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Effect of On-Pump CABG (Roller Versus Centrifugal Systems) on MCP-1, TNFsR and IL6 Behaviour | OMICS International
ISSN: 2329-9517
Journal of Cardiovascular Diseases & Diagnosis
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Effect of On-Pump CABG (Roller Versus Centrifugal Systems) on MCP-1, TNFsR and IL6 Behaviour

Renato Braulio1*, Marcelo Dias Sanches2, Antonio Lúcio Teixeira Junior3, Mauro Martins Teixeira4, Paulo Henrique Nogueira Costa1, Antonio Luiz Pinho Ribeiro3, Claudia Alves Couto3 and Claudio Léo Gelape2
1Federal University of Minas Gerais, School of Medicine, Division of Cardiology and Cardiovascular Surgery, Belo Horizonte, MG, Brazil
2Federal University of Minas Gerais, School of Medicine, Department of Surgery, Belo Horizonte, MG, Brazil
3Federal University of Minas Gerais, School of Medicine, Department of Internal Medicine, Belo Horizonte, MG, Brazil
4Federal University of Minas Gerais, School of Medicine, Department of Biochemistry and Immunology, Belo Horizonte, MG, Brazil
Corresponding Author : Renato Braulio
Av. Alfredo Balena 110
5th floor-Department of Cardiology and Cardiovascular Surgery
Neighborhood: Santa Efigenia, Cep:30130-100
Belo Horizonte, MG, Brazil
Tel: +55 31 34099437
E-mail: [email protected]
Received November 02, 2014; Accepted December 22, 2014; Published December 27, 2014
Citation: Braulio R, Sanches MD, Teixeira Junior AL, Teixeira MM, Costa PHN, et al. (2015) Effect of On-Pump CABG (Roller Versus Centrifugal Systems) on MCP-1, TNF-sR and IL6 Behaviour . J Cardiovasc Dis Diagn 3:186. doi: 10.4172/2329-9517.1000186
Copyright: © 2015 Braulio R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Background We aimed to evaluate the cytokines monocyte chemotactic protein 1 (MCP-1), TNF soluble receptor (TNF-sR1) and interleukin 6 (IL-6) behavior in patients submitted to CABG (coronary artery bypass grafting) surgeries comparing roller to centrifugal extracorporeal circulation (ECC) pumping systems. Methods We randomized prospectively 43 adults who had elective on-pump CABG with the use of a roller (group I; n = 22) or a centrifugal system (group II; n = 21). Plasma levels of MCP-1, TNF-sR1 and IL-6 were determined by Elisa before the induction of anaesthesia (T1), 35 min after initiation of ECC (T2), 1 min after aortic declamping (T3), and 2, 6 and 24 h after the operation (T4, T5 and T6, respectively). The two groups were matched according to preoperative features. The groups I and II showed similar perioperative characteristics and clinical postoperative outcomes. The plasma levels of MCP-1 and TNF-sR1 reached a peak at T4 and T5 in both groups. MCP-1 in group I was significantly higher (P = 0.020) than in group II at T5, while plasma levels of TNF-sR1 in group I were significantly (P = 0.028) higher than in group II at T4. In both groups, the levels of IL-6 reached a peak at T5. Group I showed higher IL-6 plasma levels (P = 0.006). Conclusion We conclude that both roller and centrifugal pumps induce inflammatory responses to on-pump CABG procedures but higher levels of MCP-1, TNF-sR and IL6 were verified using roller systems.

Abstract
Background
We aimed to evaluate the cytokines monocyte chemotactic protein 1 (MCP-1), TNF soluble receptor (TNF-sR1) and interleukin 6 (IL-6) behavior in patients submitted to CABG (coronary artery bypass grafting) surgeries comparing roller to centrifugal extracorporeal circulation (ECC) pumping systems.
Methods
We randomized prospectively 43 adults who had elective on-pump CABG with the use of a roller (group I; n = 22) or a centrifugal system (group II; n = 21). Plasma levels of MCP-1, TNF-sR1 and IL-6 were determined by Elisa before the induction of anaesthesia (T1), 35 min after initiation of ECC (T2), 1 min after aortic declamping (T3), and 2, 6 and 24 h after the operation (T4, T5 and T6, respectively). The two groups were matched according to preoperative features. The groups I and II showed similar perioperative characteristics and clinical postoperative outcomes. The plasma levels of MCP-1 and TNF-sR1 reached a peak at T4 and T5 in both groups. MCP-1 in group I was significantly higher (P = 0.020) than in group II at T5, while plasma levels of TNF-sR1 in group I were significantly (P = 0.028) higher than in group II at T4. In both groups, the levels of IL-6 reached a peak at T5. Group I showed higher IL-6 plasma levels (P = 0.006).
