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Eur J Cardiothorac Surg 2005;27:1057-1064
© 2005 Elsevier Science NL
Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Struempellstr. 39, 04289 Leipzig, Germany
Received 29 November 2004; received in revised form 27 February 2005; accepted 9 March 2005.
* Corresponding author. Tel.: +49 341/8651421; fax: +49 341/8696646. (E-mail: rastan{at}rz.uni-leipzig.de).
| Abstract |
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Key Words: Cardioplulmonary bypass OPCAB Beating heart surgery Myocardial injury Biomarkers
| 1. Introduction |
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For patients with acute myocardial ischemia there are also suggestions to perform coronary bypass procedures on-pump beating heart in order to preserve native coronary blood flow, unload the heart and guarantee adequate organ perfusion. Limited clinical data revealed a benefit of CPB-supported beating heart CABG in selected high-risk patients [12]. This concept is also based on the hypothesis of reduced myocardial injury by maintaining native coronary blood flow and by renouncement of cardioplegic arrest. However, no data exist about the actual myocardial damage that may be independently induced by using extracorporeal circulation.
Therefore, this study was designed to assess the isolated CPB-induced effects on the myocardium in patients with coronary artery disease by comparing beating heart coronary artery bypass grafting with and without CPB support.
| 2. Material and methods |
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2.1. Patients and study design
Forty consecutive patients (Fig. 1) who were referred for elective coronary artery bypass surgery, were prospectively randomized to off-pump (OPCAB) or on-pump beating heart (OnP-BH) coronary revascularization. Criteria for randomization were three vessel coronary disease with significant disease of all three major arteries (stenosis
70%). Exclusion criteria were patients older than 75 years of age, combined cardiac procedures, cardiac re-operations, emergency surgery, left main stenosis of greater than 70%, and ejection fraction of lower than 50%. Informed consent was obtained from all patients.
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2.2. Surgical procedures
Prior to sternotomy and already positioned on the operating room table, all patients received an 8F coronary sinus soft distal tip guide catheter (Medtronic AttainTM Access Model 6218A) that was inserted through the left subclavian vein in Seldinger technique under fluoroscopic control. It was removed 4h postoperatively on the intensive care unit (ICU). This technique ensured stable positioning deep into the coronary sinus (CS) and prevented dislocation during cardiac manipulation. Compared to the traditional right transatrial approach it allows postsurgical blood drawings and safe removal on the ICU.
All operations were performed by one surgeon (H.B.) through a median sternotomy, insertion of 12 traction sutures in the posterior pericardium, and followed by the application of a commercially available mechanical stabilizer. No preconditioning or intra-coronary shunt insertions were performed. For antegrade blood control a pledget-armed tourniquet was applied to the target vessel proximal to the anastomotic site. For all anastomoses 70 or 80 monofilament sutures were used. The mammarian arteries were prepared using a skeletonized harvesting technique in conjunction with Papaverine solution. The left internal mammarian artery to LAD was the first anastomosis in all patients. During the operation all patients received Aprotinin (TrasylolTM) at a dose of 2million units.
In OPCAB patients heparin was given at a dosage of 150IE/kg to achieve an activated clotting time (ACT) of >250s compared with 300IE/kg for OnP-BH for a target ACT of >400s. After completing the final anastomosis and removal of the venous cannula in OnP-BH operations, heparin was antagonized with protamine sulfate to return the ACT to preoperative levels. In OPCAB patients, blood was conserved by using cell saver, in OnP-BH patients all contents of the ECC circuit were re-transfused at the end of the operation.
CPB was established by standard ascending aorta cannulation and the insertion of a two-stage venous cannula through the right atrium with no additional venting of the left ventricle. OnP-BH procedures were performed in mild hypothermia of 3233°C controlled by rectal temperature probes. CPB circuit included a roller pump, an arterial filter (38µm), non-blood prime and non-pulsatile flow of 2.4l/min per m2 body surface area.
The venous cannula was placed routinely via a small pursestring inzision on the base of the right auricle. The incision was oversewn after removal by 50 prolene. In all OPCAB patients we also made a comparable sham incision in the right auricle to ensure group comparability.
Bypass grafting was indicated for vessels >1.0mm diameter and adequate supply area. Completeness of revascularization (ICOR) was expressed by the index of planned versus performed bypass graftings.
