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Eur J Cardiothorac Surg 2004;25:35-42
© 2004 Elsevier Science NL
a Department of Clinical Immunology, Institution of Medicine, Karolinska Institutet, Stockholm, Sweden
b Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden
Received 11 June 2003; received in revised form 16 September 2003; accepted 4 October 2003.
* Corresponding author. Institution of Medicine, Clinical Immunology, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tel.: +46-8-517-76701; fax: +46-8-33-57-24
e-mail: lena.wehlin{at}ks.se
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Coronary artery bypass • Off pump • Flow cytometry • Inflammation • Complement • Randomised
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The neutrophil granulocyte is an important effector cell in inflammation. They have the ability to migrate into tissues to engage in phagocytic activities and release cytotoxic substances. Performing CABG without CPB (OFFCAB) may reduce the inflammatory response seen in on pump (ONCAB) surgery. Several investigators have shown that the number of circulating neutrophils is increased after heart surgery. Studies comparing OFFCAB and ONCAB show higher leukocyte counts [3,4] and more neutrophil activation [4–6] in ONCAB patients. However, whether the modulation of neutrophil function in these settings has any clinical significance is not fully understood.
Complement activation has also been demonstrated in ONCAB, compared to OFFCAB, with increased levels of C3a [3,5,7,8] and C5a [3]. Activation of the terminal complement complex (TCC, SC5b-9) is perhaps the best marker of complement activation as it indicates that the whole complement cascade is activated [9]. To our knowledge TCC has not previously been investigated in comparative ONCAB and OFFCAB surgery.
CPB induces the release of pro-inflammatory cytokines. Several studies demonstrated increased levels of interleukin-6 (IL-6) after both ONCAB and OFFCAB with no difference between groups [6,10,11] and more increased IL-8 levels in ONCAB compared to OFFCAB [12].
The aim of this study was to investigate the influence of extracorporeal circulation on the biological functions of inflammatory cells, our hypothesis being that OFFCAB procedures would generate less activation than ONCAB. The majority of studies in this field are non-randomised and retrospective with substantial differences in patient groups, which makes evaluation difficult. Therefore, patients undergoing CABG were randomised to on pump or off pump surgery and samples were taken during and up to 24 h after the operation.
We included a combination of activity markers with different aspects of neutrophil function and combined these with in vitro activation. We also assessed complement activation, including TCC, cellular counts and the interleukins IL-6 and IL-8.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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2.2.1. ONCAB
Heparin (300 IU/kg) was administered to obtain activated clotting time (ACT) over 480 s before start of CPB. Standard cannulation of the ascending aorta and the right atrium were employed. The CPB circuit consisted of tubings (Medtronics, Minneapolis, MN, USA) without an arterial filter, primed with 1500–1800 ml Ringer's acetate and 7500 IU heparin, a membrane oxygenator (Affinity NT, Medtronics, Minneapolis, MN, USA) and a centrifugal pump (Biomedicus, Medtronics, Minneapolis, MN, USA). CPB was conducted with a flow rate of 2.4 l/m2 per min, alpha-stat acid–base management and a nasopharyngeal temperature of 34–35 °C. After aortic cross-clamping 700–1000 ml of antegrade cold blood cardioplegia was infused. During cross-clamping cardioplegia was given antegradely or retrogradely every 10–15 min. Rewarming was initiated when the last distal anastomosis was started and the patients were weaned from CPB when the nasopharyngeal temperature was above 36 °C.
2.2.2. OFFCAB
Heparin (150 IU/kg) was given and ACT was kept above 300 s. The temperature in the operating room was 23 °C and a patient warming device (Warm Touch, Mallinckrodt Medical, Hazelwood, MO, USA) blowing warm air over parts of the patient, was used.
Positioning of the heart was achieved by a deep pericardial stay suture or a suction device (Xpose CTS, Guidant, Indianapolis, IN, USA). The following stabilisers were used: OFFCAB multi use stabiliser (Guidant, Indianapolis, IN, USA), CTS stabiliser Axius or Ultima (Guidant, Indianapolis, IN, USA) or Octopus II/III stabiliser (Medtronics, Minneapolis, MN, USA). An intracoronary shunt was only used in a few cases when an anastomosis was performed on the main stem of the right coronary artery.
2.3. Anaesthesia
All patients were anaesthetised according to the clinical routine of the department. After premedication with morphine, anaesthesia was induced with fentanyl, midazolam and propofol and muscular relaxation was achieved with pancuronium or atracurium. Volume-controlled ventilation with 40–50% O2 in air was performed. Anaesthesia was maintained with intermittent fentanyl and isoflurane and continuous propofol was used as a supplement when needed. Mean arterial pressure was kept over 50 mmHg and norepinephrine was given if required.