Conclusion
We conclude that both roller and centrifugal pumps induce inflammatory responses to on-pump CABG procedures but higher levels of MCP-1, TNF-sR and IL6 were verified using roller systems.
Keywords
Cardiopulmonary bypass; Inflammatory response; Myocardial revascularization; Roller and centrifugal pumps; Inflammatory cytokines
Introduction
Cardiac surgery involving extracorporeal circulation (ECC) has been related to different extent of systemic inflammatory response (IR) resulting in patient’s morbidity and mortality [1]. The contact of blood with the non-endothelial surfaces of the ECC components induces a cascade of inflammatory reactions associated with increased levels of cytokines, such as interleukin-1 (IL-1), IL-6, IL-8 and the tumour necrosis factor (TNF) [1-3].
Many factors can influence the emergence of IR in patients submitted to on-pump CABG (coronary artery bypass grafting), including type of propelling system (roller or centrifugal), manipulations of the coagulation system, the ischemia interval and injury from reperfusion, the degree of hypothermia, the type of prime-circuit, the amount of gas exchanged by the oxygenators, and the pericardial blood suction [4]. Circulation of blood through ECC, which is necessary in many types of cardiac surgery, relies on two main types of propelling systems, namely, roller and centrifugal pumps. Roller pumps propel the fluid in a continuous flow through compression by rigid rollers of a flexible plastic tube held in a circular raceway. Centrifugal pumps comprise an impeller, driven by an electromagnetic mechanism, which propels the blood by creating pressure differences within the fluid. Even though the types of pumps have been associated to inflammatory response and clinical outcomes, results are contradictory and both systems are currently used [5,6].
A large range of inflammatory mediators has been examined after CABG. However there is little agreement as to witch inflammatory mediator is most predictive of IR, the development of organ dysfunction, or which one is important clinically after surgery. Identifying a common link to the generation of IR is important and may allow future therapies. New evidence suggests that monocyte chemotactic protein 1 (MCP-1) could be a key mediator in inflammatory process and a new target for the treatment of inflammatory diseases [7]. IL-6 and TNF soluble receptor (TNF-sR1) are well known inflammatory mediators. The aim of the present study was to investigate levels and behaviour of cytokines MCP-1, IL-6 and TNF-sR1 during on-pump CABG using roller and centrifugal pumps.
Patients and Methods
Ethical issues
The project was approved by the local Ethical Research Committee. Written informed consent was obtained from all participants prior to the study.
Patients
Potential participants were selected at the outpatient clinic of the Hospital. The inclusion criteria were: age>18 years, surgical indication for elective on-pump CABG based in international criteria, first-time cardiac surgery, ventricular ejection fraction>30% [3]. Exclusion criteria were: unstable angina, chronic obstructive pulmonary disease, active endocarditis and critical preoperative conditions. A total of 43 patients met the inclusion criteria.
The present study was conducted prospectively and the patients were assigned consecutively and randomised to procedures employing a roller pump (group I - on-pump roller CABG; n = 22) or a centrifugal pump (group II - on-pump centrifugal CABG; n = 21) for ECC according to the order of presentation for surgery. On the day allocated for the operation, the patient was admitted to the hospital and submitted to anamnesis, physical examination and operative risk assessment according to the guidelines of the European System for Cardiac Operative Risk Evaluation (EuroSCORE) [8]. All operations were performed by the same surgical team and the same group of anaesthesiologists and perfusionists.
Anaesthesia
Balanced general anaesthesia was applied through intravenous injection of midazolam (0.1 to 0.3 mg/kg), fentanyl citrate (5 to 10 μg/kg) and etomidate (0.15 to 0.30 mg/kg), with pancuronium bromide (0.1 mg/kg) as muscle relaxant. Anaesthesia was maintained with fractionated intravenous doses of fentanyl citrate (5 to 10 μg/kg) and inhaled isoflurane (0.5 to 1.0% minimum alveolar concentration).
No antifibrinolytic or anti-inflammatory agents were employed during the surgery. Antibiotic prophylaxis of the surgical site was performed using intravenous injections of cefazolin (2 g every 2 h during the operation and every 8 h during the first 24 h after the operation).
