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Eur J Cardiothorac Surg 2007;32:481-487. doi:10.1016/j.ejcts.2007.06.015
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Division of Cardiac Surgery, Department of Emergency and Organ Transplant, University of Bari, Italy
Received 19 March 2007; received in revised form 29 May 2007; accepted 14 June 2007.
* Corresponding author. Address: Division of Cardiac Surgery, Dipartimento d’Emergenza e Trapianti d’Organo (D.E.T.O.), University of Bari, Piazza Giulio Cesare 11, 70100 Bari, Italy. Tel.: +39 0805595075. (Email: dpaparella{at}cardiochir.uniba.it).
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Abstract |
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 Top Abstract 1. Background2. Material and methods3. Results4. DiscussionReferences |
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7.1 ng/ml and >7.1 ng/ml, respectively (p
= 0.003). It was 93 ± 2.2% and 80 ± 6.8% for patients with CK-MB 36.3 ng/ml and >36.3 ng/ml, respectively (p
= 0.005). Adjusted hazard ratios for mid-term mortality were HR 2.7 (CI 1–7.6), p
= 0.05 for cTnI >7.1 ng/dl and HR 3.1 (CI 1–9.1), p
= 0.04 for CK-MB >36.3 ng/ml. Conclusion: Perioperative myocardial damage should not be considered an innocuous event following OPCAB operations since the survival rate over 3 years is significantly worse in patients with the highest postoperative peak release of cTnI and CK-MB.
Key Words: Coronary artery bypass grafting • CABG • Myocardial injury • Survival analysis • Off-pump
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1. Background |
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TopAbstract1. Background2. Material and methods3. Results4. DiscussionReferences |
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Clinical experiences showed that the release of cTnI following off-pump coronary artery bypass (OPCAB) is significantly lower than after on-pump CABG [11]. In centers with experience of beating heart operations, early results are in favor of this technique [12], with graft patency equivalent to the one obtained with cardiac arrest [13]. However, two recent randomized controlled trials [14,15] revealed a worse patency rate in OPCAB patients in comparison with patients operated on cardiopulmonary bypass. Moreover, data from a large registry demonstrate that OPCAB patients experience a higher rate of perioperative myocardial infarction and have a significantly worse 3-year risk-adjusted survival [16].
No study evaluated before the threshold over which the postoperative release of cTnI and CK-MB after OPCAB should be considered clinically relevant. The aim of the present study is to evaluate if perioperative myocardial damage, measured by means of postoperative release of cTnI and CK-MB, influences short- and mid-term outcome after OPCAB.
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2. Material and methods |
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TopAbstract1. Background2. Material and methods3. Results4. DiscussionReferences |
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The design of the study was a retrospective, single-center observation, and the primary end-point was to evaluate the power of postoperative peaks of cTnI and CK-MB to predict 1- and 3-year survival after OPCAB. The secondary end-point was to evaluate the ability of these two markers to predict hospital morbidity and mortality.
With this aim, we tested four cut-offs for each marker: 0.57 ng/ml (20th percentile), 1.25 ng/ml (40th percentile), 2.45 ng/ml (60th percentile), 7.1 ng/ml (80th percentile) for cTnI; 5.3 ng/ml (20th percentile), 9.1 ng/ml (40th percentile), 14.9 ng/ml (60th percentile), 36.3 ng/ml (80th percentile) for CK-MB. Each of these cut-offs was used in order to divide the whole cohort in two groups and also to calculate crude odds ratios for hospital mortality and crude hazard ratios for follow-up mortality (Table 1 ).
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2.1 Operative technique
Normothermia was maintained during the operations by warming the operative theatre, using a heating mattress and infusing warm intravenous fluids. The heart was approached through standard median sternotomy. Temporary pacemaker wires were placed in the right atrial appendage. A single 3/0 Prolene suture, which had been passed previously through a gauze swab, was placed in the posterior pericardium at the midline between the inferior vena cava and the left inferior pulmonary vein. This retraction stitch enabled vertical displacement of the cardiac apex. Intravenous heparin (300 IU/kg) was administered prior to beginning the distal anastomoses with a target activated clotting time (ACT) of 400 s. The distal anastomosis of left internal mammary artery on left anterior descending was performed first. Proximal anastomoses of venous or free arterial grafts were made before performing distal anastomoses.
A tissue stabilizer (Octopus 3 Medtronic, Inc., Minneapolis, MN) was used in all patients, and intracoronary shunts (Clearview Medtronic, Inc., Minneapolis, MN) were used to suture most of the distal anastomoses (77%), except for small (<1 mm) and very atheromatous coronary vessels. Distal anastomoses were sutured with the aid of a CO2-water blower (Clearview Medtronic, Inc., Minneapolis, MN).