2.4. Blood sampling
Ten millilitres of arterial blood was drawn in tubes containing 0.129 M Na-citrate (Vacutainer, Becton Dickinson, Plymouth, UK). Samples were drawn preoperatively after anaesthesia, but before surgery (‘before’); 30 min after start of CPB or 20 min after start of suturing first distal anastomosis (‘during’); at start of suturing sternum (‘end’) 4 h postoperatively (‘4h’); and 20–24 h post op (‘24h’). Immunoglobulin M (IgM) was measured in order to correct for haemodilution according to the following equation:
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This equation was utilised for calculation of plasma markers and cell counts.
2.5. Preparation of cells for flow cytometry
The blood per tube (150 µl) was haemolysed for 5 min in 3 ml ice cool NH4Cl in a +15 °C water bath and centrifuged at 300xg for 5 min at +4 °C. Pellets were washed in 2 ml of PBS at 300xg for 5 min at +4 °C, and the cells were thereafter kept on ice until further analysis.
2.6. In vitro activation
Leukocyte pellets were resuspended in a final concentration of 10-7 M fMLP (N-formylmethionyl-leucyl-phenlylalanine) (Sigma, St. Louis, Missouri, US) or 10-7 M TNF-
(tumour necrosis factor) (Genzyme Diagnostics, Cambridge, MA, US), diluted in PBS, supplemented with 0.9 mg/ml glucose (PBS-glucose), and incubated for 30 min at +37 °C. Cells incubated in PBS-glucose for 30 min at +4 °C or +37 °C served as controls. Cells were finally washed in 2 ml PBS at 300xg for 5 min at +4 °C, and kept on ice until further use.
2.7. Staining with monoclonal antibodies to granulocyte markers
Monoclonal antibody to CD11b-PE (DAKO A/S, Glostrup, Denmark), CD35-FITC or CD62L-FITC (BD Biosciences, San Jose, CA, USA) was added (100 µl, final concentration: 5 µg/ml) to both resting and fMLP or TNF- stimulated leukocytes. Isotype matched control antibodies, FITC-conjugated IgG1 (Beckman Coulter Inc., Fullerton, CA, USA) and PE-conjugated IgG1 (DAKO A/S), in corresponding concentrations were used to define the cut-off value for positive fluorescence. Cells were incubated for 30 min at +4 °C followed by washing in PBS at 300xg for 5 min at +4 °C. Cells were thereafter resuspended in 0.5 ml PBS and kept on ice until analysis by flow cytometry.
2.8. Assay for oxidative burst
Leukocyte pellets were resuspended in 0.2 ml of DCFH-DA (2',7'-dichlorofluorescien diacetate) [13] at a final concentration of 5 µM, incubated for 15 min at +37 °C. Cells were then stimulated with fMLP, TNF- or PBS-glucose at times and temperatures as described above. Activation was terminated by adding 1 ml of ice cool PBS supplemented with 0.1 mM EDTA (4xNa). Cells were kept on ice for no more than 2 h before analysis by flow cytometry.
2.9. Analysis by flow cytometry
The final leukocyte preparations were analysed in an EPICS XL-MCL flow cytometer (Beckman Coulter Inc.). Peripheral blood leukocyte subpopulations were distinguished by their characteristic light scattering properties, and lymphocytes, monocytes and granulocytes were detected as three well separated populations in a two-parameter histogram. To distinguish between neutrophils and eosinophils in the granulocyte population, measurements of depolarised side scatter were done by modifying the filter settings in the flow cytometer, and inserting a dichroic plastic sheet in forward scatter position. By subsequently shifting the following filters, two colour analyses were made, as described previously [14].
The instrument was calibrated daily with standardised 10-µm fluorospheres, Flow Check (Beckman Coulter). Another fluorosphere, Flow Set (Beckman Coulter) with controlled fluorescence intensity, was run before each experiment to obtain standardisation of the mean fluorescence intensity (MFI). The fluorescent signals were expressed in logarithmic scaled histograms. A quantification of surface bound monoclonal antibodies was obtained by measuring the MFI of the positive population, which reflects the amount of antigen expressed.
2.10. Plasma analysis
Plasma was collected from 32 patients (14 ONCAB, 18 OFFCAB) and stored at -70 °C until analysis by ELISA technique. The following commercially available kits were used: Human IL-8 CytElisa (Cytimmune, MD, US), detection limit at 5.6 pg/ml; High sensitivity human IL-6 ELISA kit (Diaclone, Besancon, France), detection limit at 1.56 pg/ml; C5a ELISA (Nordic Biosite, Täby, Sweden), detection limit at 0.1 µg/ml. SC5b-9 (TCC) Enzyme Immunoassay (Quidel, CA, US) with no specified detection limit (but with all analysed samples well within the standard curve). All analyses were performed according to manufacturers instructions with no modifications.
