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Ann Thorac Surg 2007;83:1016-1023
© 2007 The Society of Thoracic Surgeons
a Cardiac Surgery Unit, Magna Graecia University, Catanzaro, Italy
b Anesthesiology and Critical Care Unit, Magna Graecia University, Catanzaro, Italy
Accepted for publication October 23, 2006.
* Address correspondence to Dr Onorati, Viale dei Pini, 28, Napoli 80131, Italy (Email: frankono{at}libero.it).
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Abstract |
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Methods: In all, 183 consecutive isolated myocardial revascularizations were prospectively enrolled in the study. Troponin I and lactate were sampled preoperatively and intraoperatively from the coronary sinus, and at 12, 24, 48, and 72 hours. Hospital outcome was recorded. Receiver operating curves for coronary sinus troponin I and lactate were constructed to differentiate patients with or without AMI and myocardial damage.
Results: Acute myocardial infarction developed in 6 patients (3.2%), with higher troponin I and lactate at all time points (p < 0.05), longer intubation time (p = 0.003), intensive care unit stay (p = 0.001), hospital stay (p = 0.001), higher atrial fibrillation (p = 0.001), and worse ventricular function (p = 0.001). Myocardial damage developed in 6 patients (3.2%), showing higher troponin I at all time points (p < 0.001), higher intraoperative lactate (p = 0.04), longer intubation time (p = 0.005), and intensive care unit stay (p = 0.03). Receiver operating characteristic curves demonstrated coronary sinus troponin I greater than 0.94 µg/L (area under the curve [AUC] 0.820 ± 0.075; sensitivity 90.0%, specificity 68.9%) as a better discriminator between patients with or without AMI than lactate level greater than 2.85 mmol/L (AUC 0.686 ± 0.090; sensitivity 80.0%; specificity 72.9%); troponin I greater than 0.65 µg/L was a better discriminator between patients with or without myocardial damage (AUC 0.834 ± 0.061; sensitivity 93.8%, specificity 71.5%), than lactate greater than 2.05mmol/L (AUC 0.627 ± 0.067; sensitivity 87.5%; specificity 70.7%).
Conclusions: Coronary sinus troponin I and lactate are predictive for cardiac complications after myocardial revascularization. Intraoperative biochemical assays should be routinely performed to establish preventative strategies to reduce further myocardial damage.
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Introduction |
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Conversely, incomplete myocardial protection is responsible for blood elevation of troponin I [3, 4, 8]. Troponin I has been recently shown to be a specific marker of myocardial damage, with a higher sensitivity and specificity; moreover, recent reports have defined postoperative troponin I as a sensitive marker of the quality of myocardial protection and of prognostic value for cardiovascular events at follow-up [9, 10]. Similarly, it has been demonstrated that persistent peripheral lactate release during the reperfusion period is an independent predictor of postoperative low output syndrome [11]. Therefore, lactate leakage, as well as the release of troponin I, can define the efficacy of myocardial protection [4, 8]. Finally, it has to be kept in mind that different degrees of myocardial impairment with different prognosis may occur after cardiac surgery, ranging from myocardial stunning to damage to infarction [12].
Therefore, it was the aim of our study to evaluate whether troponin I and lactate sampled from the coronary sinus blood during the reperfusion period have the potential for an earlier diagnosis of acute myocardial infarction (AMI) or myocardial damage in patients undergoing on-pump coronary artery bypass graft surgery (CABG).
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Material and Methods |
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Surgery, Cardiopulmonary Bypass, and Postoperative Care
Cardiopulmonary bypass (CPB) and surgical techniques were standardized and did not change during the study period. Surgery was performed by the same senior surgeons in all cases through a median sternotomy. The left internal mammary artery was always anastomosed to the left anterior descending artery; the radial artery was always harvested as a pedicle and anastomosed to the ascending aorta. Proximal anastomoses were always performed with partial clamping.
