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Eur J Cardiothorac Surg 2000;17:737-742
© 2000 Elsevier Science NL

Inflammatory response and myocardial injury following coronary artery bypass grafting with or without cardiopulmonary bypass

^a Department of Cardiothoracic Surgery, University of Vienna Medical School, AKH Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria
^b Department of Anaesthesia, University of Vienna Medical School, A-1090 Vienna, Austria

Corresponding author. Tel.:+43-1-40400 ext. 5620; fax: +43-1-40400 ext. 5642
e-mail: michael.grimm{at}akh-wien.ac.at

	Abstract

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 
Objective: In coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) the inflammatory response is suggested to be minimized. Coronary anastomoses are performed during temporary coronary occlusion. Inflammatory response and myocardial ischaemia need to be studied in a randomized study comparing CABG in multivessel disease with versus without CPB. Methods: Following randomization 30 consecutive patients received CABG either with (n=16) or without CPB (n=14). Primary study endpoints were parameters of the inflammatory response (interleukin (IL)-6, interleukin-10, ICAM-1, P-selectin) and of myocardial injury (myoglobin, creatine kinase-MB (CK-MB), troponin I) (intraoperatively, 4, 8, 16, 24 and 48 h after surgery). The secondary endpoint was clinical outcome. Results: The incidence of major (death: CABG with CPB n=1, not significant (n.s.)) and minor adverse events (wound infection: with CPB n=2, without CPB n=1, n.s.; atrial fibrillation: with CPB n=3, without CPB n=2, n.s.) was comparable between both groups. The release of IL-6 was comparable during 8 h of observation (n.s.). Immediately postoperatively IL-10 levels were higher in the operated group with CPB (211.7±181.9 ng/ml) than in operated patients without CPB (104.6±40.3 ng/ml, P=0.0017). Thereafter no differences were found between both groups. A similar pattern of release was observed in serial measures of ICAM-1 and P-selectin, with no difference between both study groups (n.s.). Eight hours postoperatively the cumulative release of myoglobin was lower in operated patients without CPB (1829.7±1374.5 µg/l) than in operated patients with CPB (4469.8±4525.7 µg/l, P=0.0152). Troponin I release was 300.7±470.5 µg/l (48 h postoperatively) in patients without CPB and 552.9±527.8 µg/l (P=0.0213). CK-MB mass release was 323.5±221.2 µg/l (24 h postoperatively) in operated patients without CPB and 1030.4±1410.3 µg/l in operated patients with CPB (P=0.0003). Conclusions: This prospective randomized study suggests that in low-risk patients the impact of surgical access on inflammatory response may mimic the influence of long cross-clamp and perfusion times on inflammatory response. Our findings indicate that multiregional warm ischaemia, caused by snaring of the diseased coronary artery, causes considerably less myocardial injury than global cold ischaemia induced by cardioplegic cardiac arrest.

Key Words: Coronary artery bypass grafting • Systemic inflammatory response syndrome • Cytokine • Adhesion molecule • Myocardial injury

	1. Introduction

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 
Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) and cardioplegic cardiac arrest is known to cause inflammatory response, which may affect the postoperative course of the patient [1,2]. Additionally, ischaemia/reperfusion-induced cardiac injury due to cardioplegic cardiac arrest may limit surgical success [3]. Stimulated by these facts, CABG without CPB has gained increasing interest. This technique is postulated to cause a marked reduction of adverse effects related to CPB [4–6].

The inflammatory response after conventional CABG is primarily associated with low blood pressure and increased heart rate, increase of body temperature, leucocytosis and tissue oedema [2,7]. These factors contribute to prolonged hospital stay after surgery [1]. Many investigators have shown that these phenomena are accompanied by increased release of cytokines such as interleukin-6 (IL-6) and interleukin-10 (IL-10) as well as by increased release of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selectin [2,3,8,9]. Based on this clinical experience, CABG without CPB now is postulated to reduce the whole body inflammatory response [1,8]. Gu et al. have shown that CABG without CPB via a small anterolateral thoracotomy results in a significant reduction in the inflammatory response (leucocyte elastase, ß-thromboglobulin, complement C3a) as compared to conventional CABG with CPB via median sternotomy [1]. In an additional study, the authors showed that in single left internal mammary artery (LIMA) to left anterior descending artery (LAD) bypass grafting without CPB, median sternotomy results in more extended inflammatory response than small lateral thoracotomy (MIDCAB). This strongly suggests that the extent of tissue injury does contribute to the inflammatory response [10].

A limiting factor of CABG without CPB is temporary coronary occlusion for performing anastomoses on the beating heart [5]. Transient ischaemia may result in myocardial injury as shown by serial measurements of serum levels of cardiac troponin I and creatine kinase (CK)-MB [11].

