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Ann Thorac Surg 2008;85:1994-2002. doi:10.1016/j.athoracsur.2008.03.012
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Biomarker Profile in Off-Pump and On-Pump Coronary Artery Bypass Grafting Surgery in Low-Risk Patients

Albert Castellheim, MD, PhDa,*, Tom N. Hoel, MDb, Vibeke Videm, MD, PhDc, Erik Fosse, MD, PhDd, Anne Pharo, BSa, Jan L. Svennevig, MD, PhDb, Arnt E. Fiane, MD, PhDb, Tom E. Mollnes, MD, PhDa

a Institute of Immunology, Rikshospitalet HF, University of Oslo, Oslo, Norway
b Department of Thoracic and Cardiovascular Surgery, Rikshospitalet HF, University of Oslo, Oslo, Norway
c Institute of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, and Department of Immunology and Transfusion Medicine, St. Olav University Hospital, Trondheim, Norway
d Interventional Center, Rikshospitalet HF, Oslo, Norway

Accepted for publication March 5, 2008.

* Address correspondence to Dr Castellheim, Institute of Immunology, Rikshospitalet, Oslo, NO-0027, Norway (Email: albert.castellheim{at}medisin.uio.no).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The purpose of this study was to investigate the cytokine and chemokine profile in low-risk patients undergoing off-pump and on-pump coronary artery bypass grafting (CABG) surgery by use of a broad panel of cytokines and chemokines.

Methods: Eight consecutive blood samples were obtained from patients enrolled into a prospective, randomized study comparing off-pump and on-pump CABG in a low-risk population. Eleven patients from each group were randomly selected for analysis of 25 different cytokines and chemokines using multiplex technology. Data were compared using two-way repeated measures analysis of variance.

Results: Of the 25 biomarkers analyzed, 11 were not detected while 14 increased significantly in both groups. Only three mediators, eotaxin, macrophage inflammatory protein (MIP)-1β, and interleukin (IL)-12 were significantly different between the two groups, increasing more in the on-pump than in the off-pump group (p < 0.001, p < 0.01, and p < 0.05, respectively). There was a marked, comparable increase in the concentrations of the cytokines IL-6, IL-10, IL-15, and IL-1Ra as well as the chemokines inducible protein (IP)-10, monokine induced by interferon gamma (MIG), monocyte chemoattractant protein 1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in both groups (p < 0.001 for all). There was only a modest, but still statistically significant, increase in IL-8, tumor necrosis factors {alpha}, and IL-2R, without any intergroup differences. When corrected for hemodilution the production of the antiinflammatory biomarkers IL-1Ra and IL-10 were significantly higher in the on-pump group (p < 0.001 for both).

Conclusions: The cytokine and chemokine production profile of the inflammatory response associated with CABG is largely similar using the off-pump and on-pump techniques in low-risk patients, but slightly higher concentrations of eotaxin, MIP-1β, and IL-12 were found in the on-pump group.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiopulmonary bypass (CPB) was introduced during the 1950s and has since then been used extensively in coronary artery bypass grafting (CABG). During CPB the blood comes into contact with a vast artificial surface and pulsatile flow is converted to nonpulsatile. Furthermore, during CPB the heart is exposed to ischemia and subsequent reperfusion. Expectedly, CPB has been associated with a substantial inflammatory response including activation of endothelium, leukocytes, platelets, and the complement system, as well as activation of the coagulation system. An intense inflammatory response may be triggered even with the use of CPB alone and without global myocardial ischemia after cardioplegic cardiac arrest [1]. In addition to CPB, surgical trauma and preexisting comorbidities are also associated with the inflammatory response in cardiac surgery [2].