2.2 Definitions
Systemic hypertension was defined as blood pressure exceeding 140/90 mmHg, having a history of high blood pressure or needing anti-hypertensive medications. Those having a history of diabetes, regardless of the duration of disease or the need of anti-diabetic agents, were considered diabetic. Hypercholesterolemia was defined as a fasting cholesterol level >200 mg/dl. Smoking history was defined as any current or past form of tobacco use. Chronic obstructive pulmonary disease (COPD) was defined as forced expiratory volume during the first second (FEV1) <75% or the need of pharmacological therapy for the treatment of chronic pulmonary compromise. On-going refractory angina that required the use of intravenous nitrate therapy for control was regarded as unstable angina. Left ventricular ejection fraction was obtained in all patients by planimetry of left ventriculogram. EuroScore was calculated by additive method.
Death within the same hospital admission, regardless of the cause, was defined as in-hospital mortality. Low output syndrome was defined as the need for postoperative inotropic support or an intra-aortic balloon pump for more than 30 min to maintain systolic blood pressure greater than 90 mmHg, mean blood pressure greater than 60 mmHg or the cardiac index greater than 2.2 l/min/m2, despite sufficient volume substitution. Extubation criteria were hemodynamic stability, absence of surgical bleeding, fully re-warming, consciousness and optimal blood gases with FIO2 0.3. Cerebrovascular disease (CVD) was regarded as any transient ischemia accident, reversible ischemic neurological deficit or stroke.
2.3 Biochemistry
Blood samples for cTnI and CK-MB mass were collected preoperatively, at 6, 12, 24 and 36 h after the end of the operations and every day from the second to the sixth postoperative day. Cardiac troponin I and CK-MB mass were measured according to the manufacturer's recommendation by standard immunoassay techniques (Dade Behring, Inc., Newark, DE).
2.4 Electrocardiogram
Daily 12-lead ECGs were performed in all patients before and after the operations and, after the evaluation of cardiologist blinded to the clinical outcome of the patient, presence and the localization of new q-waves were routinely recorded in the institutional database.
2.5 Follow-up
After discharge home, follow-up was carried out by periodic evaluation of patients at our institution or contacting patients’ general practitioner by telephone call. Maximum, minimum and median lengths of follow-up were 50, 12 and 30 (interquartile range 22–41) months, whereas completeness was 94.8% (238/251).
2.6 Statistical analysis
All continuous variables were evaluated by Shaphiro-Wilk test for normality: if non-normal, they were presented as median and interquartile range (IQR: 25th–75th percentile) and were compared by Mann–Whitney test. Instead, if normally distributed, they were presented as mean ± standard deviation and compared by t-test. Categorical variables were presented as an absolute number and percentage and were compared through Fisher's exact test. Spearman rank correlation coefficient evaluated correlation between the peaks of cTnI and CK-MB. ROC curves were used to calculate areas under the curve (AUC) of postoperative cTnI and CK-MB peaks in function of in-hospital mortality. As no patient was censored during the first 12 months of follow-up it was also possible to draw receiver operating characteristic (ROC) curves and calculate AUC for 1-year mortality. Logistic regression was used to calculate crude odds ratios for hospital mortality (Table 1). Cox hazard model was initially used to calculate crude hazard ratios for follow-up mortality according to different cut-offs of cTnI and CK-MB (Table 1). A stepwise model (Table 4) for follow-up mortality containing all preoperative, intraoperative and postoperative variables was created. Variables which reached p
0.20 at the univariable step were introduced in a multivariable model in order to adjust crude hazard ratios of cTnI > 7.1 ng/ml and CK-MB > 36.3 ng/ml for follow-up mortality. Kaplan and Meier curves and log rank test were used to estimate 1- and 3-year survival probabilities and patients at risk. For all the tests, p-values were considered significant when p
0.05. Statistical analyses were performed using the Stat-View Statistical Software Package 5.0 (SAS Institute, Inc. Cary, NC), NCSS 2001 (Number Chruncher Statistical System, Kaysville, Utah).
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3. Results |
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TopAbstract1. Background2. Material and methods3. Results4. DiscussionReferences |
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Overall in-hospital mortality for the study population was 3.8% (10/261), whereas the mean EuroScore was 5 (IQR 3–7). Therefore, the ratio between observed and expected mortality was 0.76. Causes of in-hospital death were: low cardiac output syndrome (six), arrhythmia (three) and mediastinitis (one). In our population no patient experienced postoperative cerebrovascular accident after OPCAB. One-year survival was 95.2 ± 4.8% (228 patients at risk), whereas 3-year survival was 89.5 ± 10.5% (80 patients at risk). Nineteen patients died during follow-up and the causes of death were: acute myocardial infarction (three), heart failure (six), sudden death (six), renal failure (two), stroke (one) and cancer (one).
