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Ann Thorac Surg 2006;81:1683-1690
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Comparison of Inflammatory Responses After Off-Pump and On-Pump Coronary Surgery Using Surface Modifying Additives Circuit

Janine M. Quaniers, MD a , b , Julie Leruth, MD a , Adelin Albert, MD, PhD b , Raymond R. Limet, MD, PhD a , b , * , Jean-Olivier Defraigne, MD, PhD a , b

a Department of Surgery, Biostatistics, University of Liège, Liège, Belgium
b Department of Sciences of Public Health, Biostatistics, University of Liège, Liège, Belgium

Accepted for publication November 3, 2005.

Abbreviations and Acronyms ACT = activated coagulation time; EC = extra-corporeal circulation; LPS = lipopolysaccharides; MPO = myeloperoxidase; PMN = polymorphonuclear neutrophil; SE = standard error; SMA = surface modified additive; SIRS = systemic inflammatory reaction syndrome; TCC = terminal complement complex; TCI = target control infusion

* Address correspondence to Dr Limet, Department of Cardiovascular Surgery, CHU de Liège, 4000 Liège, Belgium (Email: rlimet{at}ulg.ac.be).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Cardiac surgery is followed by various degrees of inflammation, which have harmful consequences. Because of the central role of extracorporeal circulation (EC), off-pump coronary bypass surgery is deemed preferable. Do different modalities of EC challenge this view?

METHODS: Four groups of similar patients underwent coronary surgery: (group 1) on-pump, EC with closed surface modifying additives (SMA) circuit and no pump suckers (n = 20); (group 2) on-pump, EC with open SMA circuit and pump suckers (n = 20); (group 3) off-pump (beating heart) and heparin 3 mg/kg (n = 20); (group 4) off-pump (beating heart) and heparin 1 mg/kg (n = 20). Interleukins (IL)-6, IL-8, IL-10, myeloperoxidase, elastase, and terminal complex of the complement (TCC) were analyzed at various times: at induction (time I); after heparin (time II); after complete revascularization (time III); after protamine (time IV); and 24 hours later (time V).

RESULTS: The TCC was significantly higher in groups 1 and 2 at time III. The pattern of IL-6 was the same for the four groups. No significant difference in myeloperoxydase content was noted; however, elastase was significantly higher in the two EC (on-pump) groups.

CONCLUSIONS: Except for the complement system and elastase, on-pump surgery with SMA-coated circuits did not elicit any greater inflammatory response than off-pump surgery.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
A systemic inflammatory reaction is observed after cardiac surgery, and it is generally considered to be caused by the use of extracorporeal circulation (EC). However, both types of surgery, cardiac and noncardiac, are associated with an inflammatory response due to tissue trauma. Moreover, because cardiac surgery has been exclusively carried out using EC for over four decades, it has been difficult to define the relative role played by EC and by surgery itself in the induction of the inflammatory reaction.

In order to reduce the harmful effects of EC, various improvements (mainly focused on physicochemical parameters of EC) have been proposed. In the same way, cardiac stabilization systems have been developed allowing coronary artery bypass surgery without using EC. It is of major interest to know to what extent the latter more recent technique can reduce the inflammatory reaction. Some studies have compared the off-pump technique with EC surgery performed with a classical circuit and have analyzed the evolution of different inflammatory markers. Some of these studies reported a lower inflammatory response with off-pump surgery [1, 2], but others did not see any differences [3]. However, when the off-pump technique was found to be superior in terms of the inflammatory response, it was not necessarily associated with marked benefits such as decreased morbidity or postoperative mortality [4, 5].

