Cardiac troponin I (cTnI) is a highly sensitive and specific biological marker of myocardial necrosis [1,2]. In non-cardiac surgery, any increase in cTnI above the normal range must be considered as an indication of myocardial necrosis . In cardiac surgery with cardiopulmonary bypass (CPB), the issue is far more complex since cardiac surgery and CPB can induce an increase in postoperative cTnI, even in the absence of postoperative cardiac complications [4–7]. This increase depends on the type of surgery and its subsequent degree of direct surgical trauma [8,9]. Moreover, the duration of CPB is likely to influence the postoperative cTnI release [9–11]. Irrespective of the various mechanisms that explain the postoperative cTnI release in cardiac surgery, it has been shown that a single cTnI measurement 24 h after coronary artery bypass grafting (CABG) surgery was a significant predictor of increased postoperative cardiac intensive care unit (ICU) and hospital stays  and an independent predictor of short- and long-term adverse outcome .
Several studies have previously described the kinetics of cTnI elevation in the plasma after cardiac surgery [4–6]. In case of significant myocardial infarction, peak levels of cTnI occur nearly 20–24 h after the end of surgery [5,14]. Conversely, in the absence of documented myocardial infarction, cTnI peaks earlier and plasma levels remain lower. Serial measurements for a kinetic study are, however, not easy to perform in daily clinical practice and even if a single 24-h measurement does not coincide with the postoperative peak level of serum cTnI for many patients, its simplicity may support its routine use as a relatively inexpensive tool to detect postoperative high-risk patients. We recently found that the accuracy of a single 24-h cTnI measurement to predict in-hospital outcome following elective adult cardiac surgery might be different among procedure types, being less in aortic valve surgery than in coronary surgery . Thus, a single 24-h cTnI measurement might be inadequate as a marker for perioperative myocardial damage in unselected patients undergoing elective cardiac surgery (both CABG and valve surgery) and the determination of the peak level of cTnI release and/or the integration of the area under the curve by taking several postoperative time points could be more accurate for the prediction of in-hospital outcome and/or early identification of high-risk patients. Moreover, kinetic analysis of postoperative cTnI may provide complementary information about the various causes of cTnI release. In addition, it may permit, irrespective of the surgical procedure, separation of different time-dependent mechanisms of perioperative myocardial damage following cardiac surgery.
The objectives of the present observational study conducted in adult patients undergoing elective cardiac surgery with CPB were twofold: (1) to analyse the kinetics of serum cTnI release in order to compare postoperative outcome in early (6 h) and late (24 h) peak values of cTnI and try to distinguish between different time-dependent causes of cTnI release; and (2) to compare a single cTnI 24-h measurement and kinetic analysis of serum cTnI release in predicting in-hospital poor outcome.
Consecutive adult patients undergoing cardiac surgery with CPB were enrolled prospectively in the study over a 6-month period at the Saint-Martin Hospital (Caen, France). Institutional approval was obtained from the Ethics Committee (Comité pour la Protection des Personnes (CPP) Pitié-Salpêtrière, Paris). Waived written informed consent was authorized because the study was solely observational and pre- and postoperative cTnI measurements were systematically performed from a blood sample drawn for other routine blood tests during routine care of patients, which conformed to standard procedures currently used in our institution. Inclusion criteria were primary single cardiac surgical procedures: elective CABG and aortic valve replacement. The following categories of patients were excluded: emergency surgery (<24 h), reoperative procedures, combined cardiac surgery (CABG plus aortic valve replacement), mitral valvuloplasty or replacement and other complex cardiac surgical procedures.
All patients were premedicated with oral lorazepam (2.5 mg the evening before surgery and on the morning of surgery). Beta-blocking agents and statins were given until the day of surgery in chronically treated patients. Oral antiplatelet agents were stopped within 7–10 days prior to surgery and replaced by oral flurbiprofen (50 mg twice) until the day before surgery. Standardized total intravenous (i.v.) anaesthesia (target control propofol infusion, remifentanil and pancuronium bromide) and monitoring techniques (five-lead electrocardiogram (ECG) with computerized analysis of ST segment and invasive arterial pressure) were used in all patients and complied with routine practice at our hospital [13,15]. Antifibrinolytic therapy with tranexamic acid (15 mg kg−1 twice) was routinely administered. CPB was performed under normothermia (>35.5°C) and myocardial protection was achieved by intermittent anterograde or combined (anterograde plus retrograde) warm blood cardioplegia, as previously described [13,15]. The heart was defibrillated after aortic unclamping if sinus rhythm did not resume spontaneously. After termination of CPB, catecholamines were used when necessary, at the discretion of the attending anaesthesiologist. All patients were admitted postoperatively into the ICU for at least 48 h and were assessed for tracheal extubation within 1–8 h of arrival in the ICU. Standard postoperative care included blood glucose control <8 mmol L−1 , i.v. heparin (200 U kg−1) in patients with valve disease and aspirin (300 mg, oral or i.v.) and a low-molecular-weight heparin (nadroparin 2850 U Anti-Xa, subcutaneous; Fraxiparine®, Sanofi-Synthelabo, Paris, France) in patients with coronary artery disease, beginning 6 h after surgery in the absence of significant mediastinal bleeding (>50 mL h−1). Beta-blocking agents and statins were given as soon as possible postoperatively in chronically treated patients . Postoperative care was delivered by anaesthesiologists in the ICU and by cardiac surgeons in the ward. Preoperative, intraoperative and postoperative variables were collected for all patients.
