Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress

[김기환/강원대]

Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress

Paolo Biglioli, Aldo Cannata, Francesco Alamanni, Moreno Naliato, Massimo Porqueddu, Marco Zanobini, Elena Tremoli and Alessandro Parolari^,

Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, University of Milan, via Parea 4, 20138, Milan, Italy

Received 30 July 2002; 

revised 15 April 2003; 

accepted 24 April 2003. ;

Available online 24 June 2003.

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Abstract

Cardiopulmonary bypass (CPB) has been recognized as a cause of complex systemic inflammatory response, which significantly contributes to several adverse postoperative complications. In the last few years, off-pump coronary artery bypass grafting has gained widespread diffusion as an alternative technique to conventional on-pump coronary artery bypass grafting. Surgeons supporting off-pump surgery state that the avoidance of the CPB and myocardial ischemia-reperfusion significantly reduces the postoperative systemic inflammatory response and other biological derangements and, possibly, may improve the clinical outcomes. We review, here, the available evidence concerning possible differences between off-pump and on-pump procedures in terms of inflammation, hemostasis and oxidative stress. Consistent differences in the involvement of these systems are observed, but they are limited to the final steps of the surgical procedures and the early hours after. These findings suggest that the global surgical trauma may be as important, or even more, as the CPB in terms of systemic inflammatory and coagulation–fibrinolytic pathway activation. Further studies are needed in order to confirm‎ this hypothesis.

Author Keywords: Cardiopulmonary bypass; Coronary surgery; Beating heart surgery; Inflammation; Hemostasis; Oxidative stress

Article Outline

1. Introduction

2. Historical background (Table 1)

3. Inflammation, hemostasis and oxidative stress: CABG vs. OPCAB or MIDCAB

3.1. Complement and tumor necrosis factor α (Table 2)

3.1.1. Complement

3.1.2. Tumor necrosis factor α

3.2. Interleukins (Table 3)

3.2.1. Interleukin-6

3.2.2. Interleukin-8

3.2.3. Interleukin-10

3.2.4. Other interleukins

3.3. C-reactive protein, leukocytes and elastase (Table 4)

3.4. Coagulation, platelets and adhesion molecules (Table 5)

3.5. Oxidative stress

4. Discussion

5. Limitations of the available evidences

6. Conclusions

References

1. Introduction

Cardiopulmonary bypass (CPB) has been recognized as the main cause of a complex systemic inflammatory response, which significantly contributes to several adverse postoperative outcomes such as renal, pulmonary and neurological complications, bleeding and even multiple organ dysfunction.

After the recent development of effective devices for target vessel exposure and stabilization, beating heart techniques, e.g. off-pump coronary artery bypass grafting (OPCAB) and minimally invasive direct coronary artery bypass (MIDCAB) have gained widespread diffusion as alternative techniques to conventional on-pump coronary artery bypass grafting (CABG). The avoidance of CPB and myocardial ischemia-reperfusion has been proposed to significantly reduce the postoperative systemic complications which negatively affect the perioperative course after surgical myocardial revascularization [1 and 2].

The aim of this study is to review possible differences between on-pump and off-pump coronary surgery in the perioperative activation of inflammation, hemostasis and oxidative stress markers.

2. Historical background (Table 1)

The effects of CPB on activation of the inflammation and coagulation pathways have been investigated over time [3, 4, 5, 6, 7 and 8]. In earlier studies, during the eighties and early nineties, however, the number of OPCAB performed worldwide was too limited to be considered a routine practice and to allow a comparison with CABG in terms of biological and clinical outcomes. Therefore, earlier studies documented a more marked activation of hemostatic and inflammatory systems in conventional on-pump CABG than in major vascular or general thoracic surgery [6, 7 and 8]. This was primarily related to direct interactions (e.g. surface activation) between circulating components of the hemostatic system and the apparatus of the CPB (oxygenator, tubing, etc.). Moreover, the routine use of systemic heparinization, hemodilution and hypothermia during on-pump procedures sensibly influenced the hemostatic system.