Leukocyte recruitment and the production of cytokines and chemokines play a central role in the inflammatory response associated with CPB. Cytokines, being produced and secreted by the cells in the immune system, are small soluble polypeptides and proteins that act as paracrine messengers. Chemokines, a cytokine subfamily, are chemotactic and participate in recognizing, recruiting, removing, and repairing tissue undergoing inflammation. Proinflammatory cytokines (including tumor necrosis factors (TNF)-{alpha}, interleukin (IL)-1, IL-6, IL-8, and IL-12) facilitate a wide range of inflammatory processes. Antiinflammatory cytokines (including IL-4, IL-6, IL-10, IL-11, and IL-13) inhibit inflammatory processes by reducing the production of the proinflammatory cytokines or counteracting their effects [3]. Cytokines may also influence the production of other cytokines and furthermore induce expression of cytokine receptors as well as enzymes like inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn contribute in the inflammatory response [4]. A correlation has been suggested between the circulating levels of IL-6 and IL-8 and cardiorespiratory dysfunction [5, 6].

Coronary artery revascularization may be performed on the beating heart. This procedure (off-pump CABG) was originally introduced in the 1960s but has only recently been established as a safe alternative to CABG using CPB (on-pump CABG) [7]. It has been reported that off-pump surgery may produce not only results comparable with on-pump surgery but also may have certain advantages [8]. Lower concentrations of cytokines and myocardial tissue markers [9] as well as less activation of circulating neutrophils in off-pump patients compared with on-pump patients have been described [10]. Additionally, it has been suggested that avoidance of CPB may result in reduced severity of the systemic inflammatory response to cardiac surgery [2, 11]. Inflammation is suggested to be of critical importance in the pathogenesis of organ dysfunction after CPB [12], and CPB has been recognized as a major cause of systemic inflammatory response contributing to postoperative complications [1, 13, 14]. Ischemia-reperfusion [15] and surgical trauma [14, 16, 17] are other important causes to the inflammatory response.

We have recently shown that off-pump and on-pump CABG surgery differ strikingly with respect to activation of complement [18]. The C3 activation products and sC5b-9 increased markedly in the on-pump, but not in the off-pump group. This difference was not seen for neutrophil and platelet activation. This led us to investigate the cytokine and chemokine release during on-pump and off-pump CABG using a panel of mediators representing a broad spectrum of the inflammatory response.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Design and Patient Population
The Regional Ethics Committee approved the study protocol on May 14, 1998, and written consent was obtained from the patients. Forty-four patients were randomized to on-pump (22 patients) or off-pump (22 patients) after the induction of anesthesia. The patients were followed up postoperatively and were discharged to local hospitals on the second or third postoperative day if no complications developed. The laboratory analyses in the present study were performed on blood samples from 11 randomly selected patients from each group, comprising a biomarker study population of 22 patients. The selection was done due to capacity and economic reasons. Patient characteristics and intraoperative data are summarized in Table 1. The treatment team, consisting of four surgeons and four anesthesiologists, was the same in both groups. The patient group from the original study is described in detail previously [18].


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  		Table 1 Patient Characteristics, Preoperative and Intraoperative Data
 
Operative Techniques
Anesthesia and initiation of surgery
General anesthesia was inducted with intravenous injection of thiopentone and fentanyl. At the end of surgery propofol and inhalation anesthesia were used to allow early extubation. Surgery was initiated with a standard midline sternotomy incision to expose the heart and harvesting of the internal mammary artery (IMA). An inverted T-shaped incision was used to open the pericardium. If necessary the right pleural space was opened in the off-pump group to minimize the hemodynamic impairment. Saphenous vein grafts were used as single or sequential grafts.

On-pump procedures and devices
All operations were performed in moderate general hypothermia (28°C to 32°C) with topic cooling with crushed ice. The extracorporeal system used in the on-pump group consisted of Duraflo II heparin-coated Spiral Gold membrane oxygenators, tubing sets, and cardiotomy suction (Bentley/Baxter, Uden, The Netherlands) with a roller pump (Stoeckert, Stuttgart, Germany). Ringer's acetate (1,800 mL) was used to prime the circuit. Before initiation of CPB heparin (4 mg/kg body weight) was injected intravenously to achieve a minimum activated clotting time (ACT) of 480 seconds and cold cardioplegic solution (St. Thomas II) was given in the aortic root. A single right atrial two-stage cannula and a perfusion cannula in the ascending aorta were used for CPB. Bypass was performed with a flow of 2.4 L/minute/m2 and mean arterial pressure greater than 50 mm Hg. The distal coronary anastomoses were performed prior to the proximal anastomoses, which were completed during rewarming using a partial aortic clamp. At the end of the procedure, protamine sulfate (5 mg/kg body weight) was injected intravenously to achieve the preoperative levels of ACT. The given doses of heparin and protamine sulfate were in accordance with our clinic's current guidelines for both on-pump and off-pump patients.