The primary endpoints of this prospective randomized study was to measure parameters of inflammatory response (IL-6, IL-10, ICAM-1 and P-selectin) and of ischaemic myocardial injury (CK-MB, myoglobin and troponin I) in patients suitable for both surgical techniques undergoing CABG either with or without CPB via median sternotomy. The secondary endpoint was clinical outcome.

	2. Subjects and methods

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 
2.1. Patients
After the study protocol was approved by the Ethics Committee of the University of Vienna and after informed consent was obtained from each patient, 30 consecutive patients were enrolled. In preoperative study of coronary angiography, the decision was made whether safe and complete revascularization either with CPB or without CPB seemed feasible. Primary target vessels were LAD, diagonal branches and right coronary artery. Patients with diseased circumflex branches were only enrolled when the marginal branches looked feasible to access without CPB. Fifteen patients were randomized to receive CABG with CPB and 15 patients without CPB. One patient was switched intraoperatively from surgery without CPB to surgery with CPB, due to an intramyocardial LAD and thereafter was classified to the group with CPB. Patient demographic data were comparable between both groups (Table 1).

2.3. CABG with CPB
In all 30 study patients, surgical access was gained via median sternotomy. After harvesting the arterial and venous bypass grafts the patients received heparin (300 units/kg). In patients undergoing CABG with CPB a standard technique was used. We performed normothermic CPB in all patients. Core temperature was assessed by a nasopharyngeal probe. Myocardial preservation during aortic cross clamping was achieved by 4°C cold intermittent ante- and retrograde blood cardioplegia. Heparin was antagonized with protamine sulphate. The cardiopulmonary bypass circuit consisted of a hollow-fibre oxygenator (Bard HF 5701, C.R. Bard Inc., Havorhill, MA) primed with Ringer's lactate 2000 ml, mannitol 20 g, heparin 8000 IU (Immuno, Vienna, Austria) and aprotinin 1 000 000 IU (Trasylol Bayer, Leverkusen, Germany). Flow during CPB was maintained at 2.5 l/min per m². Blood cardioplegia in a 4:1 ratio was used. Haematocrit level was kept higher than 20% with donor blood if necessary. After weaning from CPB, mean arterial pressure was maintained above 60 mmHg with fluid loading and appropriate vasoactive drugs. Treatment in the intensive care unit (ICU) was defined by institutional standards.

2.4. CABG without CPB
A myocardial coronary artery stabilizer system (Cardio Thoracic Systems, Cupertino, CA) was used in all cases. In the majority of cases the LAD was revascularized first. The vessel was stabilized, surrounded distally and proximally to the chosen anastomotic site by two 5-0 polypropylene sutures and was snared. No test of the tolerance for regional ischaemia was performed. Afterwards the left internal mammary artery–LAD anastomosis was performed on the beating heart. Thereafter, further distal anastomoses were performed using the same myocardial coronary artery stabilizer system. If venous bypass grafts had been used, central anastomoses were performed on the partially clamped ascending aorta. Heparin was antagonized with protamine sulphate until preoperative activating clotting times could be achieved.

2.5. Parameters of clinical outcome
As parameters of clinical outcome, we monitored the appearance of major adverse events (death, myocardial infarction, stroke) and minor adverse events (wound infections and postoperative atrial fibrillation). We also recorded the number of bypass grafts, requirement for blood units, intubation time, in-ICU and in-hospital stay. All patients were discharged from hospital when they were in good clinical condition. As clinical parameters of systemic inflammatory response we monitored blood pressure, heart rate, temperature and white blood cell count.

2.6. Blood samples
Blood samples were sequentially taken before surgery (baseline), immediately after skin closure and 4, 8, 16, 24 and 48 h after surgery, from the indwelling radial arterial catheter. As parameters of inflammatory response, we measured IL-6, IL-10, ICAM 1 and P-selectin. These values were obtained only up to 8 h after surgery. As parameters of myocardial injury we measured CK-MB mass, myoglobin and cardiac troponin I. These values were obtained for 48 h after surgery.

All blood samples were centrifuged immediately after taking and serum aliquots were stored at -70 and -20°C, respectively, until biochemical measurements within 4 weeks. For quantitative determinations of IL-6, IL-10, ICAM-1 and P-selectin, enzyme linked immunosorbent essays were used (R&D Systems Inc., Minneapolis, MN). For the latter parameters a volume correction of all obtained data was made by forming ratios with reference to plasma levels of IgG to eliminate the volume deviations caused by hemodilution of pump priming and volume administration. Thereafter the values of each parameter were transformed to percent deviation from the pre-anaesthesia level [12].