Cardiopulmonary bypass was conducted by the same perfusionist: heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 480 s or above. A standard CPB circuit was used: a Dideco (Mirandola-Modena, Italy) tubing set, which included a 40-µm filter, a Stockert roller pump (Stockert Instrumente, Munich, Germany), and a hollow fiber membrane oxygenator (D903 Avant; Dideco). Systemic temperature was kept between 32°C and 34°C. Myocardial protection was always achieved with intermittent antegrade and retrograde hyperkalemic blood cardioplegia [3]. Total CPB flow was maintained at 2.6 L · min–1 · m–2.
Inodilators were started immediately after aortic cross-clamp removal, always starting with enoximone at a dosage of 5 µg · kg–1 · min–1. The need for further increase in inotropes was recorded: inotropic support was defined as low dose when enoximone was administered at a dosage lower than or equal to 5 µg · kg–1 · min–1; medium dose when enoximone was employed at a dosage between 6 and 10 µg · kg–1 · min–1, or dobutamine was added at a dosage between 5 and 10 µg · kg–1 · min–1; or high dose when enoximone or dobutamine infusion was greater than 10 µg · kg–1 · min–1 or epinephrine was added at any dose.
Blood Samples
The coronary sinus was cannulated with the blind technique [13]. The correct positioning was confirmed by observing distension of the posterior interventricular vein, maintenance of coronary sinus pressure, and palpation of the coronary sinus cannula. Blood samples from the coronary sinus were obtained 10 minutes after reperfusion; peripheral samples were taken from the arterial line at 12, 24, 48, and 72 hours postoperatively. Blood samples were assayed to estimate lactate production (GEM Premier 3000 analyzer; Lexington, MA) and troponin I leakage (Access Immunoassay System, Beckman Coulter-AccuTnI; Fullerton, CA).
Definition of Perioperative Data and Events
The following criteria were used for definition of preoperative variables: hypertension, systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg, or both, or ongoing treatment with any antihypertensive medication; insulin-dependent and noninsulin-dependent diabetes mellitus, fasting blood glucose greater than 140 mg/dL on at least two occasions or use of antidiabetic medication (either oral drugs or insulin); left main stem disease, critical obstruction (greater than 50%) in left main stem; emergency cases as characterized by unstable hemodynamics despite maximal medical therapy. Left ventricular function was evaluated by echocardiography: left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and indexed left ventricular mass were recorded. A value of indexed left ventricular mass greater than 125 g/m2 was considered as a marker of left ventricular hypertrophy. Preoperative data are reported in Table 1.
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Of postoperative variables and complications, perioperative AMI was defined when new Q waves of greater than 0.04 ms or a reduction in R waves greater than 25% in at least two leads, or both, were detected, a new akinetic/dyskinetic segment was identified at echocardiography, and troponin I peaked at 3.1 µg/L at 12 hours; perioperative myocardial damage was defined as troponin I peak greater than 3.1 µg/L at 12 hours, as previously reported [12]; low output syndrome was diagnosed if the patient required an intra-aortic balloon pump for hemodynamic compromise or if the patient required inotropic medication to maintain the systolic blood pressure at more than 90 mm Hg and the cardiac index at greater than 2.2 L · min–1 · m–2 in the intensive care unit after correction of all electrolyte and blood gas abnormalities, and after adjusting the preload to its optimal value. Postoperative respiratory failure was defined as the need for mechanical ventilation longer than 48 hours; acute renal failure as the need for continuous venovenous hemofiltration or dialysis; and neurologic complication as any focal brain lesion confirmed by clinical findings or computed tomography, or both, or diffuse postoperative encephalopathy, convulsions, or severely altered mental status. Hospital mortality was defined as death occurring during hospitalization or during the first 30 postoperative days.