Postoperative diagnosis of myocardial infarction was based by at least one of the following criteria: New Q-waves, a ratio of peak CK-MB/peak total CK >10% or CK-MB fraction 5-fold upper limit for normal. All patients with evidence of perioperative myocardial infarction were reassessed for coronary angiography.
After the operation all patients were transferred to the ICU. According to our protocol all patients were ventilated postoperatively for at least 2h. The postoperative management and care was identical between the groups.
2.3. Blood sampling
The baseline blood samples were taken before sternotomy after positioning the CS catheter. Further samples from both, the CS and the arterial line were taken 1, 30, 60, and 90min after bypass flow was released of the LIMA-LAD anastomosis (Fig. 1). Four hours postoperatively blood was also taken from the coronary sinus catheter before its removal and from the arterial pressure monitoring line. Following blood samples were taken from the arterial line 12 and 24h after surgery. Blood gas analyses were immediately performed on site, blood for C-reactive protein (CRP), CK-MB and cardiac troponin I (cTnI) determinations were transferred to the hospital laboratory. Blood samples for NT-proBNP and MDA measurements were stored on ice and centrifuged 1h after sampling and serum was aliquoted and stored at 80°C until analyzed.
2.4. Laboratory analysis
For detection of intraoperative ischemia blood gas analyses including pH, lactate and pO2 were performed from the CS blood. MDA from the CS blood indicating oxidative stress was analysed as described elsewhere [13] by measuring thiobarbituric acid reacting substances (TBARS) that can be expressed as equivalents to MDA. CK-MB and troponin as markers for myocardial necrosis were measured from the CS and peripheral arterial blood. Until 4h postoperatively the CS blood values were compared between the groups. For CK-MB and cTnI we used the routine in-hospital lab analysis.
For myocardial dysfunction NT-proBNP from the CS and arterial blood was determined by a chemiluminescent immunoassay (ElecsysTM proBNP assay, Roche Diagnostics) and an automated multianalysis system (ModularTM Analytics, Roche Diagnostics). NT-proBNP is the N-terminal fragment of proBNP, the precursor protein of BNP, which is released when BNP is cleaved from its precursor. At the cleavage of proBNP NT-proBNP (aminoacid 176) and BNP (aminoacid 77108) were released equimolecularly. Recent studies have shown that serum concentrations of BNP and NT-proBNP are comparable and elevated after CABG procedures [14,15]. CRP levels for unspecific inflammation were measured by a commercially available latex-enhanced immunoturbidimetric assay (Tina-quant system, Roche Diagnostics, detection limit 0.1mg/dl).
2.5. Data analysis
Continuous variables are expressed as mean±SEM, categorical data as proportions. Categorical variables were compared using chi-square test, independent continuous variables and laboratory values were compared by 2-tailed Student's t-test or MannWhitney-U-test as appropriate at a level of significance of P<0.05. Comparison of dependent variables was performed by Wilcoxon-test. Baseline characteristics were analysed on an intention-to-treat basis, operative and postoperative data as well as all laboratory values were analyzed on a treatment basis. The statistical analysis was performed using SPSS 12.0 and Microsoft Excel. Two patients with evidence of perioperative myocardial infarction required surgical re-intervention and were excluded from the laboratory data analyses.
| 3. Results |
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Perioperative patient findings and early outcome data are presented in Table 2. Postoperative inotropic support and total length of ICU stay was siginificantly reduced in the OPCAB group. One patient of each group suffered a non-Q-wave myocardial infarction on the basis of CK-MB/total CK ratio >10%. Early postoperative angiography revealed LIMA string sign and occlusion of a radial artery graft to the right coronary artery, respectively. Both patients received successfully immediate reoperation. Another OPCAB patient had to be re-operated for bleeding 6h after the operation. One OPCAB patient died in the hospital (POD 17) due to severe mesenteric ischemia. There were no significant differences in blood loss, blood product requirements, postoperative stroke and new onset atrial fibrillation. No wound infections occurred.
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3.4. Serum NT-proBNP
At LAD flow release NT-proBNP increased to 2.3-fold compared to baseline levels in the OnP-BH group and was constant until 4h postoperatively (Fig. 4(a)). In contrast, NT-proBNP in OPCAB patients did not relevantly increase, leading to significant lower levels compared to OnP-BH patients. The concentrations increased to peak values of 700pg/ml for OPCAB and 1508pg/ml for OnP-BH patients, respectively. This corresponded to an increase of 3.8-fold for OPCAB versus 5.0-fold for OnP-BH in comparison to baseline values after 24h.