Table 1. Perioperative changes in inflammatory and coagulation mediators: on-pump cardiac surgery vs. major vascular surgery vs. major noncardiac thoracic surgery

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Cardiac, on-pump cardiac surgery; Vascular, major vascular surgery; Thoracic, major noncardiac thoracic surgery.

↑, significant increase over time with respect to baseline levels; (↑), trend towards increase over time with respect to baseline levels; ↓, significant decrease over time with respect to baseline levels; (↓), trend towards decrease over time with respect to baseline levels; =, no variations; #, statistically significant higher values in cardiac group than thoracic group at one or more time points; ##, statistically significant lower values in cardiac group than thoracic group at one or more time points; °, in this study no intergroup (cardiac vs. vascular vs. thoracic) statistical comparisons were performed.

TCC, terminal complement complex; IL-1, interleukin-1; IL-6, interleukin-6; IL-10, interleukin-10; TAT, thrombin–antithrombin complex; AT-III, antithrombin III activity; t-PA, tissue plasminogen activator antigen; PAI-1, plasminogen activator inhibitor-1 activity; n.a., not available.

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In the last 10 years, the widespread diffusion of off-pump coronary surgery offered the unique opportunity to further clarify the pathophysiology of CPB.

3. Inflammation, hemostasis and oxidative stress: CABG vs. OPCAB or MIDCAB

3.1. Complement and tumor necrosis factor α (Table 2)

3.1.1. Complement

Activation of complement, which occurs through the classical and alternate pathways, is the most clear-cut inflammatory response detectable in the early phase after coronary bypass [4 and 5]. Activated complement proteins influence several inflammatory cells, hereby inducing the secretion of proinflammatory mediators. In a time frame from 0.5 to 2 h after surgery, a marked complement activation (C3a, C5a) occurs both in CABG and OPCAB, but is sensibly more marked in CABG [9 and 10]. Starting from 4 h after surgery, however, the levels of activated complement components in CABG shift down to OPCAB levels, still relatively higher than at baseline [9 and 10]. Nonrandomized studies show increased complement activation (C3a) in CABG vs. MIDCAB [12] and in OPCAB vs. MIDCAB in terms of terminal complement complex activation, whereas the markers of earlier complement activation phases (C3a and C4a) do not differ sensibly [13]. In addition, one nonrandomized study comparing CABG with both OPCAB and MIDCAB documented some advantage in terms of C3d and C5a for MIDCAB patients with respect to CABG, and in terms of C5a for MIDCAB and OPCAB patients with respect to CABG [14]. Some degree of complement activation, however, was documented in the early postoperative period after the three surgical procedures [14]. A randomized study, which eval‎uated the activation of complement in CABG vs. MIDCAB, documented increased complement activation only in patients undergoing CABG at the end of surgery [11]. Unfortunately, this study did not include a postoperative follow-up.

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Table 2. Circulating complement and TNF-α: perioperative changes

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Random, randomized study; CABG, full access on-pump coronary artery bypass grafting; OPCAB, full access off-pump coronary artery bypass grafting; MIDCAB, off-pump minimally invasive direct coronary artery bypass grafting.

↑, significant increase over time with respect to baseline levels; (↑), trend towards increase over time with respect to baseline levels; ↓, significant decrease over time with respect to baseline levels; (↓), trend towards decrease over time with respect to baseline levels; =, no variations; *, statistically significant higher values in CABG group than OPCAB group at one or more time points; **, statistically significant higher values in CABG group than MIDCAB group at one or more time points; ***, statistically significant higher values in OPCAB group than MIDCAB group at one or more time points; °, in this study CABG was performed with the use of CPB, but on the beating heart, without aortic cross-clamp and cardioplegia administration.

TCC, terminal complement complex; TNF-α, tumor necrosis factor α; TNF-α-R, tumor necrosis factor receptor; n.a., not available.