Statistical Analysis
Statistical analysis was performed by the SPSS program for Windows, version 10.1 (SPSS, Chicago, Illinois). Continuous variables are presented as mean ± SD, and categorical variables are presented as either absolute numbers and percentage. Data were checked for normality before statistical analysis. Normally distributed continuous variables were compared using the unpaired t test, whereas the Mann-Whitney U test was used for those variables that were not normally distributed. Categorical variables were analysed using either the 
2 test or Fisher’s exact test. One-way analysis of variance (ANOVA) was used to evaluate the significance of the differences in preoperative and intraoperative variables among patients with uncomplicated course, patients with postoperative AMI, and those with postoperative myocardial damage. If the F value was significant and variance was homogeneous, Tukey’s multiple comparison test was used to assess the differences between the individual groups; otherwise, Tamhane’s T2 test was used. The Kruskal-Wallis test was used to compare the three groups in terms of dichotomous variables. Pearson correlation was calculated for coronary sinus biochemical markers and their values measured at 12, 24, 48, and 72 hours. A receiver operating characteristics (ROC) analysis was calculated to determine optimal cut-off values for troponin I, lactate, and creatine kinase sampled from the coronary sinus blood 10 minutes after reperfusion. The area under the curve and its standard deviation (AUC ± SD), the sensitivity, and the specificity was calculated to analyze the diagnostic value of all these markers. For all statistical tests, a p value less than 0.05 was taken to indicate a significant difference.
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Results |
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Overall, 171 patients (93.4%) did not had any perioperative cardiac complication. Hospital mortality was 2.7% (5 of 183, 3 patients died of post-AMI low output syndrome, 1 of pneumonia, and 1 of stroke). There were 4 postoperative pneumonias (2.1%), 2 cases of renal failure (1.09%), and 1 of perioperative stroke (0.5%). Ten patients (5.4%) demonstrated postoperative low output syndrome, 7 of whom recovered with an intra-aortic balloon pump and intravenous enoximone administration. There were 6 perioperative acute myocardial infarctions (3.2%) and 6 cases of perioperative myocardial damage (3.2%). When intraoperative variables are considered, no differences existed in number of grafts (uncomplicated, 3.49 ± 0.89; AMI, 3.78 ± 0.91; myocardial damage, 3.56 ± 0.75; p = 0.513), total arterial grafting (uncomplicated, 43 patients [25.1%]; AMI, 2 [33.3%]; myocardial damage, 2 [33.3%]; p = 0.130), and need for intraoperative defibrillation (uncomplicated, 17 patients [9.9%]; AMI, 2 [33.3%]; myocardial damage, 1 [16.7%]; p = 0.161); however, despite similar aortic cross-clamp time (uncomplicated, 45.4 ± 21.6 minutes; AMI, 47.3 ± 19.9 minutes; myocardial damage, 52.2 ± 19.0 minutes; p = 0.817), CPB time was longer in patients in whom AMI developed (105.9 ± 27.6 minutes versus uncomplicated, 91.6 ± 31.3; p = 0.01; versus myocardial damage, 93.7 ± 34.2; p = 0.03). Cardiopulmonary bypass time was slightly longer in the AMI group because of the need for slightly longer support to remove the patient from bypass. As far as inotropic support was concerned, the number of patients who required medium inotropic support was statistically higher among patients having perioperative AMI (3 of 6 [50%] versus 4 of 171 [2.3%]; p = 0.032) or myocardial damage (5 of 6 [83.3%] versus 4 of 171 [2.3%]; p = 0.026). Furthermore, high doses of inotropes were needed in a higher number of patients with perioperative AMI (3 of 6 [50%] versus 0 of 171 [0%]; p = 0.001) or myocardial damage (1 of 6 [16.6%] versus none [0%]; p = 0.012).
Patients with perioperative AMI demonstrated higher troponin I and lactate, at all time points, compared with patients with uncomplicated course and myocardial damage; similarly, patients with perioperative myocardial damage demonstrated higher troponin I at all time points, and higher intraoperative lactate compared with patients who had an uncomplicated course (Table 2; Fig 1).