Surgical procedure
The following procedures were performed subsequently: placement of sterile drapes, median sternotomy, intravenous systemic heparinization (400 IU/kg), insertion of cannulas in the aorta and right atrium, introduction of cardioplegia cannula in the aortic root, initiation of ECC and aortic clamping. Intermittent antegrade cold blood cardioplegia for cardioprotection was performed by infusion of cold (4°C) St. Thomas' Hospital cardioplegic solution into the coronary circulation every 20 min associated with passive hypothermia around 32°C. Myocardial revascularization was achieved by grafting the left internal thoracic artery to the left anterior descending artery and grafting the saphena magna vein to other coronary arteries. After completion of the coronary anastomoses, the aortic clamp was released, the patient was warmed systemically to 36.5°C, the ECC circuit was disconnected and the cannulas were removed. In order to counteract the anticoagulant effects of heparin, protamine sulphate (10 mg/1000 IU heparin) was administered by slow intravenous injection.
The ECC circuit
All procedures were carried out using the same ECC circuit comprising a microporous polypropylene membrane oxygenator (Trillium® Affinity®; Medtronic Minneapolis, MN, USA) with integrated venous cardiotomy reservoir and a heat exchanger connected with polyvinylchloride tubing (Comex, Belo Horizonte, Brazil). The ECC circuit was primed with 800 mL of 0.9% sodium chloride solution. An ALC 310® roller pump (Alcard Indústria Mecânica, Sorin Group, São Paulo, Brazil) or a centrifugal IBC FloPump with Medtronic Bio-Medicus Bio Console® (International Biophysics Corporation, Austin, USA) were used to propel blood through the ECC circuit with a targeted pulsatile flow of 2.4 L/min/m2, mean arterial pressure of 60 to 70 mm Hg and haemodilution with haematocrit of 20 to 30%. The partial pressure of oxygen in the arterial blood was maintained close to 250 mm Hg, the initial fraction of inspired oxygen was 50%, activated clotting time was 480 s and venous drainage was gravity dependent. The same catheter employed in cardioplegia was used for aspiration of the aortic root (vent). After systemic heparinization, intrapericardial blood was aspirated and returned to the patient. A negligible volume of blood entered the pleural cavity but was not returned to the patient.
Quantitative analysis of cytokines
Peripheral blood samples (3 mL) were obtained from the radial artery immediately before the induction of anaesthesia (T1), 35 min after initiation of ECC (T2), 1 min after release of the aortic clamp (T3), and 2, 6 and 24 h after surgery (T4, T5 and T6, respectively), and placed into heparinized sterile tubes (Becton & Dickinson, Franklin Lakes, NJ, USA). Plasma was separated by centrifugation at 3000 rpm for 10 min and stored in the freezer at - 80°C until required for analysis. Concentrations of MCP-1, TNF-sR1 and IL-6 in plasma samples were determined using commercial sandwich enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems®, Minneapolis, MN, USA) according to the manufacturer’s instructions.
Statistical analysis
Descriptive statistics of the data were expressed as minimum, maximum, mean ± standard deviations (SD) and median values. Data relating to IL-6 concentration were not normally distributed and, therefore, the non-parametric Mann-Whitney U test was used to compare median values between the two groups and the non-parametric Friedman test was used to detect within-group differences relating to time of sampling (T1 – T6). Categorical variables relating to groups I and II were compared using the χ2 test, but in situations in which this test could not be applied (i.e. expected values<5) the Fisher exact test was employed. In all tests, the differences between the two groups of data were considered statistically significant at P<0.05.
Results
Patients’ preoperative, perioperative features and clinical postoperative outcomes are shown on Tables 1 and 2. No significant differences between patients of groups I and II were shown.
The plasma levels of MCP-1, TNF-sR1 and IL-6 from groups I and II at times T1 to T6 are shown in Figure 1 and Tables 3, 4 and 5 respectively. The between-group differences in plasma MCP-1 concentrations were statistically significant at T5 (P = 0.020). In group I, plasma levels of MCP-1 at T4 and T5 were equivalent and significantly higher than those at T1, T2, T3 and T6, while in group II, the mean concentration of MCP-1 measured at T4 was significantly higher than those at T1, T2, T3 and T6, while the concentration at T5 was similar to that at T3 but higher than those at T1, T2 and T6 (Table 3 and Figure 1A). The levels of MCP-1 in both groups varied significantly according to the time of sampling (P = 0.0001).