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3.1.2. Tumor necrosis factor α

Tumor necrosis factor α (TNF-α) is a potent proinflammatory cytokine produced mainly by monocytes–macrophages, but also by B and T cells and by fibroblasts. The myocardium subjected to ischemia-reperfusion cycle during conventional CABG is a major source of TNF-α [15], particularly if the left ventricle is dysfunctioning [16]. The systemic release of TNF-α is limited during aortic cross-clamping, but it becomes striking after aortic declamping [17]. Diegeler et al. documented in a nonrandomized study, a significant increase in the release of TNF-α soluble receptors, p55 and p75 soon after surgery in CABG, which persisted up to 48 h; conversely, there was an early significant postoperative increase in the circulating levels of TNF-α soluble receptors in OPCAB group and no change in MIDCAB [14]. Two randomized studies comparing the kinetics of TNF-α in CABG vs. OPCAB [10 and 18] showed somehow conflicting results. Significant increases in the circulating levels of TNF-α in both groups of patients were observed [18], which were significantly greater in the CABG group throughout the study period. In contrast, in another study, no changes in TNF-α levels were observed in OPCAB, and a trend towards TNF-α increase in the early hours, reaching statistical significance only at 48 h postoperatively, was observed in CABG patients [10]. This discrepancy may be explained by the fact that, in this latter study, CABG patients underwent on-pump surgery on beating heart without aortic clamping, a condition in which the contribution of perioperative myocardial ischemia-reperfusion might have been relatively small in terms of inflammation.

3.2. Interleukins (Table 3)

3.2.1. Interleukin-6

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by several cells, such as T cells, monocytes–macrophages and fibroblasts. Experimental [20] and clinical [15, 16 and 17] studies documented that myocardium exposed to cardioplegic arrest is one of the major sources of IL-6. The exclusion of the lungs from circulation may play a role in explaining the elevated levels of IL-6 levels during CPB [21]. IL-6 participates and contributes to the acute inflammatory reaction as well as to the activation of T cells, stimulation and growth of hematopoietic precursor cells and fibroblasts [22]. Finally, there is evidence that IL-6 blunts the release of other proinflammatory cytokines [22].

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Table 3. Circulating interleukins: perioperative changes

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Random, randomized study; CABG, full access on-pump coronary artery bypass grafting; OPCAB, full access off-pump coronary artery bypass grafting; MIDCAB, off-pump minimally invasive direct coronary artery bypass grafting; MIDCABG, on-pump minimally invasive direct coronary artery bypass grafting.

↑, significant increase over time with respect to baseline levels; (↑), trend towards increase over time with respect to baseline levels; ↓, significant decrease over time with respect to baseline levels; =, no variations; *, statistically significant higher values in CABG group than OPCAB group at one or more time points; **, statistically significant higher values in CABG group than MIDCAB group at one or more time points; §, statistically significant higher values in thoracotomy groups than sternotomy groups at one or more time points; °, in this study, CABG was performed with the use of CPB, but on the beating heart, without aortic cross-clamp and cardioplegia administration.

IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; sIL-2R, soluble interleukin-2 receptor; sIL-6R, soluble interleukin-6 receptor; n.a., not available.

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No [18, 23, 24, 25, 26 and 28] or minor [19 and 27] differences in the kinetics of this cytokine were observed during CABG or OPCAB. Nonrandomized studies showed greater IL-6 levels early [12] as well as later on [14] after CABG for three vessel disease compared with MIDCAB for one-vessel disease. In contrast, another nonrandomized study, which compared OPCAB vs. MIDCAB for the treatment of single vessel disease, failed to document significant differences in IL-6 kinetics up to 24 h after operation [13]. Interestingly, in a randomized study, a significant postoperative increase of IL-6 was documented in all patients randomized to CABG, OPCAB, MIDCAB and on-pump MIDCAB for single vessel disease, with peak levels between 6 and 12 postoperative hours. Interestingly, patients subjected to thoracotomy manifested significantly higher IL-6 levels with respect to those with sternotomy, irrespective of CPB [28].

