Level of Cardiac Biomarkers in Immediate Post-Operative Period after Off-Pump CABG and Its Comparison with On-Pump CABG: A Prospective Analytical Study

Background: Coronary artery bypass grafting (CABG) is an important mod-ality of treatment for ischemic heart disease. Both off-pump and on-pump CABG have direct effect on the level cardiac biomarkers in the perioperative period. The use of cardiopulmonary bypass (CPB) and aortic cross-clamping may cause additive myocardial damage leading to further elevation of blood markers. The present study is aimed at measuring and comparing the cardiac biomarker levels in immediate post-operative period after on-pump CABG (ONCAB) and off-pump CABG (OPCAB). Methods: All the patients who underwent CABG from January 2015 to June 2016 on elective or emergency basis at Nilratan Sircar Medical College & Hospital have been included in the study. Total 106 patients were operated for CABG of which 75 patients were operated for OPCAB and 31 patients were operated for ONCAB. For the comparison of data the blood markers Troponin-T (Trop-T) and Creatine Kinase-MB (CK-MB) are measured during anesthesia before surgery, post-operatively after 1 hour, post-operatively after 4 hours and post-operatively after 20 hours. All recorded data are analyzed using standard statistical methods. Results: We found the markers are elevated immediately after surgery and gradually come down within 24 hours after surgery in both OPCAB and ONCAB OPCAB than ONCAB assuming comparable and adequate revascularization in patients of both groups. The avoidance of CPB and cross-clamp may ex-plain better myocardial functioning immediately after OPCAB. But after 20 hours, the level of cardiac markers is comparable in both groups indicating little difference in post-operative recovery and long-term prognosis.


Introduction
Ischemic Heart Disease (IHD) is the world's leading cause of mortality [1]. Premature deaths caused by the heart and blood vessel disease even among the productive age group (35 -64 years) are expected to rise by 41% by 2030 [2].
Coronary artery disease syndrome includes chronic stable angina, unstable angina, myocardial infarction, cardiogenic shock and ischemic cardiomyopathy.
Coronary artery disease (CAD) can be managed by medical therapy or myocardial revascularization, Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Grafting. Several studies have shown a better 5 years survival for CABG over medical therapy [3]. The use of CPB during surgery is associated with many systemic insults (systemic inflammatory response) and deleterious effects including complement activation, multiple organ dysfunction, neurocognitive dysfunction and coagulation abnormalities [4]. The use of the cardioplegic arrest of the heart to perform CABG also has negative effects on myocardial contractility despite the major advances in cardioplegic solutions and myocardial protection. To avoid the deleterious effects of CPB [5] a resurgence of CABG on a beating heart, also known as off-pump CABG or OPCAB took place in the middle of 1990s though it was first introduced in 1967 by Kolesov. Initially, off-pump surgery was restricted to patients with isolated single vessel or double vessel CAD and to patients with significant co-morbidities, such as renal failure, calcified aortas or significant peripheral and cerebrovascular disease; patients who could derive maximum benefit from avoiding CPB [4] [5]. Initially, the practice of OPCAB was also bedeviled by crude instrumentation and limited exposure of the lateral, posterior and inferior target coronary vessels. With the improvement of anesthetic and surgical techniques along with newer equipment for retraction and exposure, the proportion of CABG done by OPCAB has increased with figures of between 20% -30% being quoted [5] [6] [7] [8] and has expanded to include more complex coronary anatomy than single or double vessel disease. Off-pump coronary artery bypass grafting (OPCAB) avoids the deleterious effects of CPB and is increasingly reported to have better outcomes than ONCAB [9] [10] [11]. Troponin-T (Trop-T) is a major protein in Tropomyosin which is present in contractile apparatus of cardiac muscle. Although nase, is specific to heart and is involved in cardiac inflammation. Both of these enzymes are released to interstitial space from damage myocardial cells resulting rise of their concentration in serum. The serum level of these biomarkers may correlate with the extent of myocardial damage after surgery and hence can affect the cardiovascular functioning accordingly [12]. The present study aims to compare the myocardial damage in terms of blood level of these biomarkers after surgery among the both groups of OPCAB and ONCAB. anastomoses. An intracoronary shunt was used during distal anastomoses whenever possible. For ONCAB Heparin 300 IU/kg was administered to obtain activated clotting time (ACT) over 480 s before start of CPB. Standard cannulation of the ascending aorta and the right atrium were employed. CPB was conducted with a flow rate of 2.4 l/m 2 /min, alpha-stat acid-base management and a nasopharyngeal temperature of 34 -35 degree C. If required after aortic cross clamping 700 -1000 ml of antegrade cold blood cardioplegia were infused. During cross clamping cardioplegia was given antegradely every 15 min. Rewarming was initiated when the last distal anastomosis was started. The patients were weaned from CPB when the nasopharyngeal temperature was above 36 degree C. been done, followed by post hoc comparison using Holm-Sidak test when p-value is significant. For comparison between the on-and off-pump groups at different time-points, a two-way ANOVA has been used followed by post hoc comparison using Holm-Sidak test when p-value is significant. A one-way ANOVA has been done to compare the time-dependent effects of off-pump surgery on cardiac biomarkers, followed by post hoc comparison using Holm-Sidak test when p-value is significant. Comparisons between two groups have been made using unpaired Student's t-test. A p < 0.05 has been considered statistically significant. All data have been presented as mean ± standard error of mean (SEM).

