**3.2 Safety**

### *Periperative mortality*

Most of the randomized trials have included either consecutive patients or patients with low perioperative risk due to young age, few comorbidities, and need for relatively few grafts. The expected operative mortality for this group of patients is too low for any of the randomized trials to have sufficient statistical strength to detect a difference between treatment groups. This is also true for metaanalyses of randomized trials.

Among the larger non-randomized studies, Cleveland et al. analyzed data from the Society of Thoracic Surgeons (STS) database (4). They included operations performed in 1998 and 1999 in 126 centers with experience in OPCAB surgery. A total of 118.140 CCABG and 11.717 OPCAB procedures were included. The risk adjusted mortality in this comparison was 2.94% in the CCABG group and 2.32% in the OPCAB group (p < 0.0001). Magee and coworkers compared the results of 6.466 CCABG and 1.983 OPCAB procedures in two American centres in 1998-2000 (5). In spite of a significantly higher preoperative morbidity in the OPCAB-group, mortality in the OPCAB group was 1.8% against 3.5% in the CCABGgroup (p = 0.002). However, these comparisons were not performed according to the principle of intention–to-treat. This is a significant drawback, since patients who were converted to CCABG during the operation after initially attempting to perform OPCAB are analyzed as belonging to the CCABG group. Hence, the complications of the most complicated OPCAB-procedures were exported to the CCABG-group.

It is worth noting that one of the few randomized studies that specifically included high-risk patients who received an acute operation, found a significantly higher mortality in the CCABG group than in the OPCAB group (7.7% vs. 1.6%, p=0.04) (32). However, this study exclusively included patients who only needed grafting the LAD territory, which would be expected to favour OPCAB.

### **3.3 Other cardiac complications**

### *Myocardial damage*

None of the randomized studies or meta-analyses has documented any significant difference in the incidence of clinical peri-operative myocardial infarction. However, many randomized studies provide evidence of a lower, subclinical release of biochemical markers of myocardial damage among patient operated using OPCAB (12, 25, 32-42). This tendency is very robust across the different studies, and it is even preset in a study that showed a significantly higher proportion of graft occlusions in the OPCAB group (25). These differences are ascribed to ischemia and reperfusion with cardioplegia. Apart from creatinine-kinase type B (CK-MB) and Troponine T, also atrial natriuretic peptide and heart type fatty-acid binding protein tend to exhibit a higher raise after CCABG than after OPCAB (36). All of these differences, are, however in an order of magnitude smaller than what has so far been considered clinically relevant. By detailed measurement of left ventricular ejection fraction between groups, no inter-group differences were found (42). On the other hand, the long term follow-up of the OCTOPUS-study showed that the patients with the highest release of CK-MB had the highest risk of experiencing a clinical myocardial infarction during the following year (43). A number of confounding issues may, however, be relevant.

In a study of myocardial biopsies, it was found that the concentration of reduced glutathion recovered more rapidly in CCABG than OPCAB patients (38). For the OPCAB-operations, a proximal snare was used for occlusion of the vessel while performing the anastomosis. This finding suggests that cardioplegia is better tolerated than occlusion. Still, a higher increase in CK-MB was found in the CCABG-group. Together, these findings suggest that the myocardium in the territory of the occluded vessel suffers more from occlusion but a less profound damage to the entire myocardium is caused by ischemia and reperfusion. Which of these two situations pose the largest threat to heart function is not clear. Gadolinium contrast enhanced magnetic resonance perfusion imaging, reflecting permanent damage to the myocardium, failed to detect a difference between treatment groups despite a higher release of Troponine- I in the CCABG-group (39). On this background, it was speculated whether some of the Troponine leak represented protein release from non-structurally bound cytosolic pools, rather than true myocardial necrosis. In another study, micro-dialysis was used to sample myocardial interstitial fluid during and after surgery (44). More abnormal values were found during CCABG than during OPCAB. It was not stated in the paper whether samples were taken within or outside the area of the temporally occluded vessel during OPCAB.