Assays of TNF-sR1 in patients of groups I and II revealed that plasma concentrations of the cytokine receptor increased significantly with time of sampling up to T4, following which they remained stable at T5 and declined at T6 to the levels found at T3 (Table 4 and Figure 1B). The between-group differences in plasma TNF-sR1 concentrations were statistically significant only at T4 (P = 0.028).
Regarding IL-6, the plasma levels in patients of groups I and II were comparable up to T3 but increased at T4 and peaked at T5 (Table 5 and Figure 1C). The between-group differences in plasma IL-6 levels were statistically significant only at T5 (P = 0.006). Between-group differences in the plasma levels of IL-6 at the various times of sampling showed that at T5 the IL-6 levels were higher in group I (P = 0.010; Table 5). Additionally, the within-group differences in plasma IL-6 levels were: group I, T5>T4>T6>T1 = T2 = T3; group II, T5 = T4>T6>T1 = T2 = T3; the differences indicated were statistically significant (P<0.001).
The levels of all three cytokines (MCP-1, TNF-sR and IL6) increased in the postoperative period, particularly at T4 and/or T5 in both groups I and II. The peaked level of cytokines in patients of group I was always higher than those of group II (T5 -T1).
Discussion
The mechanism of the IR observed in on-pump cardiac surgeries is not clearly understood [4]. The IR has been related to many pro-inflammatory risk factors such as trauma due to large-scale surgery, blood aspiration from the pericardial cavity, ischemia interval time and injury from reperfusion, flow of blood through ECC components, contact of blood with non-endothelial surfaces, and mechanical and electromagnetic impulses generated by pumps [9,10]. These factors may lead to activation of the complement system, macrophages, cytokines, fibrinolysis, coagulation and haemolysis [9,10]. Even though a large range of inflammatory mediators has been examined, there is little agreement as to witch inflammatory is most predictive of the development of organ dysfunction or which one is important clinically after on-pump CABG. Identifying a common link to the generation of IR is important and may allow future therapies [1].
In the present study we verified that both roller and centrifugal pumps increase the release of the inflammatory cytokines MCP-1, TNF-sR1 and IL-6 after on-pump CABG in relation to preoperative levels. The increase was verified at 2 h and 6 h after surgery but return to normal levels within 24 h, indicating that ECC stimulates IR since the beginning of the procedure. This result is in agreement with previous findings that cytokines levels increase significantly in the first hours of the postoperative period and after 24 to 48 h after the procedure the levels decrease [2,11-14]. Our study further confirms that ECC induces a significant IR independent of the pumping technique employed. Furthermore, use of the roller pump was associated with higher cytokine plasma levels in comparison with the centrifugal pump. Interestingly, besides studying IL-6 and TNF-sR1 we also addressed the behavior of MCP-1.
MCP-1 is a chemokine that regulates the migration of monocytes to infection sites and to atherosclerotic lesions throughout the vasculature. MCP-1 is present at various phases of the atherosclerotic process, including during the rupture of the atherosclerotic plaques in acute myocardial infarction and in the infarcted region after the ischaemic event. MCP-1 has recently been proposed as an independent prognostic marker for acute coronary syndrome [15-17]. Elucidation of the mechanism of action of this cytokine may lead to the development of pharmaceuticals that function as antagonists of MCP-1 receptors, thus providing alternative treatments for atherosclerosis. Interestingly, laboratory experiments have shown that MCP-1 is the cytokine that suffers most change when blood contacts with the non-endothelial surfaces of the ECC circuit [16,17]. It is possible that the roller pump intensifies contact of the blood with such surfaces by virtue of the constant compression of the rollers over the tubing and the consequent shearing effect. In this context we may assume that the MCP-1 levels could be higher and on-pump roller patients.
The cytokine receptor TNF-sR1 is more stable than TNF and may serve as a valuable pro-inflammatory marker in comparative studies of ECC equipment. In the present study, differences between the preoperative (T1) levels and the postoperative (T4 and T5) concentrations of TNF-sR1 were significantly higher (P = 0.037 and 0.049, respectively) in patients who had been exposed to the roller pump rather than to the centrifugal pump. High levels of TNF-sR1 have been detected in patients who presented unfavourable evolution and mortality following acute myocardial infarction events, while elevated preoperative levels of the receptor predict a poor prognosis for cardiac surgery [18-21]. However, the clinical role of this marker in the perioperative and postoperative periods is not known and, therefore, the significance of the observed increase in TNF-sR1 in patients exposed to the roller pumping system is unclear.