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3.6. Coronary sinus versus arterial blood levels
To explore the cardiac release of CK-MB, cTnI and NT-proBNP we compared blood samples taken from both, the coronary sinus and the arterial line during the operation and 4h postoperatively. Based on myocardial release we found significantly higher concentrations of CK-MB, troponin I and NT-proBNP in coronary sinus blood from OnP-BH patients during the operation but no longer at 4h postoperatively (Table 3). However, concentrations in the coronary sinus blood from OPCAB patients were normal and did not significantly differ in comparison to peripheral arterial blood.
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| 4. Discussion |
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There are several potential reasons for myocardial injury induced by conventional coronary bypass grafting including surgical manipulation per se, cardioplegia, aortic cross clamping resulting in global ischemia and reperfusion damage, hypothermia, and the use of the cardiopulmonary bypass. In this study the consequences of global myocardial ischemia was eliminated and thus allowed to observe the clinical effects and myocardial alterations induced by the cardiopulmonary bypass circuit. However, besides a lower rate of postoperative inotropic support and a slightly reduced length of ICU stay for OPCAB patients, we could not demonstrate any clinical relevant difference in morbidity between the two groups.
Intraoperatively we found no signs for global myocardial acidosis. Neither the coronary sinus blood pH nor the partial oxygen pressure was significantly influenced by the intermittent regional ischemia during the construction of the coronary anastomoses. However, this approach was not suitable for monitoring regional ischemic events with potential risks of local hypokinesia, extrasystole or ventricular fibrillation, but these findings indicate adequate coronary perfusion not influencing the global oxygen and nutrient supply. The lactate level in coronary sinus blood was slightly increased in the OnP-BH group. These findings correspond to the systemic lactate levels and were presumably caused by increased systemic anaerobic metabolism due to redistribution in organ blood supply induced by the laminar CPB blood flow.
The term oxidative stress describes a systemically or regionally increased bioactivity of reactive oxygen species (ROS), which can contribute to endothelial or myocardial injury [20]. On ROS activate oxyradical mediated lipid peroxidation can be reflected by measuring malondialdehyde representing a catabolic product of lipid peroxidation. We could not demonstrate a measurable increase of oxidative stress neither for the OPCAB nor for the OnP-BH patients. In contrast to our findings Wildhirt and colleagues could demonstrate a significant difference in MDA levels comparing OPCAB and arrested heart surgery [21]. It can be speculated that oxidative stress predominantely occurs in the arrested ischemic heart and can be dramatically reduced by preserving native coronary blood flow.
There is increasing evidence of reduced CK-MB and troponin serum concentrations in OPCAB surgery [2,4,5,11,21]. However, all randomized trials compared cardiac biomarker release in OPCAB patients with patients undergoing CABG procedure on the arrested heart. One major finding in the present study is the difference in serum CK-MB and cTnI following OnP-BH compared with OPCAB surgery indicating an increased myocardial injury induced by the cardiopulmonary bypass. It was, however, without any clinical relation in the routine patient population examined in this study. However, in the postoperative course the cTnI increase was comparable and CK-MB level increased more in the OPCAB group leading to comparable concentrations 12h postoperatively. Reasons for that findings remain speculative. Suggestions include the cardiac manipulation per se, blower-induced air embolization, passager local ischemic injury and the retransfusion of the cell saver blood at the end of the operation in the OPCAB patients.
During the operation CK-MB and troponin concentrations were higher in the coronary sinus blood than in the peripheral arterial blood corresponding to local release mechanisms. These findings were of statistical significance for the OnP-BH patients only.
One major reason for performing CABG procedures without CPB support is to reduce the systemic inflammatory reaction induced by the extracorporeal circulation. Several experimental studies could reveal a benefit of OPCAB procedures concerning a lower release of proinflammatory cytokines [6,10,22,23]. In the present study we analyzed only the time characteristics and magnitude of acute phase reactant CRP release during the operation and in the early postoperative course. Based on this findings CRP release is predominantly related to the surgical trauma and the anesthesiolocial management and increased only moderate with the use of CPB. Similar findings were reported by others comparing OPCAB and arrested heart coronary artery procedures [10,23].