For on-pump interventions, the surface modifying additives (SMA) circuit has been reported to be more biocompatible than a classic EC circuit, notably in terms of platelet function preservation [6]. The primary goal of the present study was to compare coronary artery bypass surgery (CABG) performed with EC using SMA type circuits with off-pump beating heart surgery, in terms of inflammatory reaction. Since blood-air contact has been shown to be a major factor contributing to postoperative inflammatory reaction, the use of a closed circuit and the use of a blood recovery and washing device (cell-saver) minimize this inflammatory reaction. Thus, in our study, the influence of a closed versus an open circuit and the influence of a cell-saver during EC were also examined.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Selection
Patients in the age range of 40 to 80 years who underwent CABG surgery between November 1999 and February 2002, and who were eligible for beating-heart revascularization were included in the study. Exclusion criteria were emergency surgery, reintervention, chronic renal insufficiency, severe respiratory insufficiency, ejection fraction less than 0.30, previous history of neoplasia or of chronic inflammatory illnesses, and insulin-dependent diabetes. Patients were randomized into four groups: group 1, EC with closed SMA circuit without pump suckers (n = 20); group 2, EC with open SMA circuit with pump suckers (n = 20); group 3, beating heart (off-pump) receiving heparin at 3 mg/kg (n = 20); group 4, beating heart (off-pump) receiving heparin at 1 mg/kg (n = 20). When complete beating-heart revascularization could not be carried out for a patient allocated to groups 3 or 4, then he or she was withdrawn from the study. The Ethics Committee of the University hospital approved the study and each patient signed an informed consent prior to the operation.

Anesthesia
After rachianesthesia (0.4 to 0.5 mg morphine), the induction was carried out by intravenous injection of propofol (Diprivan; AstraZeneca SA, Brussel, Belgium) controlled by TCI (target control infusion), remifentanil (0.25 to 0.5 µg/kg/min, Ultiva; GlaxoSmithKline Manufacturing, Genval, Belgium), and rocuronium (1 mg/kg, Esmeron; Organon, Brussels, Belgium). The rectal and esophagus temperatures, the urine output, the electrocardiogram, the central venous pressure, and the pulmonary (Swann-Ganz probe) and systemic (radial) arterial pressure were monitored in the four groups. All patients received a high dose of aprotinine sulfate (Trasylol; Bayer SA, Brussel, Belgium) according to the protocol of Royston [7]. Before starting the EC and before carrying out the bypass operation in the off-pump groups, heparin was injected. In the two EC groups, the heparin was injected in bolus to attain an activated coagulation time (ACT) higher than 480 seconds (Hemochron 400; International Technidyne Corp, Edison, NJ). The ACT was also measured during the beating heart surgery, but only one dose of heparin was injected.

Extracorporeal Circulation
The extracorporeal circulation circuit was composed of a gas polypropylene micropore plaque oxygenator (Duo SMARxT; COBE Cardiovascular, Arvada, CO) and a heat exchanger. All components of the circuit in contact with blood were made from copolymeric additive modified material (SMARxT, COBE Cardiovascular), including the arterial filter. Both the arterial and venous blood gases were monitored continuously (CDI 400; Terumo Cardiovascular Systems, Ann Arbor, MI and Sat-Crit COBE, respectively). The arterial injection pressure, the left vent suction pressure, and the injection of the cardioplegia were systematically controlled.

In group 1 a closed circuit was used; the venous reservoir was composed by a closed soft reservoir with a variable capacity (COBE VRB 1200 SMARxT). The blood from the left ventricle was collected in a second soft reservoir (COBE VRB 1800 SMARxT) connected to the venous reservoir. An open circuit was used for group 2; the venous reservoir was composed of a rigid reservoir (COBE HRV 4000 SMARxT) with integrated cardiotomy reservoir (filter of 30 microns) and had a maximum storage capacity of 4,000 mL. Blood from left vent suction and the shed blood from the pleuropericardial cavities were aspirated into the reservoir. In group 1, the shed blood from the pleuropericardial cavities was aspirated in a separate cardiotomy reservoir. Then, the blood was treated with a cell-saver (BRAT 2, COBE) before being, if necessary, reinfused during EC or after heparin neutralization. In the two EC groups, the priming volume of the circuit was between 1,700 and 1,800 mL of 2/3 of a crystalloid solution (Plasmalyte A; Baxter Healthcare, Deerfield, IL) and 1/3 of synthesis gelatine (Haes-stéril 6%; Fresenius, Lexington, MA). The hemodilution was accepted down to a minimum of 20% hematocrit.

After cannulation of the ascending aorta and the right atrium, EC was established with a pulsatile flow to maintain a minimal index of 2.4 L · m2 · minute. The flow was adjusted based on the hemodynamic parameters and on the venous saturation. Patients were operated on under active normothermia (37°C). After aortic clamping, antegrade cardioplegia was obtained by injection of a crystalloid solution (St. Thomas solution) at 4°C in the ascending aorta. During EC, an additional dose of heparin (Heparine Leo; Leo Pharmaceutical Products, Breda, The Netherlands) was administered if the ACT (Hemochron Junior; International Technidyne, Edison, NJ) was less than 400 seconds. After completion of EC, the heparin was completely neutralized using protamine (Protamine 1000°; Leo Pharma, Wilrijk, Belgium) at a dose of 1 mg/100 IU of heparin. The residual volume of the circuit was reinfused into the patient and at the end of the procedure the EC circuit was rinsed and treated with the cell-saver.