3.2.2. Interleukin-8

Interleukin-8 (IL-8) is a proinflammatory cytokine produced by several cell types, such as monocytes/macrophages, endothelial cells and T lymphocytes. This cytokine plays a major role in the control of neutrophil trafficking [29]. Similar to TNF-α and IL-6, the myocardium and the lungs are among the major sources of IL-8 during CPB [15, 16, 17, 21 and 30].

Nonrandomized studies indicate that in CABG, OPCAB and MIDCAB, the perioperative levels of IL-8 increase over time, mostly in CABG compared with MIDCAB patients [12 and 14].

Ascione et al. [9] in a randomized study showed increased plasma levels of IL-8 in CABG patients from 1 to 24 postoperative hours, whereas no relevant changes in the levels of this proinflamamtory cytokine were detected over time in OPCAB. Another study [10] showed no major differences in the time course of IL-8 between CABG and OPCAB patients. In the latter, there was a significant increase of IL-8 over baseline in CABG early postoperatively. In the OPCAB group, a similar trend, although not statistically significant, towards an early perioperative increase of IL-8 was observed. Indeed, in this study, CABG patients were operated on a beating heart during CPB. In this way, the avoidance of myocardial ischemia induced by aortic cross-clamping might prevent the release of IL-8 [30] and other cytokines from the myocardium. Also, other nonrandomized studies documented higher levels of IL-8 in the early hours after surgery in CABG patients, with similar levels between CABG and OPCAB at later times [25 and 26].

3.2.3. Interleukin-10

This cytokine is produced by monocytes–macrophages, B and T cells, and it possesses anti-inflammatory properties [31 and 32]. Both randomized [23] and nonrandomized studies [25 and 26] have shown rapid and significant increases of interleukin-10 (IL-10) levels in CABG just after reperfusion, which return to baseline within 2–4 h after surgery. Instead, no statistically significant changes in IL-10 levels are observed in OPCAB [14, 23, 25 and 26] or MIDCAB [14] patients. The mechanisms responsible for the increases in the levels of IL-10 in plasma in CABG are somehow uncertain.

3.2.4. Other interleukins

Evidence concerning the kinetics of the levels in plasma of other interleukins in the different surgical approaches to coronary artery disease is still limited. The receptors for IL-2, a proinflammatory and immunostimulatory interleukin involved in the initiation of inflammatory response, have been shown to be increased in both CABG and OPCAB procedures, with relatively higher levels in CABG [18]. Finally, the kinetics of the proinflammatory IL-1 was not different in CABG, OPCAB, MIDCAB and on-pump MIDCAB [28].

3.3. C-reactive protein, leukocytes and elastase (Table 4)

C-reactive protein (CRP), one of the major acute phase reactants, enhances phagocytosis of bacteria, viruses and parasites and also activates complement. In nonrandomized studies, similar CRP levels both in CABG and OPCAB up to 24 h after surgery were observed [27 and 33]. In contrast, in a randomized study, levels of CRP were found to be increased in the early days after surgery both in CABG and OPCAB; the increase of CRP levels was greater and persisted for longer time after CABG with respect to OPCAB [18].

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Table 4. Circulating CRP, leukocytes and elastase: perioperative changes

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Random, randomized study; CABG, full access on-pump coronary artery bypass grafting; OPCAB, full access off-pump coronary artery bypass grafting; MIDCAB, off-pump minimally invasive direct coronary artery bypass grafting.

↑, significant increase over time with respect to baseline levels; (↑), trend towards increase over time with respect to baseline levels; ↓↑, initial decrease followed by increase; ↓, significant decrease over time with respect to baseline levels; (↓), (nonsignificant) trend toward decrease over time with respect to baseline levels; =, no variations; *, statistically significant higher values in CABG group than OPCAB group at one or more time points; **, statistically significant higher values in CABG group than MIDCAB group at one or more time points; °, in this study, CABG was performed with the use of CPB, but on the beating heart, without aortic cross-clamp and cardioplegia administration.

CRP, C-reactive protein; n.a., not available.