BNP (=NT-proBNP, see Section 2) is a highly sensitive and specific marker for left ventricular dysfunction and a powerful predictor for mortality and cardiovascular events after adjustment for traditional risk factors [24]. In a limited number of studies the impact of natriuretic peptides to assess postoperative myocardial dysfunction in conventional CABG patients is contradictory [14,15,25]. Less data are available about the BNP release in OPCAB surgery. In OPCAB patients we found no significant increase of BNP during the operation. However, after 24h a peak of 4-fold baseline level was determined. In contrast, in the OnP-BH group we identified an increase to 2.3-fold the baseline level measured already at the time of LIMA-LAD flow release. Reasons for these findings remain also speculative and include severe wall stress, myocardial trauma induced by direct manipulation as well as an increased ischemic injury. A positive correlation between BNP and troponin I levels (r=0.56) seems to point to the latter hypothesis.
At the operation BNP concentrations in the OnP-BH group were significantly higher in the coronary sinus blood than in the peripheral arterial blood. These findings again reflect on the local cardiac release of BNP.
In conclusion we found a reduced postoperative inotropic support and a reduced ICU stay in OPCAB patients compared with OnP-BH patients. However, this was without further implication for the clinical outcome. OnP-BH surgery was associated with slightly increased myocardial injury on a subclinical level. We conclude from our results that OnP-BH is not favorable compared to OPCAB for routine coronary patients. Further studies are warranted to determine the clinical relevance of these findings on patients with critical myocardial oxygen reserve supply.
4.1. Limitations
The intention of the study was to compare the operative strategies of OPCAB versus OnP-BH surgery on a biochemical level. Because of the relatively small patient cohort the validity of the clinical outcome data is limited, although a level of significance was achieved through the power of the prospective randomization of the patients. It also remains speculative that our results in routine patients are transferable to patients with increased preoperative risk.
| Appendix A. Conference discussion |
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Dr Rastan: This is an interesting finding. We haven't thought about this. We didn't retransfuse the blood which was lost after the operation. However, in the OPCAB patients, we used cell saver systems, but we didn't do any measurements on that.
Dr Wahba: Well, there are very high levels, not in the cardiotomy suction blood in our study, but in the blood that comes out of the drain afterwards, the retransfusion blood, the postoperative retransfusion blood. And also it's on-pump arrested heart cases, so it may be something completely different.
Dr C. Yankah (Berlin, Germany): First, you were saying that the on-pump surgery is detrimental to the patients. This is a very important message for encouraging the interventional cardiologists to justify a delay in referring patients for early surgery. This is a challenge for us to improve our -extracorporeal circulatory method. How are you going to improve technique of extracorporeal circulation in order to minimize your complications and offer a better prognosis for your coronary patients?
The second question is, how could you start training residents without extracorporeal circulation? Do you have any program for training, or you use the on-pump technique for training your residents as well?
Dr Rastan: You mean train OPCAB surgery for younger surgeons?
Dr Yankah: Trainees, how are you going to deal with them?
Dr Rastan: In our hospital indication for OPCAB surgery is restrictive for the trainees to allow them to get experienced in basic technical aspects. Later we think that OPCAB surgery is as safe as on-pump beating heart surgery. So we don't use the cardiopulmonary bypass to teach OPCAB surgery routinely, especially because this is a completely different situation to operate on a deloaded heart. So I think it's not real training for OPCAB surgery.
Dr J. Pirk (Prague, Czech Republic): Could you give me the explanation, what is the mechanism that the extracorporeal circulation is damaging the heart. It's a beating, nonworking heart, so it shouldn't harm the heart. So what is the explanation? What is the mechanism?
Dr Rastan: The CPB dependent myocardial injury is triggered by several cytokine cascades that are well known in the literature. Cytokines include TNF-alpha and interleukin-2 and -6 for example. But the interesting thing for us was when does it occur. Does it occur immediately during the operation or in the postoperative course?
What we didn't do, actually, is to measure the interleukin levels in our study now. So I just cannot give the answer in detail now.
| Acknowledgments |
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| Footnotes |
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Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting Society of Thoracic Surgeons in Leipzig, Germany, September 12-15, 2004. | References |
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