IL-6 is produced by a variety of cell types, including monocytes, endothelial cells and lymphocytes, and influences antigen-specific immune responses and inflammatory reactions. In the present study, the difference between the preoperative (T1) and postoperative (T5) concentrations of IL-6 was significantly higher (P = 0.013) in patients who had been exposed to the roller pump rather than to the centrifugal pump. This finding is in agreement with previous reports that plasma IL-6 increases significantly during the first hours after beginning of ECC [2]. Moreover, longer procedures result in more intense IR, and a direct correlation between plasma IL-6 levels and mortality following ECC has been observed [20,21].
We found that centrifugal pump had less negative effects on the IR compared to roller pumps. Accordingly, advantages of centrifugal over roller pumps has been reported by some authors, especially in procedures involving prolonged (>120 min.) ECC in which the risks of haemolysis, alterations in blood clotting, IR and perioperative and postoperative clinical complications are higher [22,23]. However, as far as shorter perfusion time of less than 120 min, the advantages of centrifugal pumping remain controversial. In the present study, the meantime of ECC was 59.4 and 62.6, in groups I and II, respectively. However, other investigators comparing the outcomes of on-pump CABG procedures with roller or centrifugal systems have failed to show haematological or haemodynamic significant differences between patients operated on with two pumping devices [22-24]. Furthermore, a recent study verified greater number of postoperative cognitive deficits in patients submitted to on-pump centrifugal CABG [5]. The before mentioned authors did not studied cytokines profile [5,22-24].
Attempted to explain the emergence of IR in patients submitted to on-pump CABG by addressing cellular responses, plasma inflammatory mediators and components of the complement system has pursued but most of the studies have involved small numbers of patients and have showed conflicting results [9,11-13,23-25]. Moreover, these results may be somewhat dated since current ECC circuits are fabricated using up-to-date pump technology together with novel and more biocompatible materials such as heparinized tubes and nanometric thin film membranes, features that offer significant advantages independent of the pumping system employed. Although both roller and centrifugal systems have been used throughout the world for many years, controversy remains regarding the functional superiority of one system over the other. The very few previous studies that analysed IR in patients submitted to elective on-pump centrifugal CABG compared to on-pump roller CABG showed conflicting results. In this context, Ashraf et al. verified greater levels of cytokines IL-1β, IL-6, IL-8 and TNFα, complement component C5b-9 and neutrophil elastase in patients submitted to elective on-pump centrifugal CABG compared to on-pump roller CABG [12]. Baufreton et al. determined the concentrations of TNFα, IL-6, IL-8, adhesion molecules, complement activation complex SC5b-9 and elastase in randomized groups of patients who had been submitted to on-pump roller CABG (n = 15) or on-pump centrifugal CABG (n = 14) [13]. More intense activation of the complement and of neutrophils was observed in on-pump centrifugal CABG group. After the operation, however, both groups showed similar levels of IR. It is important to emphasize that, in this study, the antifibrinolytic agent aprotinin was administered to the patients during the operation, and the preoperative use of acetyl salicylic acid was not interrupted. However, Morgan et al. evaluated the pro-inflammatory markers IL-2, IL-6 and IL-8 and compared haemolysis (free plasma haemoglobin), leukocyte counting and degree of platelet and complement (C3a and C5a) activation verifying that haemolysis, platelet activation and IR were less intense on on-pump centrifugal CABG compared to on-pump roller CABG [25]. Our study, adds to the knowledge by evaluating the behavior of MCP-1 that, to the best of our knowledge, had not been previously associated with coronary surgery besides to the other cytokines (TNF-sR1 and IL-6) evaluated. Additionally, different from others, we included diabetic individuals with ventricular ejection fraction>30%, since these patients are frequent candidates for elective cardiac surgery [3].
We demonstrated that the cytokines MCP-1, TNF-sR1 and IL-6 increase after CABG in relation to preoperative levels. The higher increase was noticed on on-pump roller CABG procedures with no translation in clinical postoperative outcomes.
Conclusion
Both roller and centrifugal ECC pumping systems induced inflammatory responses in adult patients submitted to CABG as showed by increased levels of the cytokines MCP-1, TNF-sR1 and IL-6 at 2 and 6 h after the procedure. Although the roller technology induced a significant increase in cytokines, there were no differences between the two groups of patients regarding clinical evolution in the postoperative period.
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