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Both in CABG and in OPCAB, leukocyte counts are increased and peak at 24–48 postoperative hours. Such increases are slightly more elevated in CABG [9 and 10]. Neutrophilic leukocytosis and elastase levels, a marker of neutrophil activation [9 and 10], increase during the first 12 h after CABG, whereas this leukocyte marker rises in delayed fashion (12–24 h after surgery) in OPCAB [9]. In both studies [9 and 10], at later time periods (24–48 h), the differences in elastase levels tend to narrow.

Nonrandomized studies showed significant increases over time of leukocytes [13 and 34] and neutrophils [34] in the postoperative period in CABG and MIDCAB with no differences between these two surgical techniques. Concerning elastase behaviour, only one randomized study [11] reported levels of elastase higher in CABG than in MIDCAB.

3.4. Coagulation, platelets and adhesion molecules (Table 5)

To our knowledge, only one recent nonrandomized study has investigated coagulation and fibrinolysis variables in CABG vs. OPCAB up to 24 h after surgery [35]. Both in CABG and OPCAB, remarkable changes in some of the coagulation and fibrinolytic variables occur perioperatively. CABG, however, is associated with early (<24 postoperative hours) lower platelet counts, lower plasminogen and higher D-dimer levels soon after surgery, whereas after 24 h, these differences are no more detectable.

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Table 5. Coagulation, platelets and adhesion molecules: perioperative changes

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Random, randomized study; CABG, full access on-pump coronary artery bypass grafting; OPCAB, full access off-pump coronary artery bypass grafting; MIDCAB, off-pump minimally invasive direct coronary artery bypass grafting.

↑, significant increase over time with respect to baseline levels; ↓↑, initial decrease followed by increase; (↑), trend towards increase over time with respect to baseline levels; ↓, significant decrease over time with respect to baseline levels; (↓), trend towards decrease over time with respect to baseline levels; =, no variations; *, statistically significant higher values in CABG group than OPCAB group at one or more time points; **, statistically significant higher values in CABG group than MIDCAB group at one or more time points; $, statistically significant lower values in CABG group than OPCAB group at one or more time points; °, in this study, CABG was performed with the use of CPB, but on the beating heart, without aortic cross-clamp and cardioplegia administration.

GBPR, glass-bead platelet retention; β-TG, β-thromboglobulin; F1.2, prothrombin fragment 1.2; FDP, fibrin degradation products; vW factor, von Willebrand factor; ICAM-1, intercellular adhesion molecule-1; n.a., not available.

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A limited number of studies observed no differences in CABG vs. OPCAB in terms of platelet activation, P-selectin [23], thrombomodulin [10] and glass-bead platelet retention [36]. Similarly, two randomized studies did not show significant differences in postoperative levels of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selectin [22] or of endothelial cell activation markers, like E-selectin [10]. This suggests that CABG, with respect to OPCAB, causes a transient increase in fibrinolysis and a decrease in platelet count that, however, does not sensibly affect platelet function or endothelial activation markers.

It is noteworthy that a randomized trial comparing one-vessel CABG and MIDCAB showed, even in this case, considerable changes in terms of activation of coagulation and fibrinolytic pathways in both groups. This study, however, reported no differences between the two study groups [37]. On the other hand, some controversy exists concerning effects of CABG or MIDCAB on platelet activation. Gu et al. in a randomized study showed that CABG is accompanied by increased platelet activation at the end of surgery [11]. A later randomized study, however, from the same group did not confirm‎ this finding [37].