Off-pump procedures and devices
Heparin (1 mg/kg body weight) was injected during IMA takedown aiming at an ACT above 250 seconds. If targeted ACT was not achieved complementary doses were given. The mean cumulative dose of heparin was 2 mg/kg body weight. Snares (Gore Tex 3-0) and Octopus I and II stabilizers (Medtronics Inc, Minneapolis, MN), combined with a deep pericardial retraction suture and an apical suction device (Starfish; Medtronics Inc), were used for performing of the distal anastomoses. Coronary shunts were only used when a large or noncollateralized coronary artery was grafted. A carbon dioxide blower (Ethicon Cardiovations, Summerville, NJ) was used to obtain a bloodless field. The distal anastomoses were performed prior to the proximal anastomoses using a partial aortic clamp. At the end of the procedure an ACT of 150 to 200 seconds was targeted, and if needed protamine sulfate was injected. The mean dose of given protamine sulfate was 0.3 mg/kg body weight.

Blood Sampling
All blood samples were obtained from the arterial line using the ethylenediaminetetraacetic acid (EDTA) as anticoagulant. The samples were kept on ice until centrifugation at 2,000g within four hours. Plasma was stored at –70°C until analysis. Blood sampling was performed at the following time points: T0 = after induction of general anesthesia and before systemic heparinization; T1 = immediately after institution of CPB or 30 minutes after T0 in the off-pump group; T2 = 45 minutes after T1; T3 = 60 minutes after T1; T4 = 90 minutes after T1; T5 = at termination of CPB or 120 minutes after T1 in the off-pump group; T6 = during skin closure; T7 = two hours postoperatively.

Laboratory Analyses
The EDTA plasma samples were examined for the concentrations of 25 biomarkers using multiplex technology (Human Cytokine 25-plex-kit; Catalogue number: LHC0009, BioSource Europe, Nivelles, Belgium). This is a solid phase sandwich immunoassay, which simultaneously measures the following 25 human biomarkers in one single sample: IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-2 receptor (IL-2R), IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p40/p70, IL-13, IL-15, IL-17, TNF-{alpha}, interferon (IFN)-{alpha}, IFN-{gamma}, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1{alpha}, MIP-1β, interferon-inducible protein (IP)-10, monokine induced by IFN-{gamma} (MIG), eotaxin, regulated on activation, normal T cell-expressed and secreted (RANTES), and monocyte chemoattractant peptide (MCP)-1. The analyses were performed according to the kit procedure. Shortly, beads of defined spectral properties are conjugated to analyte-specific capture antibodies. The analytes in the samples bind to the capture antibodies on the beads. Thereafter, added analyte-specific biotinylated detector antibodies bind to the appropriate immobilized analytes. Finally, streptavidin conjugated to the fluorescent protein R-phycoerythrin binds to the biotinylated detector antibodies associated with the immune complexes of the beads, forming a solid phase sandwich. The beads were analyzed with a Luminex 100, Bio-Plex array reader (Bio-Rad Laboratories Inc., San Diego, CA). Standard curves were generated for each analyte using the mixed analyze standard provided with the kit. Lower detection limit was in the range of 5 to 50 pg/mL for all analytes, except for IL-1Ra, for which it was 1,300 pg/mL.