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As far as echocardiographic results were concerned, patients with AMI demonstrated worse postoperative left ventricular function (preoperative LVEF 45.5 ± 22.9 versus postoperative LVEF 33.8 ± 31.2; p = 0.001; preoperative WMSI 1.61 ± 0.23 versus postoperative WMSI 1.82 ± 0.35; p = 0.001). In all these patients, new regional wall motion worsening was detected. On the other hand, compared with patients with an uncomplicated course, those with perioperative myocardial damage demonstrated longer intubation time (19.6 ± 15.9 versus 11.6 ± 8.3 hours; p = 0.05) and intensive therapy unit stay (2.9 ± 1.9 versus 1.9 ± 0.3 days; p = 0.03), but a similar hospital stay (7.1 ± 1.9 versus 6.2 ± 2.1 days; p = 0.07). Echocardiography did not demonstrate in patients with myocardial damage any postoperative improvement of left ventricular function (preoperative LVEF 44.1 ± 18.7 versus postoperative LVEF 42.9 ± 15.6; p = 0.640; preoperative WMSI 1.58 ± 0.34 versus postoperative WMSI 1.56 ± 0.30; p = 0.770).
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Comment |
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In the last few years, the introduction of troponins—with their higher sensitivity and specificity in diagnosing such complications—has widened the debate. Although new Q waves on the electrocardiogram or new akinetic/dyskinetic segments on echocardiography suggest transmural infarction, minimal necrosis and various degrees of myocardial damage are not recognized unless plasma troponins are detected [15]. Many authors have clearly demonstrated that troponin I is the most sensitive biochemical marker for the diagnosis of even minimal myocardial damage, and is therefore a good marker of the quality of myocardial protection [9, 15]. We have previously demonstrated that postoperative troponin I greater than 3.1 µg/L (12 hours) predicts significant perioperative myocardial damage in cases without electrocardiographic or echocardiographic findings, whereas concomitant electrocardiographic or echocardiographic findings diagnose perioperative AMI [12]. Moreover, such differences have an impact not only on hospital outcome, as confirmed by the results of the present study, but also on follow-up survival [12, 15]. In particular, the results of the present study demonstrated that patients with postoperative AMI had the worst hospital outcome, with worsening of the LVEF, whereas those with perioperative myocardial damage had a longer intubation time and intensive therapy unit stay, and did not demonstrate postoperative improvement of LVEF seen in patients with an uncomplicated course.
Therefore, the early detection of an incomplete myocardial protection, responsible for some sort of myocardial damage, plays a critical role in determining hospital outcome and follow-up results [1, 2, 8, 12, 14]. It is known that a sensitive marker of inadequate protection and of the onset of myocardial ischemia is the development of myocardial tissue acidosis and lactate production [4], and that coronary sinus blood sampling 10 minutes after aortic declamping is the best predictor of postischemic cardiac dysfunction [5]. We decided therefore to sample blood from the coronary sinus at this time point, adding the troponin evaluation to the metabolic study.
Perioperative changes in lactate metabolism in CABG were first decribed by Carlson and coworkers [16]. Khuri and colleagues [17] demonstrated the direct correlation of the degree of myocardial acidosis during cross-clamp time with long-term outcome, showing that patients who experienced acidosis have decreased survival compared with patients who did not [17], and that prevention of intraoperative acidosis should improve long-term survival [18]. Moreover, our study suggested different cut-off values in coronary sinus lactate release in patients in whom perioperative AMI and myocardial damage developed, being higher in patients with perioperative AMI and myocardial damage compared with patients who had an uncomplicated course. Therefore, although not very highly discriminant (C-statistic of 0.68 for AMI and 0.63 for myocardial damage), intraoperative lactate sampling seems to be an additional tool in the armamentarium for the early diagnosis of AMI and myocardial damage. Moreover, it has been demonstrated that persistent lactate release during reperfusion suggests a delayed recovery of normal aerobic myocardial metabolism, related to intraoperative misadventure or inadequate myocardial protection, leading to depressed myocardial function predictive for postoperative low output syndrome [11].