CK-MB, myoglobin and cardiac troponin I were processed in the laboratory on a Opus Plus immunoassay system (Behring Diagnostic Inc., Westwood, MA) using test modules, calibration-and control material from the given manufacturer. The limits of detection were 0.6 ng/ml, 1.0 ng/ml and 0.5 ng/ml for CK-MB mass, myoglobin and cardiac troponin I, respectively. Release of these parameters is given as area under the curve and we have chosen that time point when the lower parameter has reached the peak value.

2.7. Statistical analysis
Data are reported as mean±standard deviation. Analysis was performed for categorical variables with the ²-test or Fisher's exact test as appropriate. Continuous variables were analysed with the t-test for clinical parameters and with the Mann–Whitney U-test for markers of inflammatory response and myocardial injury (SAS Inc., Cary, NC). For multiple comparisons, Bonferroni correction was applied. Areas under the curve were calculated using Microsoft Excel 97. The Mann–Whitney U-test was applied and a P-value of less than 0.05 was considered significant. If a significance was found, the exact P-value is given. If no significance was found, the term n.s. (not significant) is given.

	3. Results

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 
3.1. Clinical outcome
Patients undergoing CABG with CPB received more grafts than patients undergoing CABG without CPB (P=0.038, Table 2). In operated patients with CPB there occurred one major adverse event (death from acute Type-A aortic dissection 7 days after surgery). Despite this, the incidence of major adverse events (death, myocardial infarction, stroke) and minor adverse events (wound infections and postoperative atrial fibrillation) was comparable in both groups (Table 2).

3.2. Parameters of inflammatory response
The release of IL-6 was comparable during 8 h of observation (n.s., Fig. 1). Immediately postoperatively, IL-10 levels were higher in the operated group with CPB (211.7±181.9 ng/ml) than in operated patients without CPB (104.6±40.3 ng/ml, P=0.0017). Thereafter no differences were found between both groups (Fig. 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Serum levels of interleukin-6 and interleukin-10 with and without CPB. Continuous line, with CPB; dotted line, without CPB. Values are given as mean±SD.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Serum levels of P-selectin and ICAM-1 with and without CPB. Continuous line, with CPB; dotted line, without CPB. Values are given as mean±SD.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Serum levels of troponin I, myoglobin and CK-MB mass with and without CPB. Values are given as areas under the curve.

	4. Discussion

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

Clinical outcome was comparable for both patient groups. This can be seen in the comparable ICU and in-hospital stay of both patient groups, although intubation times were significantly shorter in patients undergoing CABG without CPB. There was one postoperative death in an operated patient with CPB, who died from acute Type-A dissection 7 days after surgery. Due to the limited number of patients enrolled in our study, differences in clinical outcome may be mimicked. However, from recent surgical experience, it seems likely that differences in clinical outcome – with or without CPB – may only be seen in high-risk patients undergoing CABG, e.g. the very elderly, in whom in-hospital mortality rates following conventional CABG can be above 10% [13–15]. In this study we included only elective, low-risk patients. In these patients one would not expect marked adverse effects of CPB on postoperative clinical course.

The systemic inflammatory response, which goes along with an increased release of cytokines and adhesion molecules, after conventional CABG with CPB has been shown to provoke postoperative organ dysfunction [9,16,17]. This has primarily been attributed to CPB and to the exposure of blood to foreign surfaces [8]. In a recent study comparing CABG with and without CPB, Strüber et al. have found a marked difference in inflammatory response [18]. However, this study is strongly limited by the fact that patients undergoing CABG with CPB had three-vessel disease whereas patients undergoing CABG without CPB had single-vessel disease. Furthermore, in patients undergoing CABG with CPB, median sternotomy was used as surgical access in comparison to patients undergoing CABG without CPB, in whom lateral thoracotomy was used as surgical access.

Gu et al. showed that in single LIMA to LAD bypass grafting without CPB, median sternotomy results in a more extended inflammatory response than does small anterolateral thoracotomy [10]. This strongly supports the hypothesis that the extent of tissue injury does contribute to inflammatory response. To a certain degree this can be found in other major surgical – non-cardiac – procedures, which were also shown to provoke systemic inflammatory responses [20–22]. Extensive tissue injury of median sternotomy may explain a similar pattern of release of cytokines and adhesion molecules in patients undergoing CABG without CPB compared with patients undergoing conventional CABG with CPB. On the other hand, Wan et al. were able to demonstrate a reduced pattern of release of markers of the systemic inflammatory response in patients undergoing CABG without CPB via median sternotomy as compared to patients undergoing conventional CABG with CPB [19].

In our study, IL-10 was higher only immediately postoperatively in the patient group undergoing CABG with CPB. Four hours postoperatively a difference in inflammatory response could no longer be found and also, none of the other inflammatory parameters showed differences between the two groups. We suggest that in elective low-risk patients undergoing rather simple surgical revascularization with short cross-clamp and perfusion times, the differences in inflammatory response are smaller than in patients undergoing complex reconstructions requiring longer cross-clamp and perfusion times. In low-risk patients the impact of surgical access on inflammatory response therefore gains importance and may mimic the influence of long cross-clamp and perfusion times on inflammatory response.