Statistics
Due to nonnormal distributions of many variables, data are given as medians with nonparametric 95% confidence intervals. For categoric variables, differences between groups were compared using the {chi}2 test or Fisher exact test, as appropriate. The Mann-Whitney U test was used to compare continuous variables between the groups. Parameters measured repeatedly were compared using repeated measures analysis of variance (SPSS for Windows, Release 12.0.1; SPSS Inc, Chicago, IL). If necessary to achieve appropriate model fit, logarithmic or rank transformations were used. A p value less than 0.05 was considered significant. Data were analyzed both before and after correction for hemodilution.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Among the 25 different biomarkers measured, the concentrations of the following 11 biomarkers were below the lower detection limit: IL-1β, IFN-{alpha}, IFN-{gamma}, IL-2, IL-4, IL-5, IL-7, IL-13, IL-17, GM-CSF, and MIP-1{alpha}. The remaining 14 biomarkers increased significantly in both groups, with significant intergroup differences only for three of them.

Biomarkers With Significant Differences Between the Groups
The concentrations of eotaxin, IL-12, and MIP-1β increased significantly (p < 0.001 for all) both in the on-pump and off-pump groups (Fig 1). The increase was significantly higher in the on-pump group (p < 0.001, p < 0.05, and p < 0.01, respectively). The concentrations of eotaxin and IL-12 reached a peak and declined at the end of the observation period whereas MIP-1β concentrations increased late during the observation period (Fig 1). After correction for hemodilution, the increase in the antiinflammatory mediators IL-1Ra and IL-10 also became significantly higher (p < 0.001 for both) in the on-pump than the off-pump group.


Figure 1
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  		Fig 1. Concentrations of eotaxin, IL-12, and MIP-1β in patients undergoing off-pump or on-pump cardiac surgery (median and 95% nonparametric confidence interval). T0 = after induction of general anesthesia and before systemic heparinization; T1 = immediately after institution of cardiopulmonary bypass (CPB) or 30 minutes after T0 in off-pump group; T2 = 45 minutes after T1; T3 = 60 minutes after T1; T4 = 90 minutes after T1; T5 = at termination of CPB or 120 minutes after T1 in the off-pump group; T6 = during skin closure; T7 = two hours postoperatively. Statistical differences from T0 within each group is indicated as * (p < 0.05), ** (p < 0.01), and *** (p < 0.001). Statistical differences between the groups are indicated as # (p < 0.05), ## (p < 0.01), and ### (p < 0.001). (IL = interleukin; MIP = macrophage inflammatory protein.)

 
Biomarkers Without Significant Differences Between the Groups
The concentrations of the cytokines IL-6, IL-10, IL-15, and IL-1Ra increased significantly (p < 0.001 for all) both in the on-pump and off-pump groups, but there were no significant difference between the two groups, whether comparing the uncorrected data (Fig 2) or data corrected for hemodilution. The IL-6 concentrations increased late during the observation period whereas IL-10, IL-15, and IL-1Ra increased from the start and remained elevated.


Figure 2
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  		Fig 2. Concentrations of IL-6, IL-10, IL-15, and IL-1Ra in patients undergoing off- or on-pump cardiac surgery (median and 95% nonparametric confidence interval). For definition of time points, see legend to Figure 1. Statistical differences from T0 within each group are indicated as *(p < 0.05), **(p < 0.01), and ***(p < 0.001). The differences between the groups were not significant.

 
The concentrations of the chemokines IP-10, MIG, MCP-1, and RANTES increased significantly (p < 0.001 for all, except for off-pump RANTES) both in the on-pump and off-pump groups, but there were no significant differences between the two groups whether comparing the uncorrected data (Fig 3) or data corrected for hemodilution. The concentrations of MCP-1 and RANTES increased late during the observation period whereas IP-10 and MIG reached a peak and declined at the end of observation period.


Figure 3
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  		Fig 3. Concentrations of IP-10, MIG, MCP-1, and RANTES in patients undergoing off- or on-pump cardiac surgery (median and 95% nonparametric confidence interval). For definition of time points, see legend to Figure 1. Statistical differences from T0 within each group are indicated as *(p < 0.05), **(p < 0.01), and ***(p < 0.001). The differences between the groups were not significant. (IP = inducible protein; MCP = monocyte chemoattractant protein; MIG = monokine induced by interferon gamma; RANTES = regulated on activation, normal T cell expressed and secreted.)