2.11. Statistics
For between group analysis of operative and postoperative clinical data, t-test and Fisher's exact P test were used. Outcome data are presented as median±interquartile range (IQ). The time courses within and between groups were analysed by analysis of variance for repeated measures (ANOVA) followed by Tukey honest significant difference (HSD) test as post hoc analysis. Statistical evaluation was made using STATISTICA 6, by StatSoft, Inc., Tulsa, USA. Differences were considered significant at P values <0.05.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Monocyte counts were unchanged during operation but were significantly increased after 24 h, with no differences between the groups (Fig. 1c).
The eosinophilic granulocytes decreased significantly during and after operation and only 15% of eosinophils remained in circulation at 24 h in both groups (Fig. 1d).
3.3. Neutrophil granulocyte activation
The expression of CD35 was stable during operation but, increased after 24 h in both groups (Fig. 2
a). The ability to respond to TNF- was decreased during operation until end of operation and recovered at 24 h (Fig. 2b). The response to fMLP was unchanged during and at end of operation but, increased at 24 h. There were no significant differences between groups (Fig. 2c).
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was reduced during operation but, responsiveness was restored at 24 h (Fig. 3b). fMLP stimulation revealed a decreased ability to respond at end of operation in both groups. No restoration in fMLP-responsiveness was seen in any group (Fig. 3c).
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was moderate and we could find no differences in the response either within or between groups (data not shown).
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3.4. Eosinophil granulocyte activation
During operation there was no change in either adhesion molecule expression or metabolic activity. Due to the very low numbers of eosinophils after 24 h it was not possible to interpret the expression of adhesion molecules or metabolic activity (data not shown).
3.5. Plasma markers
C5a increased in both groups at end of operation. In the on pump group, but not in the off pump group, this rise could be seen already during operation with significant differences between groups
The on pump group had an approximately fivefold increase in TCC at the end of the operation compared to before and the increase was significant already during the operation. The off pump group also had an increase at the end of the operation but it was more moderate and could not be seen during the operation. There were significant differences between groups both during and at the end of operation (Fig. 5 b).
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Many investigators have shown complement activation in relation to CABG and CPB. We could detect elevated levels of C5a at the end of the operation in both groups but with a more rapid onset in the ONCAB group. Levels of C5a returned to normal after 4 h. Ascione et al. [3]showed increased levels of C5a 1 h postoperatively in ONCAB patients as compared to OFFCAB but, after that detected no differences between groups. Diegler et al. [7]demonstrated an increased level of C5a at the time of reperfusion in both ONCAB and OFFCAB patients, which remained elevated after 4 and 24 h in the ONCAB group but returned to normal in the OFFCAB group. This, however, is a non-randomised study with different patient populations in the groups. The disparity in results from different investigators indicate that many aspects in coronary artery bypass surgery have influence on complement activation and that ON- or OFFCAB settings must be chosen carefully to make useful comparisons. In addition, analysis of C5a is problematic to interpret due to the rapid binding to cell surfaces, making the circulating fraction not representative for total C5a formation. An additional more useful marker for complement activation is the terminal complement complex, TCC, owing to the longer half-life in circulation, and a low physiological level, making an increase easily detected. Increased levels of TCC constitute an important sign on the entire complement cascade activation. Both the soluble form of TCC and the membrane attack complex have important pathophysiological properties, and are believed to be important for ischaemia/reperfusion induced tissue injury [9].
The levels of TCC increased in both groups but were more rapid and much more pronounced in the ONCAB group. To our knowledge, this is the first randomised study to evaluate the terminal complement complex in ON- and OFFCAB patients. Our results indicate that OFFCAB procedures give less complement activation in CABG operations than ONCAB.
There were no differences between ONCAB and OFFCAB in total leukocyte counts in our study although in both groups there was a remarkable increase the day after surgery. One explanation for the mechanism behind this could be found in several studies reporting of demargination of neutrophils from lung capillaries as a response to exercise, glucocorticoids and interleukins [15–17]. There is also evidence that an increased release from the bone marrow occurs as a response to IL-6 and IL-8 [17,18]. We did not measure the proportion of band cells in the neutrophil population and can thus not draw any conclusions to whether the increase of neutrophils seen in this study is due to demargination, bone marrow release or both. At the end of surgery, there is an increase of neutrophils in the ONCAB, but not in the OFFCAB group in our study. This could be due to the faster onset of complement activation, represented in the present study by C5a. It is reported that C5a, in addition to being a direct mediator of inflammation, can induce release and synthesis of IL-8 from monocytes [19], and so further influence bone marrow release. Ascione et al. [3]showed that the number of neutrophils differed significantly between ON- and OFFCAB, but this difference was not apparent until 2–3 days after surgery.