Cardioplegic cardiac arrest is safe and effective in protecting the myocardium during CABG with CPB and the clinical relevance of myocardial injury related to cardioplegic cardiac arrest is acceptably low [11]. Nevertheless, there remains a certain number of patients who suffer from postoperative myocardial injury which is primarily not related to graft dysfunction [8]. This ischaemic injury may be caused by incomplete distribution of cardioplegia in the heart and by unexpected aortic regurgitation, which results in non-uniform myocardial perfusion [23–25]. On the other hand, recent data suggest that temporary coronary occlusion on the beating heart causes subclinical myocardial injury, as shown by elevated cardiac troponin I levels postoperatively [11]. In our study we observed identical clinical outcome in both study groups. Subclinical myocardial injury was significantly lower in operated patients without CPB as than in operated patients with CPB and cardioplegic cardiac arrest. This is expressed by a lower release of myoglobin in the first 8 h, of CK-MB during 24 h and of cardiac troponin I during 48 h. These findings indicate that multiregional warm ischaemia, caused by snaring of the diseased coronary artery, causes considerably less myocardial injury than global cold ischaemia induced by cardioplegia. These findings are supported by the recent work of Wan et al. [19].

In conclusion, this prospective randomized study suggests that in low-risk patients undergoing elective, isolated CABG, the impact of CPB on inflammatory response is smaller than expected by the surgical community. In line with previous reports the amount of myocardial injury is lower following CABG without CPB. A larger study with a higher number of patients is needed in order to assess the clinical benefits of CABG without CPB as compared to conventional CABG with CPB.

	Footnotes

 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8, 1999.

	Appendix A Conference discussion

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 
Dr J. Svennevig (Oslo, Norway): I agree that there may not have been differences with respect to your chemical outcome variables, but I think to draw the conclusion, it would be too far when you conclude that the systemic inflammatory reaction is the same, because you have yet to define what you mean by the inflammatory reaction, and you would probably come to an opposite result if you would measure, for instance, complement activation.

Dr Grimm: Yes, this is certainly right; however, there is a huge variety of parameters involved with the systemic inflammatory response syndrome (SIRS), even from the standpoint of laboratory parameters, and I think it was our intention just to check simple patients, and I think we cannot say that this is valid for risk patients, for high-risk patients with several co-morbidities, but I think in the simple patients, the fear for cardiopulmonary bypass is certainly overestimated, since this has been short pump times, short cross-clamp times.

Dr L. von Segesser (Lausanne, Switzerland): Unfortunately the definition for SIRS is so large that almost all of us in here have some type of SIRS. So everybody who goes to the ICU has SIRS, and probably we have to define more clearly what we are talking about when we want to identify patient groups that have more or less negative signs.

Dr Grimm: I completely agree with you.

Dr A. Moritz (Frankfurt, Germany): You selected a very low-risk patient group, and we didn't compare such a group to an off-pump group, but we checked the neurologic outcome for a very low-risk group, and we didn't find those neurologic deficits. Many other studies found it in a more complex group of patients. So did you do find similar things in the neurology, or the cognitive functions, between these low-risk groups in off-pump and on-pump surgery? The problems we anticipate with the pump that we all know, are that they are only focused for higher risk patients, long pump runs. So does this short pump run in an uncomplicated patient do any harm or do we overestimate this?

Dr Grimm: We did a lot of brain studies. We focused actually on the measurement of cognitive brain function by means of auditory evoked potentials, and what we found is that the primary targets of adverse events related to the cardiopulmonary bypass, at least in our experience or in our research experience, is brain function. So although you find a minor cognitive impairment in the simple patient, I think it is not the problem of the simple patient, it is the problem of the complicated patient, and I think the higher the risk of the patient, the older the patient, certainly the higher the risk is also of neuropsychological impairment after the operation.

Dr V. Subramanian (New York, NY, USA): Michael, you have elegantly shown that in low-risk patients there is no difference in inflammatory response. There are other factors which may come into play. Since you have shown this, what is your preference for a single LAD lesion which has been re-stented three or four times? Would the approach be beating-heart surgery or non-beating-heart surgery? What are you doing in your centre right now?

Dr Grimm: I think from the quality of the anastomosis, we are nowadays able to do a very nice anastomosis of the beating heart, so I think I would go for beating-heart surgery.

Dr Subramanian: Why do you go for beating heart then if there is no difference?

Dr Grimm: I think maybe it's cheaper.

Dr Subramanian: All right, thank you.

	References

Top Abstract 1. Introduction 2. Subjects and methods 3. Results 4. Discussion Appendix A Conference discussion References

 

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