Measurements of cTnI concentration
Serial blood samples were drawn into dry tubes the day before surgery, at the end of surgery and 6, 24 and 120 h after surgery. cTnI measurements at these five time points were systematically performed from blood samples drawn for other routine blood tests. A technician who was blinded to the clinical and ECG data performed assays. cTnI was analysed with a sensitive and highly specific immunoenzymometric assay (AxSYM Troponin-I ADV assay, Abbott Laboratories, Rungis, France) that detects both free and complex bound troponin. The assay allows the detection of cTnI within the range of 0.02–23 ng mL−1 with appropriate dilutions. Values greater than 0.04 ng mL−1 were considered abnormal. The within-run coefficient of variation was 6% and the between-run coefficient of variation was 11%.
Patients were divided into two groups according to the time course of postoperative peak serum cTnI: Group 1 = early peak cTnI (6 h after surgery) and Group 2 = late peak cTnI (24 h after surgery).
To try to distinguish between different time-dependent causes of postoperative cTnI release, the following perioperative variables were recorded: recent myocardial infarction (<4 weeks), abnormal preoperative values of serum cTnI >0.04 ng mL−1, abnormal preoperative coronary angiography, left main coronary artery stenosis >70%, type of surgery, CPB time, aortic cross-clamping time, circulatory support time (CPB − aortic cross-clamping time), number of grafts, complete revascularization (assessed by a systematic cardiac surgeon interview), pharmacological preconditioning with volatile anaesthetics, type of cardioplegia (anterograde or combined) and time between cardioplegia (aortic cross-clamping time/number of cardioplegia).
To analyse the in-hospital outcome, the following postoperative variables were recorded: length of stay in ICU, time to discharge from hospital, Simplified Acute Physiologic Score , total chest drainage, renal dysfunction, non-fatal cardiac events and in-hospital death. In-hospital death was defined as death at any time during the hospital stay. Causes of death were recorded and classified as cardiac (heart failure, myocardial infarction, ventricular arrhythmia) or non-cardiac (haemorrhage, respiratory failure, sepsis or other causes). Sudden death was considered as death from a cardiac cause. Non-fatal cardiac events included new atrial fibrillation or flutter, sustained ventricular arrhythmias requiring treatment, postoperative myocardial infarction and postoperative congestive heart failure. Daily 12-lead ECG recordings and postoperative two-dimensional echocardiography (systematically performed within 5 days after surgery according to standard procedures currently used in our institution) were assessed by two experienced physicians blinded to the clinical and biochemical information. Diagnostic criteria for myocardial infarction were the appearance of new Q waves of more than 0.04 s and 1 mm deep or a reduction of more than 25% in R waves in at least two continuous leads of the same vascular territory, as previously described [13,15] and/or occurrence of postoperative severe wall motion abnormalities in the same area. Postoperative congestive heart failure was defined as any two of the following: delayed extubation >24 h, requirement of an inotropic agent or use of an intra-aortic balloon pump, symptomatic acute pulmonary oedema and a ≥20% decrease in preoperative-to-postoperative left ventricular ejection fraction. Postoperative renal dysfunction was defined as a ≥30% increase in preoperative-to-maximum postoperative serum creatinine concentration within 7 days after surgery .
Major adverse cardiac events (MACE) and in-hospital death were chosen as study end-points. A MACE was defined as one of the following: (1) sustained ventricular arrhythmias requiring treatment; (2) postoperative myocardial infarction as defined above; and (3) postoperative congestive heart failure as defined above. Because of the rare occurrence of death, the primary end-point was a composite end-point defined as the occurrence of MACE and/or in-hospital death.