### *Atrial fibrillation*

168 Special Topics in Cardiac Surgery

On the other hand, a significant increase in self-reported, health related quality of life is invariably found in both groups comparing preoperative and postoperative status (24, 27,

Most of the randomized trials have included either consecutive patients or patients with low perioperative risk due to young age, few comorbidities, and need for relatively few grafts. The expected operative mortality for this group of patients is too low for any of the randomized trials to have sufficient statistical strength to detect a difference between

Among the larger non-randomized studies, Cleveland et al. analyzed data from the Society of Thoracic Surgeons (STS) database (4). They included operations performed in 1998 and 1999 in 126 centers with experience in OPCAB surgery. A total of 118.140 CCABG and 11.717 OPCAB procedures were included. The risk adjusted mortality in this comparison was 2.94% in the CCABG group and 2.32% in the OPCAB group (p < 0.0001). Magee and coworkers compared the results of 6.466 CCABG and 1.983 OPCAB procedures in two American centres in 1998-2000 (5). In spite of a significantly higher preoperative morbidity in the OPCAB-group, mortality in the OPCAB group was 1.8% against 3.5% in the CCABGgroup (p = 0.002). However, these comparisons were not performed according to the principle of intention–to-treat. This is a significant drawback, since patients who were converted to CCABG during the operation after initially attempting to perform OPCAB are analyzed as belonging to the CCABG group. Hence, the complications of the most

It is worth noting that one of the few randomized studies that specifically included high-risk patients who received an acute operation, found a significantly higher mortality in the CCABG group than in the OPCAB group (7.7% vs. 1.6%, p=0.04) (32). However, this study exclusively included patients who only needed grafting the LAD territory, which would be

None of the randomized studies or meta-analyses has documented any significant difference in the incidence of clinical peri-operative myocardial infarction. However, many randomized studies provide evidence of a lower, subclinical release of biochemical markers of myocardial damage among patient operated using OPCAB (12, 25, 32-42). This tendency is very robust across the different studies, and it is even preset in a study that showed a significantly higher proportion of graft occlusions in the OPCAB group (25). These differences are ascribed to ischemia and reperfusion with cardioplegia. Apart from creatinine-kinase type B (CK-MB) and Troponine T, also atrial natriuretic peptide and heart type fatty-acid binding protein tend to exhibit a higher raise after CCABG than after OPCAB (36). All of these differences, are, however in an order of magnitude smaller than what has so far been considered clinically relevant. By detailed measurement of left ventricular ejection fraction between groups, no inter-group differences were found (42). On the other hand, the long term follow-up of the OCTOPUS-study showed that the patients with the highest release of CK-MB had the highest

treatment groups. This is also true for metaanalyses of randomized trials.

complicated OPCAB-procedures were exported to the CCABG-group.

31).

**3.2 Safety** 

*Periperative mortality* 

expected to favour OPCAB.

*Myocardial damage* 

**3.3 Other cardiac complications** 

In the BHACAS-1 study, Heart rate and rhythm were continuously monitored for 72 postoperative hours. The incidence of postoperative atrial fibrillation was found to be 45% among CCABG patients as compared to 8% among patients operated with OPCAB (p<0.001) (45). A large number of later studies, including the BHACAS-2 study, have confirmed this tendency but with a much smaller difference between groups. The tendency is statistically significant in some of these studies and in meta-analyses (21).

### *Postoperative inotropic support and low cardiac output syndrome*

Need for inotropic drugs after the operation may reflect either transient or permanent heart failure. Several, larger studies do not report this end-point (13-14), but among the ones that do, there is a trend towards a higher incidence in patients operated using cardiopulmonary by-pass. A meta-analysis of 16 studies including 1655 patients found a need for inotropic support postoperatively in 23.6% of CCABG and 15.1% of OPCAB patients (p=0.04)(21). Other studies report the incidence of "low cardiac output syndrome", defined as need for intra-aortic balloon pump, need for inotropic drugs or pressor drugs. One of the larger studies reports a significant difference (12), while others do not (13, 46).