Beating Heart
The surgical approach was a median sternotomy. The stabilization material was the second model Octopus system (Medronic Inc, Minneapolis, MN). One 4-0 Prolene (Ethicon, Somerville, NJ) suture was used to temporarily occlude the coronary artery above the anastomotic site. No coronary shunt was used. Suture for pericardial traction and Trendelenburg manipulation were used to facilitate the exposure with preservation of the hemodynamic stability. At the end of the intervention, the circulating heparin was neutralized after ACT control.

Biochemical Measurements
The arterial blood samples were collected from the radial artery catheter into sterile vacuum tubes. After centrifugation, the plasma was collected and then stored at –70°C until biochemical analysis. Results were corrected for hemodilution at each time point. Interleukins (IL-6, IL-8, and IL-10), myeloperoxydase (MPO), and the terminal complex of the complement (TCC) were measured during and after the operation. Specifically, measurements were made at induction (time I), after the injection of heparin (time II), after myocardial revascularization (time III), after neutralization of heparin by the protamine (time IV), and 24 hours after the surgery (time V). In addition, the leukocyte count, the neutrophil percentage, the hemoglobin, and the hematocrit were also measured at each time point. Elastase was assayed at times I, IV, and V. The IL-6, IL-8, and IL-10 in plasma were analyzed by "sandwich" solid-phase enzyme amplified sensitivity immunoassay (MEDGENIX-EASIA; Biosource Europe SA, Fleurus, Belgium) performed on a microtiter plate. Polymorphonuclear neutrophil (PMN) elastase was determined by homogenous immunoassay (Ecoline, Merck, Darmstadt, Germany), MPO by double radioimmunoassay (Pharmacia MPO RIA, Pharmacia and Upjohn JAB, Uppsala, Sweden). The sC5b-9 (TCC) was measured by enzyme-linked immunosorbent assay (Quidel, San Diego, CA).

Statistical Analysis
Results were expressed as means ± standard deviations for quantitative variables and as frequencies and proportions (%) for categoric variables. In figures, means were plotted with their standard error (SE).

Patients serial biochemical measurements were analyzed by the general linear mixed model (GLMM), which allows to assess the time effect, the group effect (type of surgery), and the interaction effect (time x group), while accounting for repeated data within each subject. For interleukins, a log-transform was applied to the data to normalize their distributions. The GLMM was then carried out on the transformed data. Results were considered significant at the 5% critical level (p < 0.05). Calculations were done using SAS and S-PLUS statistical packages (SAS Institute Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Demographic and Preoperative Data
The four groups were similar in terms of age, sex, and left ventricular function (see Table 1). No statistically significant differences were found for the two EC groups with respect to the clamping time and the total pump time. The average number of bypasses was similar in the four groups as were the total operative time, the postoperative blood loss in the first 24 hours, and postoperative complications. Two deaths occurred in group III (beating heart, heparin 3 mg/kg).


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  		Table 1. Patient Characteristics in the Four Experimental Groups
 
Terminal Complement Complex
The evolution of TCC during the operation in each study group is depicted in Figure 1. The GLMM analysis revealed a highly significant time effect (p < 0.0001), group effect (p = 0.0053), and interaction effect (p < 0.0001). At time III (after myocardial revascularization), TCC concentrations rose to about 800 mg/mL in the two EC groups, while remaining stable in the off-pump surgical patients. Concentrations remained high at time IV (protamine injection) in the EC groups, and then returned to values similar to initial ones 24 hours after the operation. Overall, no difference was observed between the time evolution of TCC in the two EC groups (p = 0.31). In the "beating heart" groups, TCC concentrations did not change during the operation and were comparable in both groups (p = 0.72).