 
The IL-8, TNF-{alpha}, and IL-2R showed only modest increases, though still statistically significant, but without any significant intergroup differences whether comparing the uncorrected data (Table 2) or data corrected for hemodilution.


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  		Table 2 Concentrations (pg/mL) of IL-8, TNF-{alpha}, and IL-2R (Medians and 95% Confidence Intervals) in Off-Pump and On-Pump Patients
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
The present data underscore that the inflammatory reaction reflected by on-pump and off-pump cardiac surgery is more complex than generally accepted and that a differential approach has to be emphasized with respect to the role of the various factors contributing to the inflammatory response reaction during coronary artery surgery. Trauma and surgery generally evoke the inflammatory reaction as seen in patients undergoing both off-pump and on-pump surgery [19]. However, the general inflammatory reaction may further be modified by additional stimuli, like extracorporeal circulation, shifting it to a more explicit reaction, which is characterized with more specific biomarkers [1]. Thus, we recently showed that complement was extensively activated in on-pump patients, whereas off-pump patients displayed no complement activation [18]. The present study supports a possible role for a limited number of cytokines to be induced by complement activation, whereas the major cytokine response was independent of the cardiopulmonary-induced inflammatory reaction.

The theoretical and clinical benefits of off-pump CABG compared with on-pump CABG have been subjected to extensive discussion in literature [20–26]. Claimed benefits of off-pump surgery have included shorter operating room time and ventilation time, shorter length of hospital stay, and lower costs. Decreased perioperative bleeding, fewer transfusions, and transfusion-related complications as well as fewer surgical reexplorations have been observed. Furthermore, less myocardial injury, reduced postoperative atrial fibrillation, reduced incidence of stroke and neurologic morbidity with improved neurocognitive function, and less postoperative renal and other organ dysfunction have been found in off-pump groups, supporting a better clinical outcome with reduced morbidity and mortality.

Despite early promising results, off-pump CABG is not without concerns and has not generally replaced on-pump surgery. One reason may be that results from on-pump surgery have improved, both due to better perioperative care and surgical techniques [27], and to improvement of CPB equipment and technique [28]. In fact, recent data suggest that excellent medium-term results may be obtained with both on-pump and off-pump techniques [29]. Furthermore, some of the major beneficial aspects of the off-pump technique are still controversial, including lower incidence of atrial fibrillation [30, 31] and the risk of neurological adverse effects [32, 33]. Indeed, patients may achieve excellent outcomes with either type of procedure where other factors than the surgical procedure per se might be more predictive. Large prospective randomized trials are necessary to establish whether one technique is superior to the other in specific patient groups [34].

It is necessary to distinguish between normal and high-risk patients when assessing the clinical outcome of patients undergoing on-pump or off-pump CABG surgery. There are indications that only high-risk patients, including elderly patients and patients with comorbidities like obesity and diabetes as well as patients with acute myocardial infarction and those needing reoperation, may benefit from off-pump CABG surgery [23, 24, 35, 36]. Notably, there is recent evidence that on-pump CABG on beating heart (ie, using CPB but avoiding cardioplegic arrest) can also be performed safely in high-risk patients, and in addition it would be more beneficial in hemodynamically unstable patients [37]. In low-risk patients, however, the multicenter randomized controlled Octopus study recently showed that avoidance of CPB had no effect on 5-year cognitive and cardiac outcomes or on quality of life [38].