Discussion
Coronary artery bypass grafting with cardiopulmonary bypass (ONCAB) is a routine operation with well documented long-term results. However, cardiopulmonary bypass (CPB) per se leads to a systemic inflammatory reaction which may cause postoperative dysfunction of the heart, lungs, kidney, and brain [13]. Furthermore, aortic cross clamping and cardioplegic arrest induces an ischemic insult to the heart and is a risk factor for neurologic injury [14] [15].
During the last 10 years off pump coronary artery bypass grafting (OPCAB) has become an established and safe alternative to ONCAB. OPCAB can be performed in a large percentage of the patients on all coronary artery systems with good graft patency [9] and good early [10] and midterm [11] results.
Previous studies show less release of cardiac enzymes [10] [16] [17], fewer myocardial infarctions [18], reduced incidence of arrhythmias [16] and reduced frequency of low cardiac output [19] following OPCAB. However, others fail to show such differences [20] [21]. Studies also show shorter stay in the intensive care unit (ICU) and overall shorter length of stay in hospital [14]. The prospective, randomized trial carried upon by Vedin J. et al. [22] showed that patients undergoing OPCAB had improved cardiovascular performance immediately after surgery as compared to ONCAB patients. This may be important during very early critical period because hemodynamic stability during the first few hours after cardiac surgery is important for the further post-operative course. The improved cardiovascular performance may be due to better cardiac function, less myocardial damage and better peripheral vasodilation in the OPCAB patients.
The rise of biomarkers after CABG is multifactorial. Myocardial injury may be due to direct cardiac manipulation during positioning or suturing, reperfusion injury of myocardium, myocardial injury mediated by free oxygen radicals, fail- Propensity scoring decreases dissimilarity between the two groups being compared with respect to major cardiac and non-cardiac morbidities. The results, however, do not consider intraoperative findings which themselves are significant factors for increasing the level of cardiac enzymes after CABG independent of use of CPB. Small, calcified, diffusely atherosclerotic coronary arteries, intra-myocardial or intra-adipose coronary arteries, or other conditions that make revascularization technically more demanding may increase the level of biomarkers due to manipulation of heart, inadequate revascularization or inappropriate grafting [23]. These factors also increase the likelihood of the procedure being performed with CPB. As such, technically difficult revascularizations are more prevalent in the ONCAB group. Conversion from OPCAB to CABG-CPB intra-operatively occurs occasionally for several reasons including anatomical factors like inadequate exposure of target vessel, deep intra-myocardial course of target vessel, small vessels, adhesions or an enlarged heart, hemodynamic instability due to manipulation or repositioning of the heart, mitral and/or aortic regurgitation, bleeding, acute ischemia as detected by ST segment or wall motion changes, left ventricular dysfunction and electrical disturbances during the procedure like ventricular fibrillation, ventricular tachycardia, heart block or severe bradycardia [22]. A large number of patients are converted during grafting of the obtuse marginal vessels or the ramus intermedius due to difficult positioning particularly in large hearts [24]. The consequence of intra-operative conversion  [25]. The conversion rate quoted in literature ranges between 0% -8.8% [26]- [31]. This has a direct impact on elevation of cardiac enzymes immediately after surgery.

Conclusion
The present study shows that the cardiac biomarkers are significantly elevated in the immediate postoperative period after on-pump CABG patients. In off-pump group, the markers are much less in comparison to on-pump group in immediate post-operative period indicating less myocardial damage after off-pump surgery. This may be the cause of hemodynamic instability and low cardiac output being more prevalent in the immediate post-operative period after on-pump CABG. However after 20 hours of surgery, the levels of both the markers are comparable indicating a little effect of CPB or clamp related myocardial injury in long-term recovery.

Limitation of the Study
Although this is a prospective observational study but the patients were not randomly allocated in both the groups and the study was not completely free from selection bias because of ethical issues. Single vessel disease was exclusively operated by OPCAB and all ONCAB patients have multi-vessel involvement.

Ethics Declarations
The present prospective study has been approved by Institutional Ethical committee of NRS Medical College No/NMC/127. The need to obtain informed consent was waived by the local ethical committee.