### **3.4 Neurological complications**

### *Stroke*

Theoretically, the use of cardiopulmonary by-pass may cause stroke by a number of different mechanisms. These include the manipulation of the ascending aorta for cannulation and clamping, gaseous or particulate emboli formed in the by-pass circuit, and accidental interruption of flow.

Also, post-operative atrial fibrillation may cause strokes in spite of adequate antithrombotic treatment. For these reasons, an important argument for favouring OPCAB has been the intention to reduce the rate of peri-operative strokes.

In low risk patients, the risk of suffering a peri-operative stroke is between 1 and 1.5%. Hence, none of the individual, randomized, controlled trials have had the statistical strength

Current Evidence of On-Pump Versus Off-Pump Coronary Artery By-Pass Surgery 171

undergoing CCABG than in patients undergoing OPCAB (48, 53). One study showed a correlation between the number of HITS detected in the CCABG-group and the results of one out of three neurocognitive tests. This correlation, however, according to a figure in the publication, relies heavily on the results from one patient (48). No correlation was found with the results of any of the other two tests nor, in the OPCAB group, between the number of HITS and the results of any of the three tests. In a larger study, a lower neuro-cognitive score was found at discharge from hospital in patients who had undergone CCABG compared to patients operated with OPCAB-tecghnique (53). This difference was not found at six weeks and six months follow-up and no correlation was found between number of

To summarize, there is strong evidence of more HITS when performing CCABG than OPCAB. There is, however, no evidence that these HITS represent emboli or that they have

In another study, cerebral SPECT-scans revealed more evidence of microemboli after CCABG than after OPCAB (50). However, like in the case of HITS and S-100 release, this finding could

One study suggests that changes in neuro-cognitive function and tendency to mental depression after both CCABG and OPCAB are related to disturbance of the circadian rhytms of cortisol and melatonine release (57). These disturbances are, though, also susceptible to other factors and they occur after both types of procedures. The clinical significance of this

Transient or permanent renal impairment are well known complications to cardiac surgery (58). This risk has be attributed to the systemic, inflammatory response, hypoperfusion of the kidneys during operation and, possibly, the non-pulsatile nature of flow during

Clinically significant, new onset renal failure – defined either as need for dialysis or by increase in biochemical markers to pathological levels – occur at a rate of approximately 1-2 per cent of the low-risk patients typically included in randomized, controlled trials. None of these studies have, therefore, had the statistical strength to detect a difference in the incidence of this end-point between patients operated with OPCAB or CCABG. Even in a large meta-analysis by Cheng et al (21) showing an odds ratio of 0.58 in favour of OPCAB

On the other hand, when comparing biochemical markers of sub-clinical renal damage, evidence from several clinical trials is in favour of OPCAB (11, 60-61). This difference is clear whether glomerular or tubular damage is compared (60). In one study, the difference between creatinine clearance after CCABG compared to OPCAB was especially high in patients with diabetes, hypertension and heart failure (11). In one trial, comparing patients operated using pulsatile flow in the cardiopulmonary by-pass circuit, no difference in postoperative renal function was found between patients operated with OPCAB and CCABG. This finding seems to confirm the theory that non-pulsatile flow contributes to the subclinical renal impairment

During cardiopulmonary by-pass, ventilation is commonly stopped to prevent the motion of the lungs interfering with surgery. During the early postoperative period patients who have

the confidence limits were too wide to allow statistical significance.

often seen after cardiac surgery using cardiopulmonary by-pass (61).

any significance with regard to early or late postoperative cognitive dysfunction.

not be shown to correlate with the performance of patients in neuro-cognitive tests.

HITS and postoperative cognitive function.

finding is not clear.