In this study, eotaxin, MIP-1β, and IL-12 increased significantly in the on-pump group compared with the off-pump group when compared either before or after correction for hemodilution. Eotaxin-1 (CCL11), a small cytokine produced by a variety of cell types, is a potent eosinophil chemoattractant [39]. Eosinophils are important sources of lipid mediators, cytokines, and growth factors. Primarily they were associated with defense against parasitic infection but the current understanding is that eosinophils also are involved in immune modulation and tissue repair [40]. Macrophage inflammatory protein-1 (MIP-1) family members (MIP-1{alpha} and MIP-1β) are chemokines (chemotactic cytokines) involved in the pathogenesis of many inflammatory diseases. They orchestrate acute and chronic inflammatory responses mainly through T-cell chemotaxis and regulation of transendothelial migration of monocytes, dendritic cells, and NK cells. However, neutrophils and eosinophils are less responsive to the chemotactic effects of MIP-1 [41]. Interleukin-12, together with IL-23 and IL-27, constitute a family of structurally related cytokines, which regulate cell-mediated immune responses and Th1-type inflammatory reactions in addition to regulating inflammation through effector T cells, macrophages, and neutrophils [42, 43]. When corrected for hemodilution the increase in IL-1Ra and IL-10 also became significantly higher (p < 0.001 for both) in the on-pump than in the off-pump group. The increased production of the antiinflammatory cytokines IL-1Ra and IL-10 in the on-pump group is particularly interesting and may, to some degree, explain the surprisingly similar inflammatory reaction generally seen in these two groups of patients. Our findings underscore that it is necessary to evaluate both proinflammatory and antiinflammatory cytokines to evaluate the balanced inflammatory load in patients undergoing CPB.

The occurrence of higher concentrations of inflammatory markers in on-pump patients compared with off-pump patients has been suggested [36], but this is a controversial field [44]. A main limitation of previous studies is that only a limited number of mediators have been included, thus not necessarily reflecting the systemic response satisfactorily. Conclusions should therefore be drawn with great caution. In the present study we aimed to cover the cytokine and chemokine response broadly by measuring 25 biomarkers, of which 14 increased. Importantly, all these 14 increased in both the on-pump and the off-pump group. Furthermore, only three of these biomarkers showed significant differences between the two groups, most pronounced for eotaxin and less marked for MIP-1β and IL-12. The comparable increases in the other mediators suggest that patients in both groups responded to surgery with a cytokine inflammatory reaction, which is largely similar and relatively independent of CPB. This is in sharp contrast to activation of the complement system, which we recently showed to be limited to the on-pump group in the same patients from which our samples were recruited [18]. However, activation of neutrophils and platelets showed no significant differences between the groups and leukocyte and platelet counts were similar in both groups, consistent with the findings with respect to cytokines in the present paper. Thus, complement may rather selectively be activated by the CPB circuit and discriminate between the on-pump and off-pump techniques, whereas the remaining inflammatory reaction is less CPB-dependent.

Strengths and Limitations of the Study
The scope of this study was to analyze the inflammatory response during and immediately after the operations. This explains the relatively short window of postoperative blood sampling and the fact that we may have missed differences in the later postoperative course. All patients experienced an uncomplicated immediate postoperative course until discharge to their local hospital. During the study there were no conversions from off-pump to on-pump surgery, no use of antifibrinolytic agents like aprotinin, and no transfusions during the sampling intervals. Additionally, cardiotomy suction was used in all on-pump patients and a cell-saver was used in all off-pump patients. The production of most of the biomarkers occurred to a similar extent in both groups. However, the limited number of patients in this study and the relatively large number of tested biomarkers may pose a risk of false negative conclusions and spurious intergroup differences. The duration of CPB was relatively short and in many cases did not exceed 90 minutes, which may interfere with the consistency of the comparison between the groups. Blood sampling schedule might also have been more frequent than necessary, but was chosen because the patterns of changes for most of the measured biomarkers were unknown.

In summary, the present study suggests that the differences in the cytokine inflammatory response between patients operated with the on-pump or off-pump techniques are small and probably have a limited impact on outcome in low-risk patients. The role of activation of the complement system induced by CPB in high-risk patients and its correlation with the long-term clinical outcome, however, remains to be investigated.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Financial support was provided by The Norwegian Council on Cardiovascular Disease, The Odd Fellow Foundation, The Research Council of Rikshospitalet (RCR), The Family Blix Foundation, and NIH grant number R01-EB-003968-01.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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