3.5. Oxidative stress

Oxidative stress is the result of imbalance between local antioxidant defenses and the formation of reactive oxygen species. This is known to occur during myocardial reperfusion. Off-pump procedures are associated with lower degrees of oxidative stress than on-pump coronary surgery. Gerritsen et al. [38] in a prospective, although not randomized study comparing patients with similar preoperative clinical features showed that OPCAB was associated with significantly lower levels of urinary excretion of hypoxanthine, xanthine and malondialdehyde during the first 24 h after surgery. Even if the burst of oxidative stress that occurs during CABG has been related to myocardial ischemia-reperfusion due to cardioplegic arrest of the heart [39 and 40], a separate contribution of CPB to oxidative stress has also been recently shown. In fact, Matata et al. [10] in a prospective randomized study comparing OPCAB with on-pump coronary bypass with the beating heart and without cardioplegia showed that, in the early hours after surgery, OPCAB patients display significantly lower levels of lipid hydroperoxides, protein carbonyls and nitrotyrosine, all markers of oxidative stress. In this latter case, both on-pump and off-pump procedures were performed on a beating heart and the coronary arteries target for revascularization were clamped only for the time necessary to perform the distal anastomosis in both groups, which suggests similar degrees of myocardial ischemia-reperfusion in both groups.

4. Discussion

OPCAB is a surgical technique under clinical eval‎uation for its role and indications in ischemic heart disease. The avoidance of CPB may protect from perioperative systemic activation of the inflammation and reduce hemostasis changes. This has been shown to be associated, in retrospective studies, to a variable degree of improvement of the clinical outcomes as compared with on-pump CABG only in terms of early morbidity [1 and 2]. Small randomized trials reported similar [41] or slightly better outcomes [42] after OPCAB than after CABG in selected groups of patients. Until now, however, the demonstration of the clinical superiority of OPCAB coming from a large randomized controlled trial is still lacking [43].

Consistent advantages of OPCAB over CABG are limited to some inflammatory markers and to the time span between the final steps and the very early hours after the surgical procedure. Some inflammatory markers (activated complement factors, TNF-α, IL-8, IL-10 and elastase) increase with respect to baseline both in CABG and OPCAB, but the peak levels are highest in CABG; afterwards, the differences in terms of inflammatory profile progressively fade and finally cancel out (Fig. 1). Indeed, in the early phase, CPB is the major determinant of the onset of the inflammatory reaction, but in the late phases, the surgical trauma itself is likely to play a predominant role. Evidence about other markers (IL-1, IL-6, some leukocyte subsets) is less consistent and in some cases, even contradictory. Overall, it can be hypothesized that CPB itself only minimally influences the circulating levels of these markers. Thus, the trauma derived from the surgical procedure may be likely the major determinant of inflammatory reaction. The activation of the inflammatory system, although less marked than that of CPB, documented during vascular and noncardiac thoracic surgery [6 and 7], further supports this hypothesis.

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Fig. 1. During surgery and the very early hours of the postoperative period, some proinflammatory mediators peak to significantly higher levels in CABG than OPCAB patients. However, during the following postoperative period, the differences in terms of the inflammatory state progressively fade and finally cancel out. TNF-α, tumor necrosis factor α; IL-8, interleukin-8; CABG, on-pump coronary artery bypass grafting; OPCAB, off-pump coronary artery grafting; CPB, cardiopulmonary bypass.

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Moreover, the small differences between on-pump and off-pump strategies may be further reduced or even canceled out if both the CPB time and the aortic cross-clamping time are maintained at the minimum of duration, as in the case of one-vessel grafting procedure or in on-pump beating heart CABG [10 and 30]. In fact, the myocardium and the lungs are considered a major source of proinflammatory cytokines (TNF-α, IL-6, IL-8) during CPB after organ reperfusion [15, 17, 21 and 30]. Moreover, levels of cytokines in plasma are positively related to the aortic cross-clamping duration [12 and 14], increasing exponentially after 60 min of cross-clamping [44]. Massoudy et al. [21] reported that the avoidance of the oxygenator from the CPB circuit, using the patient's lungs as autogenous oxygenator (i.e. maintaining lung perfusion, so called Drew circulation) significantly reduces the proinflammatory state compared with the conventional CPB circuit. It is still unclear, however, if the lack of increases in circulating levels of proinflammatory cytokines is secondary to the avoidance of reduction of in pulmonary blood flow or it is consequent to the preservation during CPB of the normal scavenger properties of the lungs, which eliminate from the circulation proinflammatory mediators by means of pulmonary enzymatic systems.