**3.5 Renal function** 

**3.6 Lung function** 

cardiopulmonary by-pass (59).

to prove a difference. A single meta-analysis only just managed to show a significant difference (47), but other analyses, comprising just as many or more trials and patients, failed to prove OPCAB superior (21). Therefore, until the time of the publication of the ROOBY-trial (14), evidence was ambiguous. In the ROOBY trial, however, the trend was opposite that of most earlier studies with 1.3% strokes in the OPCAB-group and 0.7% in the CCABG-group (p=0.28). In view of the large volume of this trial compared to all the other trials, it can no longer be stated that there is a clear trend in favour of OPCAB to reduce the rate of peri-operative strokes in younger, low-risk patients. It is, however, worth noting, that the OPCAB technique is still being developed in order to reduce stroke rate. An increasing number of surgeons favour a "no-touch-aorta" technique, placing proximal anastomoses end-to-side in a mammary artery graft rather than on the aorta itself. In addition, some centers aim to reduce the risk of embolisation due to atrial fibrillation by ligating the left atrial appendage. Excellent results have been produced, but not tested in randomized trials.

#### *Neurocognitive dysfunction*

Several randomized trials have used neuro-psychological or neuro-cognitive tests to detect perioperative cerebral damage lesser than overt stroke. In some of these studies, early postoperative testing favoured OPCAB (48-49) while others found no significant difference (50-53). Zamvar and coworkers, only including patients with triple-vessel disease, performed a battery of neuro-cognitive tests one week and ten weeks postoperatively, comparing with preoperative test results. At both occasions, they found a significantly higher degree of neurocognitive dysfunction in CCABG-patients than in OPCAB-patients (54).

In the Octopus trial (6, 41, 49), a significant difference in favour of OPCAB was found after three months but not after one year nor after five years of follow-up. At five years follow-up, a more than fifty per cent decline in scores at neuro-cognitive testing was found in both groups, illustrating the fact that patients with ischemic heart disease in general have an increased risk of neurocognitive decline. A similar decline has been documented after three years in a non- surgical control group (55).

Surrogate end-points of brain damage are often used in randomized trials comparing OPCAB with CCABG. These include release of the S-100 peptide and detection of High Intensity Transcranial Doppler Signals (HITS) as well as changes in serum concentrations of different hormones.

When S-100 is detected in peripheral blood, it is seen as a marker of damage to, and increased permeability of, the blood-brain barrier. There is good evidence from randomized controlled trials that the increase of S-100 is higher after CCABG than after OPCAB (48, 51, 56). In two out of three studies these increases are compared to the results of postoperative, neurocognitive tests, but none of the studies showed any correlation between S-100 levels and neurocognitive function. In one of the studies one patient suffered a major stroke resulting in paralysis of an arm and a leg without a major increase in blood concentrations of S-100. Hence, the clinical significance of relase of S-100 is uncertain.

Characteristic high-intensity signals – HITS - can be detected by trans-cranial measurement of Doppler signals from the medial cerebral artery. The amount of HITS increase during manipulation of the aorta, especially during cannulation, clamping, and declamping. A lower number of HITS are observed at the beginning of cardiopulmonary by-pass. It is not clear, to what extent HITS represent particulate emboli being released from vessel walls, tubes or filters and what proportion of HITS are being generated by gaseous microemboli and turbulence. Several studies have demonstrated a larger amount of HITS in patients undergoing CCABG than in patients undergoing OPCAB (48, 53). One study showed a correlation between the number of HITS detected in the CCABG-group and the results of one out of three neurocognitive tests. This correlation, however, according to a figure in the publication, relies heavily on the results from one patient (48). No correlation was found with the results of any of the other two tests nor, in the OPCAB group, between the number of HITS and the results of any of the three tests. In a larger study, a lower neuro-cognitive score was found at discharge from hospital in patients who had undergone CCABG compared to patients operated with OPCAB-tecghnique (53). This difference was not found at six weeks and six months follow-up and no correlation was found between number of HITS and postoperative cognitive function.

To summarize, there is strong evidence of more HITS when performing CCABG than OPCAB. There is, however, no evidence that these HITS represent emboli or that they have any significance with regard to early or late postoperative cognitive dysfunction.

In another study, cerebral SPECT-scans revealed more evidence of microemboli after CCABG than after OPCAB (50). However, like in the case of HITS and S-100 release, this finding could not be shown to correlate with the performance of patients in neuro-cognitive tests.

One study suggests that changes in neuro-cognitive function and tendency to mental depression after both CCABG and OPCAB are related to disturbance of the circadian rhytms of cortisol and melatonine release (57). These disturbances are, though, also susceptible to other factors and they occur after both types of procedures. The clinical significance of this finding is not clear.