3.1 Cardiac TnI
Preoperative and intraoperative characteristics of patients with cTnI postoperative peak >7.1 ng/ml after OPCAB were quite similar to the ones of patients with cTnI 7.1 ng/ml (Table 2
). Minor differences were found regarding the incidence of diabetic patients undergoing insulin therapy before the operation (p
= 0.08), incidence of patients with acute myocardial infarction less than 21 days (p
= 0.06), incidence of patients arriving to the operation with a preoperative cTnI over the 75th percentile (p
= 0.06) and incidence of patients who received more than one arterial graft during the operation (p
= 0.08). However, neither the numbers of graft nor intracoronaric shunts used were different between these two groups (Table 3
).
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7.1 ng/ml (log rank test p
= 0.003). Introducing the multivariable hazard model for follow-up mortality (Table 4
) the crude hazard ratio previously calculated for cTnI postoperative peak >7.1 ng/ml (HR = 3.6, CI 1.4–9, p
= 0.006) was adjusted to HR 2.7, CI 1–7.6, p
= 0.05. Moreover, AUC obtained drawing ROC curve for 1-year mortality according to cTnI postoperative peak was only 0.68 ± 0.1, suggesting that only very high release of cTnI (>7.1 ng/dl) affects survival after OPCAB.
Preoperative clinical state was found to be similar between patients with postoperative CK-MB peak greater than or 36.3 ng/dl (Table 2); only insulin-dependent diabetes was significantly more frequent in the >36.3 ng/dl CK-MB postoperative peak. The number of grafts, the number of arterial grafts or the number of intracoronaric shunts used was not associated with higher release of CK-MB.
Hospital mortality was similar between the groups. In fact, AUC for hospital mortality was 0.48 ± 0.1. Patients with postoperative CK-MB peak >36.3 ng/dl experienced longer mechanical ventilation, ICU stay and had a higher incidence of new q-waves after the operation. One- and 3-year survivals for patients with CK-MB postoperative peak >36.3 ng/ml were 89.2 ± 5.1% (38 at risk) and 80 ± 6.8% (14 at risk), respectively, versus 96.5 ± 1.4% (190 at risk) and 93 ± 2.2% (66 at risk) for patients with CK-MB 36.3 ng/ml (log rank test p
= 0.005). Introducing in the multivariable hazard model (Table 4) the crude hazard ratio of CK-MB peak >36.3 ng/ml on mid-term mortality (HR 3.5, CI = 1.4–8.7, p
= 0.008), it was adjusted to HR 3.1, CI 1–9.1, p
= 0.04. AUC of 1-year mortality according to CK-MB peak value was 0.66 ± 0.1.
3.2 Onset of new q-wave
The number of patients who experienced the onset of a new q-wave was 39 (14.9%). Hospital mortality for these patients was not different compared to the rest of the population (5.1% vs 3.6%, p
= 0.64), while the incidence of postoperative low cardiac output was significantly higher (25% vs 6.3%, p
= 0.0001). One- and 3-year survivals for patient with onset of new q-waves were 97.1 ± 2.8 (39 at risk) and 86.3 ± 10.5 (10 at risk), respectively, whereas patients without new q-waves after the operation had the following survivals: 94.8 ± 1.7% at 1 year (189 patients at risk) and 89.4 ± 2.6 at 3 years (70 at risk) (log rank test p
= 0.87).
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4. Discussion |
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TopAbstract1. Background2. Material and methods3. Results4. DiscussionReferences |
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In our study, the degree of postoperative cTnI and CK-MB does not predict in-hospital mortality and incidence of low cardiac output, but we found that ICU length of stay and duration of mechanical ventilation were significantly longer in patients with cTnI and CK-MB over the 80th percentile. Moreover, postoperative electrocardiograms revealed a more frequent onset of new q-waves in patients belonging to the 80th percentile.
Our study confirms that ECG changes observed in the immediate postoperative period do not possess a clinical relevance and the ability to predict postoperative outcome [2]; unfortunately we are not able to document further evolution of the ECG in the following months.
We first demonstrate that very high peaks of cardiac enzyme release after OPCAB is associated with a worse mid-term survival. In fact, considering the 80th percentile as the cut-off for cTnI and CK-MB, both crude and adjusted hazard ratios are significant predictors of death during the follow-up.