The distinct decrease in eosinophil numbers after thoracic surgery has been reported earlier by Romankova et al. in 1968 [20]. Eosinophils are involved in wound healing, and in asthmatic inflammation, eosinophils are prominent effectors cells, causing remodelling and fibrosis in the lung epithelium. Since complement split products are known to act as strong chemoattractants for eosinophils, our results suggests a rapid migration into tissue, possibly the lungs, where eosinophils might contribute in the systemic inflammation. Further studies are warranted to delineate the potential role of tissue eosinophils in relation to thoracic surgery.
The extent of neutrophil activation in on pump versus off pump CABG is not fully clarified. The expression of CD11b did not increase during operation in neither group in our study. This is in contrast to Chello et al. [21]who found increased levels in both ONCAB and OFFCAB. However, the onset of CPB has been shown to cause a rapid increase, within 15 min, of CD11b expression on neutrophils with following marginalisation into tissues [22]. That being the case, we might not have detected this peak in activation, due to different sampling intervals. The expression of complement receptor 1, CD35, was also stable during operation in both groups. This was not unexpected since many similarities exists between these two receptors in relation to mobilisation kinetics. CD62L was significantly increased at the end of the operation. This phenomenon usually precedes the shedding of CD62L from activated cells and the subsequent transmigration into tissue. At 24 h, however, the expression of all markers showed signs of activation but with no differences between groups.
Neutrophil function is modulated by cytokines and chemotactic factors. Therefore, we also introduced in vitro activation in an attempt to evaluate the physiological inflammatory response of neutrophils in ON- and OFFCAB. The proinflammatory cytokine TNF- has been reported to have a prominent role in the inflammatory response to CPB [2]. In our study the response to in vitro stimulation with TNF- was reduced at the end of surgery as compared to before, for both CD11b and CD35. It has been reported that neutrophils shed their receptors for TNF- both in ON- and OFFCAB patients [23]. This shedding of receptors could be one explanation for the reported unresponsiveness in our model. The bacterial peptide fMLP, has been used in many settings as a marker for activation ability in neutrophils. In this study we have small but significant decrease in the ability to mobilise CD11b as a response to fMLP stimulation, in both groups, at the end of the operation.
Blackwood et al. [24] has in an in vitro study shown that stimulation with IL-8 or C5a inhibits, for a substantial time period, subsequent re-activation of neutrophils with the same stimuli. In our patients, these inflammatory factors are present, in plasma, throughout the surgery indicating a constitutive stimulation. The all together in vitro response indicates a desensitised, refractory circulating neutrophil population at the end of the operation as a result from CABG.
The inflammatory reaction in CABG with increased cytokine and interleukin levels might stimulate the production of oxygen free radicals. Matata et al. [12] detected increased levels of circulating products of oxidative stress in ONCAB but not in OFFCAB patients during operation. These levels then returned to normal. This is in contrast to the data in the present study in which we did not find any difference between on and off pump patients. This discrepancy can probably be related to the methods used. Our assay for oxidative burst detects production of intracellular hydrogen peroxide, H2O2, as a reaction to stimuli [13], while Matata and co-workers used a method that detects cumulative, extracellular oxygen radical products.
IL-6 and IL-8 increased during the operation but no difference between groups over time could bee seen. Other investigators showed no difference between ONCAB and OFFCAB patients in IL-6 levels [7,10,11,25]. This indicates that IL-6 is affected mainly by the surgical trauma and not CPB itself. Contrary to our findings, other investigators showed much higher concentrations of IL-8 in ONCAB than OFFCAB surgery [3,21]. The divergent results could be related to how CPB is conducted. Although OFFCAB procedures are becoming more common, ONCAB is still dominating and the different settings of CPB, with different pump systems, priming solutions, cardioplegia, etc., makes it difficult to evaluate results from studies comparing ONCAB and OFFCAB.
Taken together, the obvious inflammatory response in both groups, and the lack of significant differences between groups, suggests other factors than CPB responsible for cellular and cytokine activation. Since the beginning of cardiac surgery with CPB, extensive research has been conducted on the effects of CPB on inflammatory mediators, blood cells and blood cascade systems. It might well be that, in the earlier days the CPB had more damaging effects than present day equipment. However, today these effects may be lessened, the ‘dark side’ of CPB may be overestimated and the surgical trauma could be the more important contributing factor to the enhanced inflammatory response during cardiac surgery.
This investigation was aimed at studying continuous data like neutrophil activation and not powered for clinical conclusions. We could, however, not see any difference in clinical outcome between groups.
In conclusion, this prospective, randomised study showed less complement activation in low risk OFFCAB, compared to ONCAB patients. This indicates a reduced inflammatory response, which could lead to an improved clinical outcome in these patients. Studies designed to specifically address this hypothesis are highly warranted.
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Acknowledgments |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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