### **3.5 Renal function**

170 Special Topics in Cardiac Surgery

to prove a difference. A single meta-analysis only just managed to show a significant difference (47), but other analyses, comprising just as many or more trials and patients, failed to prove OPCAB superior (21). Therefore, until the time of the publication of the ROOBY-trial (14), evidence was ambiguous. In the ROOBY trial, however, the trend was opposite that of most earlier studies with 1.3% strokes in the OPCAB-group and 0.7% in the CCABG-group (p=0.28). In view of the large volume of this trial compared to all the other trials, it can no longer be stated that there is a clear trend in favour of OPCAB to reduce the rate of peri-operative strokes in younger, low-risk patients. It is, however, worth noting, that the OPCAB technique is still being developed in order to reduce stroke rate. An increasing number of surgeons favour a "no-touch-aorta" technique, placing proximal anastomoses end-to-side in a mammary artery graft rather than on the aorta itself. In addition, some centers aim to reduce the risk of embolisation due to atrial fibrillation by ligating the left atrial appendage. Excellent results have been produced, but not tested in randomized trials.

Several randomized trials have used neuro-psychological or neuro-cognitive tests to detect perioperative cerebral damage lesser than overt stroke. In some of these studies, early postoperative testing favoured OPCAB (48-49) while others found no significant difference (50-53). Zamvar and coworkers, only including patients with triple-vessel disease, performed a battery of neuro-cognitive tests one week and ten weeks postoperatively, comparing with preoperative test results. At both occasions, they found a significantly higher degree of neuro-

In the Octopus trial (6, 41, 49), a significant difference in favour of OPCAB was found after three months but not after one year nor after five years of follow-up. At five years follow-up, a more than fifty per cent decline in scores at neuro-cognitive testing was found in both groups, illustrating the fact that patients with ischemic heart disease in general have an increased risk of neurocognitive decline. A similar decline has been documented after three

Surrogate end-points of brain damage are often used in randomized trials comparing OPCAB with CCABG. These include release of the S-100 peptide and detection of High Intensity Transcranial Doppler Signals (HITS) as well as changes in serum concentrations of

When S-100 is detected in peripheral blood, it is seen as a marker of damage to, and increased permeability of, the blood-brain barrier. There is good evidence from randomized controlled trials that the increase of S-100 is higher after CCABG than after OPCAB (48, 51, 56). In two out of three studies these increases are compared to the results of postoperative, neurocognitive tests, but none of the studies showed any correlation between S-100 levels and neurocognitive function. In one of the studies one patient suffered a major stroke resulting in paralysis of an arm and a leg without a major increase in blood concentrations

Characteristic high-intensity signals – HITS - can be detected by trans-cranial measurement of Doppler signals from the medial cerebral artery. The amount of HITS increase during manipulation of the aorta, especially during cannulation, clamping, and declamping. A lower number of HITS are observed at the beginning of cardiopulmonary by-pass. It is not clear, to what extent HITS represent particulate emboli being released from vessel walls, tubes or filters and what proportion of HITS are being generated by gaseous microemboli and turbulence. Several studies have demonstrated a larger amount of HITS in patients

cognitive dysfunction in CCABG-patients than in OPCAB-patients (54).

of S-100. Hence, the clinical significance of relase of S-100 is uncertain.

*Neurocognitive dysfunction* 

different hormones.

years in a non- surgical control group (55).

Transient or permanent renal impairment are well known complications to cardiac surgery (58). This risk has be attributed to the systemic, inflammatory response, hypoperfusion of the kidneys during operation and, possibly, the non-pulsatile nature of flow during cardiopulmonary by-pass (59).

Clinically significant, new onset renal failure – defined either as need for dialysis or by increase in biochemical markers to pathological levels – occur at a rate of approximately 1-2 per cent of the low-risk patients typically included in randomized, controlled trials. None of these studies have, therefore, had the statistical strength to detect a difference in the incidence of this end-point between patients operated with OPCAB or CCABG. Even in a large meta-analysis by Cheng et al (21) showing an odds ratio of 0.58 in favour of OPCAB the confidence limits were too wide to allow statistical significance.

