a predictor of poor outcome, either at short-term and long-term follow-up. In fact, intraoperative need for aortic counterpulsation is the witness of intraoperative troubles, ranging from postoperative hypotension-hypoperfusion and difficulty in weaning from CPB, to ECG changes suggestive of postoperative ischemia. All these conditions may affect myocardial perfusion, resulting in temporary or long lasting ischemia, leading to TnI level augmentation. The combined antegrade and intermittent retrograde delivery of blood cardioplegia and post-cross-clamp removal infusion of enoximone proved to be the only variables associated with a lower risk of post-CABG TnI elevation (OR 0.12 and 0.53, respectively).
Experimental studies have shown that, in the presence of coronary occlusions, retrograde cardioplegia results in better distribution, myocardial cooling, and more complete recovery of function in the areas beyond the occlusion [18]. Moreover, we have previously demonstrated that the combined route of cardioplegia administration results in a lower incidence of postoperative complications, a lower need in postoperative inotropic support, and lower postoperative TnI leakage [19]. These findings have also been reported by several other investigators [20].
Postoperative enoximone administration was the only other "protective" factor of our study. Despite the most accurate myocardial protection, temporary post-CABG myocardial dysfunction and stunning may complicate postoperative course, leading to hypotension and myocardial hypoperfusion. Therefore, in order to facilitate weaning from CPB, and to maintain adequate cardiac output and mean arterial pressure, it is common practice to start inotropic support after aortic cross-clamp removal. A recent metaanalysis of trials of intravenous inotropic agents suggested a nonsignificant trend towards increased mortality when cathecolamines are used [21]. On the other hand, some authors have demonstrated that patients treated with enoximone post-CABG showed lower plasma levels of troponin T, a more prolonged hemodynamic improvement, a higher vasodilation in arterial grafting, and a lower myocardial oxygen consumption, compared to cathecolamines [22]. Our data confirmed these results and may be further emphasized if total arterial grafting, with its trend in widened indication (21.9% of our experience), is considered.
In conclusion, postoperative TnI greater than 3.1 µg/L at 12 hour diagnosis significant perioperative MD in cases without ECG or echocardiographic findings. Patients with associated ECG or echocardiographic criteria for perioperative AMI show a worse hospital outcome. These data pose the problem of redefinition of postoperative MD and AMI. Using our large prospectively gathered, double-institution database we were able to identify several independent risk factors for perioperative MD. Identification of these predictors is important for understanding the pathogenesis of perioperative MD and for developing possible preventative strategies, with the caveat that retrospective analyses are always subject to possible selection bias. The increased use of combined antegrade and retrograde cardioplegia and perioperative enoximone infusion may be preventative strategies, given their association with a significantly lower risk of postoperative MD.
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Appendix |
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References |
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6) Eur J Cardiothorac Surg 2003;23:360-367.This article has been cited by other articles:
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  L. Petaja, M. Salmenpera, K. Pulkki, and V. Pettila Biochemical Injury Markers and Mortality After Coronary Artery Bypass Grafting: A Systematic Review. Ann. Thorac. Surg., June 1, 2009; 87(6): 1981 - 1992.e3. [Abstract] [Full Text] [PDF]
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 E Romagnoli, F Burzotta, C Trani, M Siviglia, G G L Biondi-Zoccai, G Niccoli, A M Leone, I Porto, M A Mazzari, R Mongiardo, et al. EuroSCORE as predictor of in-hospital mortality after percutaneous coronary intervention Heart, January 1, 2009; 95(1): 43 - 48. [Abstract] [Full Text] [PDF]
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= ECG/echo; 
= isolated TnI; • = no TnI.)