On the basis of a pilot study, we made the hypothesis that the primary end-point occurred in less than 10% of patients with an early peak cTnI and more than 20% of patients with a late peak cTnI, and estimated that 15% of the scheduled patients had a late peak cTnI. Assuming an α risk of 0.05 and a β risk of 0.20, we determined that at least 180 patients should be analysed in the study (NQuery Advisor 3.0, Statistical Solutions Ltd, Cork, Ireland).
Data are expressed as mean ± SD, or median (95% CI) for non-normally distributed variables, or number and percentage. Continuous variables were analysed with the unpaired t-test and U-tests. Categorical variables were compared by Fisher's exact method. To determine the accuracy of a single cTnI 24-h measurement, the kinetics of serum cTnI release and the peak value of cTnI in predicting an adverse postoperative outcome, we determined the receiver-operating characteristic (ROC) curves and calculated the area under the ROC curve and its 95% CI . Comparison of areas under the ROC curve was performed using a non-parametric technique, as previously described . The ROC curves were also used to determine the best threshold for cTnI to predict the occurrence of MACE and/or in-hospital death. The best threshold was the one that minimized the distance to the ideal point (sensitivity = specificity = 1) on the ROC curve.
A P value of less than 0.05 was considered significant and all P values were two-tailed. Statistical analyses were performed using NCSS 2001 (Statistical Solutions Ltd) and Statview® (Deltasoft, Meylan, France) software.
During the study period, 243 consecutive adult patients were included prospectively. In all, 59 (24%) patients were excluded because of emergency surgery (n = 7), reoperative procedures (n = 5), combined and other complex cardiac surgical procedures (n = 38) and incomplete data for cTnI analysis (n = 9). The remaining 184 patients were divided into two groups according to the time course of postoperative peak serum cTnI release: early peak cTnI (6 h after surgery, Group 1) in 152 (83%) patients and late peak cTnI (24 h after surgery, Group 2) in 32 (17%) patients.
The two groups of patients differed only according to preoperative medications taken (Table 1). Postoperative data were not significantly different between groups except for in-hospital death and for the primary end-point (MACE and/or in-hospital death), which reached the statistical significance (Table 2). In all, 5 (3%) patients died during the stay in hospital, 2 (1%) patients died of cardiac causes (1 congestive heart failure, 1 sudden death) and 3 (2%) patients died of non-cardiac causes (1 septic shock, 1 acute respiratory distress syndrome, 1 pancreatitis). Among these 5 patients, 2 were in Group 1 and 3 were in Group 2 : 1% vs. 9%, P = 0.03 (Table 2). All deaths from cardiac causes were in Group 2.
Five blood samples were collected in all patients. Figure 1 shows the time course of postoperative serum cTnI release in both groups. While peak values of cTnI were not significantly different (Group 1; median 3.8 (CI 95% 3.3–4.3) vs. Group 2; median 4.1 (CI 95% 0.0–8.2) ng mL−1, respectively, P = 0.31), the integrated area under the cTnI curves markedly differed between groups: Group 1; median 159 (CI 95% 142–178) vs. Group 2; median 321 (CI 95% 255–590) respectively, P < 0.001. Moreover, postoperative serum cTnI release was significantly different between both types of cardiac surgical procedure (Table 3). The integrated area under the cTnI curve and the peak value of cTnI were no more accurate than a single 24-h measurement in predicting the occurrence of MACE and/or in-hospital death (Fig. 2). No significant difference was found among areas under the ROC curves: AUC24 h cTnI; 0.65 (0.58–0.72) vs. AUCareacTnI; 0.68 (0.61–0.74) vs. AUCpeak cTnI; 0.68 (0.61–0.75), respectively, all P values were non-significant (Fig. 2). The best thresholds to predict MACE and/or in-hospital death were 1.9 ng mL−1 for a single cTnI 24-h measurement, 178 for the area under the cTnI curve and 3.6 ng mL−1 for the peak value of cTnI.
The main finding of the present study is that neither the total amount of postoperative serum cTnI released nor the peak value of serum cTnI (both assessed by taking several postoperative time points) was more accurate than a single 24-h measurement in predicting in-hospital poor outcome after elective adult cardiac surgery with CPB. The finding of this study supports current routine clinical practice where only a single 24-h time point is measured, providing an inexpensive tool for the early detection of postoperative high-risk patients.