Similarly, in patients undergoing percutaneous coronary intervention (PCI) an elevation in cardiac enzymes has been shown to predict outcome. Kini et al. [18] found on 2873 patients who had undergone successful PCI that post-procedural CK-MB greater than five times the normal level is an independent risk factor (OR 6.7, p = 0.002) for 1-year mortality. Ricciardi et al. [19] found on 286 patients who had undergone PCI that a threefold elevation of cTnI after successful PCI independently predicts major adverse cardiac events (MACE), especially the need for early repeated revascularization, 1 year after the procedure. To explain the relationship between post-procedural cardiac markers elevation and adverse follow-up after PCI, Nageh et al. suggest [20] that myocardial damage due to procedural complications and the related tissue remodeling and scar formation may form a substrate for an adverse outcome secondary to reduced left ventricular function and arrhythmic events.
We can hypothesize that, in a similar way, postoperative release of cardiac enzymes may influence mid-term outcome because of increased myocardial damage. Using magnetic resonance imaging (MRI), Steuer et al. [21] showed that elevated cTnI, CK-MB and troponin T after on-pump CABG correspond to the amount of perioperatively infarcted myocardium. The correlation between the release of cardiac enzymes and the loss of vital myocardium could probably explain the excess of almost 20% on 4-year survival that we observed after OPCAB in patients belonging to the 80th percentile of cTnI and CK-MB peak release.
Several factors can influence the release of cardiac enzymes during a surgical myocardial revascularization: in on-pump CABG, the length of cardioplegic arrest, the delivery and the composition of cardioplegic solutions; during OPCAB, the number of grafts done, the time required to complete each anastomosis and the use of intracoronaric shunts [22]. Recently, Rastan et al. [23] demonstrated that myocardial revascularization carried out with cardiopulmonary bypass without cardioplegic arrest induces a greater release of cardiac enzymes compared to OPCAB. However, independent of the techniques used, we think that graft failure and incomplete revascularization are the most probable causes of postoperative release of cardiac enzymes: microembolism, graft thrombosis, spasm, kinking or overstretching of the conduits, stenosis or occlusion of the anastomotic sites can be the cause of acute graft failure either after OPCAB or on-pump CABG. A recent work by Thielmann et al. [6] on 55 patients with perioperative myocardial infarction over 2078 patients who had undergone on-pump CABG evidenced, after early angiographic control, that 63% had graft failure. Patients with graft-related perioperative myocardial infraction had similar hospital mortality, incidence of major complications, onset of new q-wave, but a higher peak of catnip compared with patients with no graft-related perioperative myocardial infraction. Rasmussen et al. [24] demonstrated graft failure in 43 out of 59 patients (73%) who received acute postoperative re-angiography because of a highly suspected perioperative MI. Unfortunately a similar evaluation is not yet available for OPCAB patients.
According to several surgeons’ opinion other mechanisms can provoke cardiac enzymes release, such as surgical dissection required to expose intramyocardial coronary arteries, heart manipulation and epicardium suction by heart stabilizer employed during OPCAB. However, there is no scientific evidence to support these hypotheses.
In our experience, the predictive role of cTnI after on-pump CABG appears quite different from OPCAB. A recent analysis by our institution [5] on 230 patients who had undergone on-pump CABG evidenced that a postoperative peak release of cTnI > 13 ng/ml increases 10-fold the risk of in-hospital mortality, is associated with higher incidence of short-term complications, but does not predict mid-term survival. The adoption of 13 ng/dl as cut-off of cTnI was supported by previous publications and confirmed by ROC curves. After OPCAB, the degree of myocardial damage, also considering very high cTnI and CK-MB peak release, is not enough to impair mortality. However, even a limited release (compared to on-pump CABG) of cardiac enzyme after the OPCAB may suggest an imperfect revascularization (graft failure or incomplete revascularization) and this may explain the worse survival during follow-up.
Major limitations of our study are the retrospective design, the consequent lack of angiographic evaluation of graft patency and the absence of serial echocardiographic or MRI evaluation of left ventricular function to possibly correlate myocardial function to survival.
In conclusion, a very high release of cTnI and CK-MB significantly affects mid-term survival, but it appears less effective in predicting short-term outcome after OPCAB. Along with previous work, the onset of new q-waves seems less useful predicting short- and mid-term outcome after OPCAB. The major cause of very high cardiac enzyme release after OPCAB could be graft failure and incomplete myocardial revascularization. In order to confirm this hypothesis and improve mid-term results, future studies with angiographic controls should be performed in patients with high cTnI and CK-MB postoperative peaks, despite an acceptable short-term outcome.
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References |
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TopAbstract1. Background2. Material and methods3. Results4. DiscussionReferences |
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