Figure 1
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  		Fig 1. Plasma concentrations of the terminal complement complex (TCC) at: time I, induction of anesthesia; time II, after the injection of heparin; time III, after myocardial revascularization; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 
Interleukin-6
Figure 2 displays the time evolution of IL-6 concentrations in the four patient groups. Overall, no significant differences could be discerned between the IL-6 evolution in the study groups (p = 0.13). By contrast, GLMM analysis confirmed a highly significant time effect (p < 0.0001); IL-6 increasing stepwise during the surgical operation. Twenty-four hours after surgery, concentrations amounted to 167 ± 70 pg/mL in group 1, 323 ± 311 pg/mL in group 2, 264 ± 121 pg/mL in group 3, and 257 ± 163 pg/mL in group 4. The GLMM analysis revealed no interaction effect (p = 0.077).


Figure 2
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  		Fig 2. Plasma interleukin-6 (IL6) concentrations at: time I, induction of anesthesia; time II. after the injection of heparin; time III, after myocardial revascularization; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 
Interleukin-8
Mean serial levels of IL-8 in each patient group are plotted on a log-scale in Figure 3. Group comparison just reached the 5% critical level (p = 0.051) being essentially due to group 2, which differed from group 1 (p = 0.042) and from group 4 (p = 0.015), while being similar to group 3 (p = 0.50). The statistical analysis also revealed a highly significant time effect (p < 0.0001) and a moderate but significant time-group interaction effect (p = 0.019).


Figure 3
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  		Fig 3. Plasma interleukin-8 (IL8) concentrations at: time I, at induction of anesthesia; time II, after the injection of heparin; time III, after myocardial revascularization; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 
Despite an overall increase of IL-8 levels from time I (induction) to time IV (after protamine) in each group (except for group 3, p = 0.15), the time evolution was not similar in all groups. A significant drop in IL-8 levels were observed at time II (after heparin) in groups 1 (p = 0.014) and 3 (p = 0.0065), while a highly significant increase was found between times III (revascularization) and IV (protamine injection) in group 1 (p < 0.0001). It should be observed that, 24 hours after operation, IL-8 levels were still significantly increased with respect to baseline: 13 ± 15 vs 3.2 ± 5.3 pg/mL in group 1 (p = 0.0009), 17 ± 15 vs 5.8 ± 9.2 pg/mL in group 2 (p = 0.0008), 14 ± 11 vs 7.9 ± 9.3 pg/mL in group 3 (p = 0.066), and 11 ± 14 vs 4.3 ± 10.9 pg/mL (p = 0.0006) in group 4.

Interleukin-10
For the different groups, the minimal detection limit was never reached for the analyzed samples.

Myeloperoxydase
The evolution of MPO in the four groups is displayed in Figure 4. Overall, no significant difference between the groups could be highlighted by GLMM analysis (p = 0.061). There was a clear time effect (p < 0.0001) but no interaction effect (p = 0.072), indicating that the time-related evolution of MPO was parallel in each group. The MPO concentrations increased after the injection of heparin, reached a peak in concentration after myocardial revascularization, and then decreased until 24 hours after the surgery, reaching levels observed at baseline. Peak levels observed after complete revascularization (time III) were 136 ± 67 ng/mL in group 1, 191 ± 127 ng/mL in group 2, 115 ± 76 ng/mL in group 3, and 106 ± 39 ng/mL in group 4, respectively.


Figure 4
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  		Fig 4. Plasma myeloperoxidase (MPO) concentrations at: time I, induction of anesthesia; time II, after the injection of heparin; time III, after myocardial revascularization; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 
Elastase
As seen in Figure 5, the evolution of elastase activity differed markedly according to the type of operation. This was confirmed by GLMM analysis, which yielded significant group (p < 0.0001), time (p < 0.0001), and time x group interaction (p < 0.0001) effects. Group 2 differed significantly from group 1 (p = 0.0021), group 3 (p < 0.0001), and group 4 (p < 0.0001), while the two off-pump groups were similar (p = 0.79). At time IV (after protamine), elastase levels reached 107 ± 59 µg/mL in group 1, 220 ± 145 µg/mL in group 2, 43 ± 50 µg/mL in group 3, and 33 ± 15 µg/mL in group 4. One day after surgery, as compared with baseline (induction), elastase levels were still increased; in group 1 (84 ± 44 vs 36 ± 42 µg/mL, p < 0.0001), in group 2 (84 ± 36 vs 38 ± 31 µg/mL, p < 0.0001), in group 3 (77 ± 36 vs 25 ± 10 µg/mL, p < 0.0001), and in group 4 (92 ± 36 vs 30 ± 19 µg/mL, p < 0.0001). Thus elastase levels dropped in the EC groups after complete revascularization (ie, between times IV and V) while increasing in the two off-pump groups.