Our study similarly showed persistent lactate production only in patients with AMI, who probably had significant hemodynamic impairment, compared with either patients having myocardial damage or those having an uncomplicated course. According to these data, patients with myocardial damage did not have significant hemodynamic impairment because of the absence of persistent acidosis. Therefore, lactate sampling also suggests as a pathogenetic mechanism of myocardial damage a myocardial injury during cardioplegic arrest that temporarily produces myocardial dysfunction, and AMI as a coronary artery or graft problem that maintains long-lasting myocardial ischemia. However, we were unable to demonstrate that intraoperative lactate correlates with postoperative lactate release; maybe that is because hemodynamic stability is only one of the determinants of peripheral blood lactate—lactate production during the postoperative period mostly depends on "peripheral" production and is due to multiorgan functions. In other words, peripheral lactate sampled during the postoperative course is only partially of cardiac origin.
However, if lactate sampling reflects a metabolic aspect of myocardial protection techniques, several structural proteins of myocytes are traditionally used to similarly evaluate the effectiveness of myocardial protection. We decided to test the predictive value of troponin I, being a newly available tool to detect myocardial ischemia [8, 9, 12, 19]. Koh and associates [8] have examined coronary sinus levels of troponin T and found it to have a greater correlation with ischemic time and quality of myocardial protection. Mair and coworkers [9] similarly demonstrated troponin I as the optimal marker to diagnose perioperative AMI. We also previously demonstrated postoperative troponin I greater than 3.1 µg/L at 12 hours to be predictive for myocardial damage or AMI according to its association or not with electrocardiographic and echocardiographic criteria [12].
Confirming the results of prior studies, which demonstrated troponin to be a sensitive and specific marker of myocardial damage, the present study established ROC with definite cut-off values to predict myocardial damage or AMI after CABG. In particular, early troponin I sampling from the coronary sinus during the intraoperative time is yet able to define different cut-off values for two different degrees of myocardial ischemia. Therefore, intraoperative troponin I, better than lactate, may allow investigators to quantify the degree of myocardial impairment immediately during the reperfusion time. In fact, Raman and coworkers [20] demonstrated coronary sinus troponin I to positively correlate with lactate levels, and troponin I release to occur in conjunction with myocardial lactate release.
According to these and our data, it can be stated that inadequate cell protection is the explanation for the pathogenesis of troponin I release and that it always represents some sort of myocardial injury. Furthermore, the higher sensitivity—compared with specificity—of troponin I and lactate for both AMI and myocardial damage suggests that surgeons may be sure of the safety of the employed strategy of myocardial protection and revascularization, whenever a troponin I or lactate value below the cut-off suggested is evidenced from the coronary sinus blood. Moreover, contrary to the lactate sampling, and according to the fact that isoform I of the troponins is only of cardiac origin, we found intraoperative troponin I to correlate with "peripheral" measurements at 12, 24, 48, and 72 hours, giving an indication to the surgeon of the postoperative myocardial function.
In conclusion, troponin I and lactate sampled from the coronary sinus during the intraoperative time course are predictive for cardiac complications after CABG, also dichotomizing patients with perioperative myocardial damage and AMI. Intraoperative sampling of troponin I and lactate recognizes the degree of intraoperative myocardial injury, and may improve the safety of cardiac surgery by mandating preventative strategies to reduce further myocardial damage whenever an intraoperative troponin I or lactate rising level is detected.
Limitations of the Study
It has to be kept in mind that some anatomic variations of the cardiac venous anatomy exist, in which only some major epicardial veins drain into the coronary sinus, being therefore coronary sinus blood an admixture of blood from many, but not all, regions of the heart, and therefore not fully representative of global myocardial metabolism.
This study was a single institutional experience on patients undergoing isolated CABG. It is well known that biochemical results of myocardial revascularization strictly depend on the myocardial protection and the surgical time; therefore, our results can not be extrapolated to patients undergoing different strategies of myocardial protection or different types of heart surgery, as, first of all, off-pump procedures.
Although the single-center design of the study limits the conclusions, on the other hand, it guarantees uniformity of the perioperative management of the patient population throughout the experimentation. Moreover, on an intention-to-treat basis, we prospectively enrolled patients with the most similar risk profile, as high-risk patients without severe organ comorbidities or extensive extracardiac atherosclerosis, which may mislead the results.
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