One potential explanation for the limited difference between off-pump and on-pump techniques may be that, with the exception of the CPB and myocardial ischemia-reperfusion, both techniques share the necessarily invasive nature of the surgical access. Surgical incisions commonly adopted in open heart surgery, sternotomy and thoracotomy, are highly traumatic accesses, which impose a significant injury to the tissues and elicit a marked inflammatory response even before the institution of CPB. Gu reported that neutrophil preactivation occurs after the start of the cardiac operation before full dose systemic heparinization and institution of CPB; moreover, the capability of neutrophils to be preactivated is relatively low during and after CPB as compared with the time period before CPB [45]. In a recent study, Chello et al. [19] observed that the surgical stress itself (independently of the use of CPB) by decreasing neutrophil apoptosis in patients undergoing on-pump and off-pump coronary surgery prolongs the survival of activated neutrophils and, consequently, amplifies the inflammatory response.

Information concerning potential advantages of OPCAB with respect to CABG in terms of activation of the hemostatic system is still limited. During OPCAB, reduced platelet consumption as well as less activation of the fibrinolytic system than during CABG have been reported. These differences, however, can be perceived only up to 24 h after surgery. Interestingly, no differences in terms of endothelial or platelet activation markers were observed during the two surgical procedures. No information, however, is still available concerning potential differences in the activation of the coagulation pathway as well as in terms of thrombin generation in these conditions.

Previous studies by our group [46] and by others [47] showed that, during and early after cardiac surgery performed with CPB use, there is a massive activation of coagulation with elevated levels of prothrombin fragment, F1.2 and of thrombin–antithrombin complexes; activation of the fibrinolytic system follows [46]. Indeed, increased levels of cross-linked fibrin degradation products [8] and plasmin–antiplasmin complex [47] have been reported as a consequence of the activation of the coagulation system. If on one side, the interaction of blood with extensive nonendothelial surfaces of the bypass circuit is one of the causes of the activation of these pathways, on the other side, other mechanisms, e.g. surgical trauma and retransfusion of pericardial blood collected intraoperatively may significantly contribute to activation of the coagulation–fibrinolytic systems. This latter observation may explain the sensible activation of these pathways even during and early after off-pump procedures.

In fact, during the operation continuous oozing and bleeding from the cut edges and particularly from the sternal spongiosa into the surgical field, even after meticulous hemostasis, may activate monocytes after contact with the pericardium [48 and 49]. There is evidence of high levels of markers for thrombin and fibrin generation and inflammatory markers in mediastinal shed blood [49]. Activated shed blood may return into the circulation by suction from the surgical field after processing of cell-saver devices, and it is well known that washing of blood by cell-savers reduces but does not eliminate proinflammatory cytokines and the procoagulant properties of the blood returned to the patient [50 and 51]. It is noteworthy that blood-saving devices may be used also in off-pump surgery [35 and 41], and this can justify the changes that occur even during these procedures.

Finally, surgical chest wound is a major source of tissue factor and cytokines [48], which activates the extrinsic pathway of the coagulation cascade and contributes to the onset of a postoperative hypercoagulable state.

In addition, it should be stressed that during OPCAB, this potentially hypercoagulable state is unopposed by a full course of intravenous heparin and hemodilution as in CABG, and likely contributes to frequently reported reduction of mediastinal blood losses and blood transfusions, but also to early thrombotic complications [52, 53 and 54]. Quigley et al. observed by means of thromboelastography, a twofold increase in coagulation index in patients undergoing OPCAB after 72 h after surgery, whereas in patients undergoing CABG, the coagulation index had returned to preoperative values.

Finally, for what oxidative stress is concerned, OPCAB seems to be associated with significantly lower degrees of oxidative stress with respect to CABG, and a separate contribution of CPB and ischemia-reperfusion injury is also likely. An increasing body of evidence suggests that oxidant stress is involved in the pathogenesis of many cardiovascular diseases, including hypercholesterolemia [55], atherosclerosis [56], hypertension [57], diabetes [58] and heart failure [59]. However, further studies in this field are warranted, in order to clarify pathogenetic mechanisms and to prevent and treat oxidative stress.