Figure 5
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  		Fig 5. Plasma elastase concentrations at: time I, induction of anesthesia; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 
Polymorphonuclear Neutrophil Count
The evolution of PMN count as seen in Figure 6 was globally the same in each surgical group (p = 0.93). However, a highly significant time effect (p < 0.0001) was found, mainly explained by a marked increase of the PMN count 24 hours after the operation (time V). The GLMM analysis also revealed a significant time-group interaction effect (p < 0.0001), indicating that group differences exist at various time points. In particular, as compared with time III (after complete revascularization), the mean PMN count decreased in the two off-pump groups at time IV (after protamine); 3.2 ± 1.6 vs 2.9 ± 2.0 in group 3 (p = 0.014), and 3.9 ± 1.5 vs 3.0 ± 1.6 in group 4 (p = 0.0025). By contrast, an increase was seen in the EC groups; 3.5 ± 1.0 vs 4.0 ± 1.5 in group 1 (p = 0.040) and 3.9 ± 1.4 vs 4.6 ± 1.5 in group 2 (p = 0.014).


Figure 6
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  		Fig 6. Variations of the polymorphonuclear neutrophil (PMN) count at: time I, induction of anesthesia; time II, after the injection of heparin; time III, after myocardial revascularization; time IV, after neutralization of heparin by protamine; time V, at 24 hours after surgery. Data are expressed as the mean ± the standard deviation. (—— = group 1; ... ... = group 2; - - - - - = group 3; – – – – – = group 4.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Through the dosage of its numerous markers, the activation of the complement is probably the most documented in cardiac surgery under EC as well as in renal dialysis (both involving biomaterial). The contact of blood with artificial material induces a series of reactions leading to, among others, the activation of the complement, essentially attributed to the activation of the alternative pathways [8–10]. In our study, the TCC concentrations were significantly higher in the two EC groups, confirming existing scientific evidence. However, the biomaterial is not the only cause of activation, since the classic pathway can also be notably activated by the heparin-protamine complex [11, 12], as well as the lectin pathway, activated by the lipopolysaccharide [13], among others. The ischemia-reperfusion activates the classic and the alternative pathways [14, 15] as well as other factors (blood transfusions, air-blood contact, surgical trauma) which also activate the complement. This complement activation leads, in theory, to the inflammatory activation cascade.

In fact, some studies have demonstrated a relationship between activation of the complement and some interleukins, such as IL-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF{alpha}) [4, 16, 17]. However, in our study the concentrations of IL-6 evolved similarly in the four groups, while the complement activation was different. Our results are in agreement with other studies that do not show a direct relationship between IL-6 and IL-10 and the complement [13]. The IL-6 concentration is an important parameter reflecting the importance of the surgical trauma [18–20] because it is closely associated with the development of complications, an unfavorable evolution for the patient, and the initiation of a systemic inflammatory reaction syndrome [20]. The IL-6 is a central mediator in the cytokines network and it plays a pivotal role in modulating the inflammatory response [21, 22]. An overexpression of IL-6 is associated with morbidity and mortality of the trauma or infected patients [23, 24]. Of particular interest is the absence, in our study, of a relationship between IL-6 and the activation of the complement suggesting that it is no longer the only or main factor stimulating the inflammatory reaction. Moreover, in beating heart surgery as compared with EC surgery, the IL-6 concentrations are lower only if the surgical approach is different or if the average number of bypasses and myocardial ischemia are also lower.

In the same way, IL-8 could not be related to the activation of the complement, which contradicts other studies [16, 25]. There is no relation between the evolution of IL-8 and IL-6, MPO, or elastase. This chemokine, known to play a role in migration, activation, and chemotactism of the PMNs and T lymphocytes, is not only produced by the PMNs, but also by the monocytes, mastocytes, endothelial cells, fibroblasts, and smooth muscle cells. The myocardium is a major source of IL-8 during consecutive reperfusion after a long period of ischemia [26, 27], and in rabbits an injection of antibody anti-IL8 prevented the development of myocardial ischemia-reperfusion-mediated lesions [28]. Some authors have advanced the hypothesis that the type of procedure (with or without EC) influences the production of IL-8 (notably by means of the activation of the complement) and thus myocardial complication is observed postoperatively [4]. However, in this study the average number of bypasses in the beating heart group was significantly less than in the EC group. Therefore, it is likely that the operative myocardial ischemia was less intense in the beating heart group. An inverse relationship hypothesis may be suggested: the production of IL8 depends, among other things, on the degree of operative myocardial ischemia, which could explain the absence of a relationship between TCC and IL-8 in our study because the average number of bypasses was similar in each of the four groups studied. This hypothesis is reinforced by the study of Struber and colleagues [29], who showed that IL-8 concentrations were lower in surgery where only one bypass was carried out by anterior thoracotomy as compared with an average of three bypasses for the EC groups in this study.