Several studies have previously shown that a single cTnI measurement 24 h after cardiac surgery was both a significant predictor of increased postoperative ICU and hospital stays  and an independent predictor of short- and long-term adverse outcome [8,13]. Kinetic studies have also reported that earlier cTnI measurements were less accurate in predicting the occurrence of postoperative myocardial infarction following CABG surgery [5,6]. In the current study, more than 80% of patients, irrespective of the surgical procedure, had an early peak of cTnI (6 h after surgery) followed by a rapid decrease, giving substantially lower concentrations at 24 h. Other workers have found similar results in uncomplicated cardiac surgery [22,23]. In contrast, less than 20% of patients had a late peak of cTnI (24 h after surgery). In these patients, the peak value of cTnI was not greater but the total amount of postoperative cTnI released (calculated by integrating the area under the cTnI curve) was increased, meaning most important myocardial damage following cardiac surgery, irrespective of mechanism [1,13]. As a consequence, these patients experienced a worsened postoperative outcome, suggesting that the prognostic value of peak cTnI was time related.
Neither the total amount of cTnI released nor the peak value of cTnI was more accurate than a single 24-h measurement to predict the occurrence of an adverse postoperative outcome in the present study. A likely explanation is that the 24-h time point occurred once the early fraction of cTnI had been released in serum. This early and reversible release of cTnI could be mainly related to the cardiac surgical trauma itself, with a low accuracy for prediction of a poor outcome [5,6]. Postoperative concentrations of serum cTnI in both types of surgical procedures only differed up to 6 h after surgery in our study, being greater after aortic valve replacement than after CABG surgery. These findings are also consistent with previous reports showing a lower release of cTnI following CABG surgery [9,24]. On the contrary, the late fraction of cTnI released in serum, more reliably reflected by a single 24-h time point, could be mainly related to ischaemic irreversible myocardial damage, thus explaining its accuracy in predicting in-hospital poor outcome following cardiac surgery, irrespective of the surgical procedure type . Importantly, the late release of cTnI remained detectable until 5 days after cardiac surgery and offered a prolonged time window for the prediction of poor outcome in routine clinical practice. The area under the ROC curves ranged from 0.65 to 0.68 for a single cTnI 24-h measurement, the peak value of cTnI and the area under the cTnI curve. These values were somewhat lower than those previously reported in elective CABG surgery [5,6]. A likely explanation is that both CABG and aortic valve replacement were included in the present study. Indeed, we have shown recently that the diagnostic performance of an elevated cTnI in predicting a severe cardiac event and/or death was less in aortic valve surgery than in CABG surgery .
Patients with early and late peak values of cTnI differed according to preoperative medications taken in the present study, suggesting a more serious underlying cardiac disease when the peak of cTnI was late. Nevertheless, we did not find other significant differences in perioperative collected variables. In particular, neither an increased rate of recent myocardial infarction or severe left main coronary artery stenosis, nor longer times of CPB or incomplete coronary revascularization were observed in patients with a late peak of serum cTnI. Thus, even if a lack of statistical power cannot be eliminated, no other clinical events differed between both groups and could explain, in addition to the cardiac surgical type, different time-dependent mechanisms involved in postoperative cTnI release following cardiac surgery.
Some comments are necessary concerning the limitations of the present study. First, we only provided four postoperative time points to integrate the area under the cTnI curve with time intervals ranging from 6 to 18 to 96 h. More time points (especially 12 and 48 h following surgery) would have been helpful to improve the accuracy of AUC analysis. However, cTnI measurements were performed only from blood samples drawn for other routine blood tests in the present study. Second, our study was performed in low-risk patients and thus further studies are required to determine if our results are applicable for more high-risk patients. Third, our study does not test appropriate strategies to improve outcome in identified high-risk patients. Futures studies should also address this important issue. Lastly, the present study was conducted in a single centre. Thus, the threshold values we reported must probably be interpreted with caution.
In conclusion, the kinetic analysis of cTnI release was no more accurate than a single 24-h measurement as an early predictor of the occurrence of in-hospital poor outcome in unselected cardiac surgery patients. Given the benefits of the use of a single biochemical test to predict adverse outcome and the difficulty in performing daily serial measurements, the current study supports the use of this routine clinical practice in elective adult cardiac surgery.
The authors thank Valérie Fellahi, Research Fellow, for her participation in this work, and Dr David Baker, MD, FRCA (Staff Anesthesiologist, Department of Anesthesiology and Critical Care, Centre Hospitalier Universitaire Necker-Enfants Malades, Paris, France) for reviewing the manuscript.
Financial support: The study was partly supported by Abbott Laboratories (Rungis, France). Other support was provided by Institutional Departmental sources.
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Keywords:© 2008 European Society of Anaesthesiology
TROPONIN I; CARDIAC SURGERY; POSTOPERATIVE PERIOD; OUTCOME ASSESSMENT