In summary, the analysis of the available data shows that in terms of biological impact, there are subtle differences between OPCAB and CABG and the general surgical trauma may play a even more significant role. Nevertheless, we have to recognize that in most of the studies quoted into the present review, the CPB was structured and conducted in a standard way, i.e. using mild or moderate systemic hypothermia, cold cardioplegia, uncoated circuits, without the administration of anti-fibrinolytic drugs or of any other inflammation modulating drug and using the cardiotomy suckers. However, during the last decade, the practice of the CPB has been subjected to major refinements and improvements in the field of biocompatibility like the introduction of warm heart surgery, coated circuits, anti-fibrinolytic drugs and the elimination of cardiotomy suckers. Warm cardioplegia seems to reduce the oxidative stress [60, 61 and 62] and inflammatory response [63 and 64]. Routine use of heparin-coated circuits and the elimination of cardiotomy suction has been related to the reduction of thrombin generation, platelet activation and inflammation during CABG [65]; moreover, the use of both heparin-coated and phospholipid-coated circuits were associated to reduction to the release of proinflammatory molecules [66, 67 and 68]. Also, these improvements to the routine CPB gained widespread diffusion in the clinical practice during the last years.

Few studies comparing CABG and OPCAB adopted in their protocol normothermic systemic perfusion [9, 23, 24 and 28], warm cardioplegia [9, 14 and 25] and aprotinin [14, 23, 24, 28 and 34]. It is noteworthy that in the studies adopting only normothermic techniques [9 and 25], the authors observed a significant increase in the inflammation and oxidative stress in the CABG group, as compared with the OPCAB group, whereas, in the studies adopting simultaneously both normothermic techniques and aprotinin [14, 23, 24, 28 and 34], the inflammatory response was related to the general surgical trauma, derived by the surgical access, rather than the use of CPB. It is unknown if this difference is linked only to the administration of the aprotinin per se or to the combined use of normothermia and aprotinin. Strong and definitive evidences about the superiority of these techniques are still lacking probably because they are often adopted separately. Baufreton et al. [69] observed that the use of heparin-coated circuits reduced complement activation, whereas the administration of aprotinin resulted in the reduction of thrombin and D-dimer generation; they suggested that the combined adoption of heparin-coated circuits and aprotinin may be advisable in order to achieve maximal reduction of both pathways of blood activation during CPB.

We may thus speculate that the simultaneous and integrated use of warm surgery techniques, coated circuits, anti-fibrinolytic and anti-inflammatory drugs and the elimination of the cardiotomy suckers may enhance the biological compatibility of the CPB. Any reduction of the impact of the heart–lung machine on the inflammation, coagulation and oxidative stress may probably further minimize the differences, already subtle, between CABG and OPCAB.

5. Limitations of the available evidences

The limitations affecting most of the quoted studies prevent us from drawing definitive and unquestionable conclusions about the biological effects of CABG as compared with OPCAB. First, a significant number of reports are represented by nonrandomized trials. Second, each study enrolled an average of only 20–30 patients. The same limitations make impossible any clinical inference from biological data. With no doubt, this represents a very complex field of investigation, which needs well-constructed protocols and imposes heavy workload because of numerous blood sampling. Moreover, some determinations can be conducted only in highly specialized laboratories. However, there is a compelling need of larger and randomized trials in order to expand the knowledge about this topic.

6. Conclusions

Both on-pump CABG and OPCAB surgeries elicit systemic inflammatory activation and hemostatic derangements. Consistent biological differences are limited to some markers of inflammation and hemostasis for the time span between the final steps of the surgical procedure and the early hours of the postoperative course. The surgical trauma, due to the unavoidable tissue injury produced by the surgical access itself, may be as important as the CPB, or even more important, in terms of systemic inflammatory and hemostatic activation. Finally, the biological effect of the recent improvements of the CPB in terms of biocompatibility, as compared with OPCAB, needs further investigations.

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