In the present study, the MPO and the elastase concentration profiles, both demonstrating the activation of PMNs, were different. The evolution of the MPO concentration was similar in the four groups while the elastase was significantly higher in the two EC groups. A close relationship between activation of the complement and elastase concentration has been previously described [30, 31]. The activation of PMNs by C5a [29, 32] could explain the direct relationship between TCC and elastase. Lastly, in addition to the PMNs, the production of elastase by the mastocytes and the monocytes, and of MPO by the macrophages, could also explain a difference in the concentrations of these two molecules.

The PMN counts were not significantly different between the groups. However, a decrease in the count at time IV (injection of protamine) was observed for the two beating heart groups, while they increased in the EC groups. Although this fall is often associated with hemodilution during EC, a relationship between the activation of the complement and the decrease of circulating PMNs has also been described. Even if the hemodilution and the activation of the complement are significantly more important in the two EC groups, it is not associated with a decrease in the PMN count. This suggests a possible role played by the treatment of SMA surface, perhaps through preservation of the platelet function as previously described [6], and the interactions between the platelets and the leukocytes or endothelial cells.

Some surface treatments, like heparin-coated circuits, are potentially able to reduce the activation of the complement [33]. In contrast, the SMA circuits used in EC reduce platelet activation and diminish the postoperative blood loss, but they do not affect the complement activation [17]. In our study, difference between complement activation and the other inflammatory markers suggests that if the activation of the complement's alternative pathway by EC occurs, then other factors related to cardiac surgery can also be involved. First, the complement activation can also occur in beating heart surgery. In cardiac surgery performed with EC, EC could maintain or even amplify the activation induced by surgery by the amplification loop of the alternative pathway, through fixation of the complement on the protein layer adsorbed at the circuit luminal surface. In beating heart surgery this amplification could not happened, but the first steps of this activation could induce a significant activation of the inflammatory cascade, notably by C3a and its effect on the PMNs, causing their degranulation. In a study comparing pediatric cardiac surgery with and without EC, Tarnok and colleagues [16] demonstrated a significant activation of the complement in the two groups with a specific activation of the alternative pathway by EC, but also a significant production of C3d and C5a in the group without EC. In addition, the consumption of C3, C4, C5, and C1 inhibitor factors, already observed after the induction of anesthesia, was similar for the two groups. In contrast, if some studies comparing heart bypass surgery with and without EC observe different complement marker concentrations, some parameters are often different (shorter operating times, smaller number of bypasses, or minimal invasive access during off-pump surgery) [34]. This could explain the differences regardless of whether or not EC was used. Finally, the global inflammatory cascade is initiated, beside the complement activation, by several phenomena such as ischemia-reperfusion, tissue trauma, and others.

In conclusion, it is well-recognized in cardiac surgery that EC is associated with the activation of the complement, mainly by the alternative pathway. However, EC is probably not the only factor involved. Even if the activation of the complement remains higher than in the off-pump groups, some markers reflecting inflammatory reaction reach similar values to those observed in off-pump surgery. The protection of the platelet function may explain this phenomenon if consideration is given to the well-known interactions between leukocytes, endothelial cells, and platelets in all inflammatory processes. Moreover, this study shows that the closed circuit without pump suckers results in an additional advantage. Therefore, additional studies, combining the markers used in this study with others, are needed to determine the real contribution of surgery and EC to the genesis of the inflammatory response and to the clinical outcomes. One study could concern the comparison between off-pump surgery and a heparin-coated circuit, which have shown an impact on complement activation [[33].


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by a grant from the "Fonds de Recherche Clinique du CHU de Liège" and by COBE Cardiovascular, a division of the Sorin Group.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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