On the other hand, when comparing biochemical markers of sub-clinical renal damage, evidence from several clinical trials is in favour of OPCAB (11, 60-61). This difference is clear whether glomerular or tubular damage is compared (60). In one study, the difference between creatinine clearance after CCABG compared to OPCAB was especially high in patients with diabetes, hypertension and heart failure (11). In one trial, comparing patients operated using pulsatile flow in the cardiopulmonary by-pass circuit, no difference in postoperative renal function was found between patients operated with OPCAB and CCABG. This finding seems to confirm the theory that non-pulsatile flow contributes to the subclinical renal impairment often seen after cardiac surgery using cardiopulmonary by-pass (61).

### **3.6 Lung function**

During cardiopulmonary by-pass, ventilation is commonly stopped to prevent the motion of the lungs interfering with surgery. During the early postoperative period patients who have

Current Evidence of On-Pump Versus Off-Pump Coronary Artery By-Pass Surgery 173

this inflammatory over-activation can be harmful and lead to organ failure and infections. No definitive coupling has, however been made in coronary artery by-pass patients between

Similarly, oxidative stress is known to be higher in patients undergoing cardiopulmonary by-pass. Theoretically, this may cause tissue damage, but no practical clinical consequence

Transfusions have been shown to be associated with substantial incremental increases in risks of mortality and morbidity for patients undergoing cardiac surgery. There is good evidence from a number of large, randomized trials that blood loss and need for transfusions is lower after OPCAB than after CCABG (7,15, 24, 45, 74-76). This finding is often explained by the activation and subsequent deactivation of platelets and humoral coagulation factors by the non-biological surfaces of the cardiopulmonary by-pass circuit. The alpha granules of the platelets are being depleted and the platelet count is reduced by

Some characteristics of the study protocols may, however, influence these results. Typically, different protocols for heparinization and reversion with protamine are used for the study groups, increasing bleeding tendency in the CCABG-groups. In addition, some studies apply a fixed value of haematocrit as an indication for transfusion. Because of dilution caused by the priming volume of the cardiopulmonary by-pass circuit this will increase the risk of transfusion in the CCABG-group compared to the OPCAB-group, even if this

Some of the clinical trials have covered heath economic analyses up to twelve months after surgery. All these studies find OPCAB to be less costly while providing a similar gain of Quality Adjusted Life Years (12-13, 24, 29, 50). As an example, the Octopus study (24) found costs of OPCAB to be \$13.069 versus \$14.908 (P<0,01) at one year follow up for a one year QALY of 0,83 in the CCABG group versus 0,82 in the OPCAB group. Long term data on

In conclusion, this review of currently published randomized controlled trials comparing



outcomes after OPCAB and CCABG resulted in the following findings:

OPCAB, but not in very experienced centres.

inflammatory markers and clinical outcome.

dilution. Also fibrinolytic cascades are activated.

dilution were better treated using diuretics.

**3.10 Cost-effectiveness** 

**4. Summary** 

health economics are not available.

has been proven in patients (74).

**3.9 Blood loss and coagulation** 

undergone cardiac surgery are prone to develop atelectasis. Theoretically, this may be prevented by OPCAB where the lungs are continuously ventilated.

Most of the authors addressing this question, found that postoperative ventilation times were longer for patients who underwent CCABG than for those who underwent OPCAB. There is good evidence from a meta-analysis for a lower incidence of chest infections and shorter postoperative need for ventilator assistance after OPCAB (21), although one study of low-risk patients contradicts this finding (23). Most of these studies may be biased by the fact that the staff members deciding the time when the patients should be weaned from the ventilator were not blinded with regard to the type of operation that had been performed. On the other hand, evidence is strengthened by the fact that the one study in which the staff was indeed blinded also found a shorter postoperative need of ventilation in the OPCAB group (12).

In two trials, patients with chronic obstructive pulmonary disease were studied specifically. In one of these studies, a significantly higher postoperative decrease in lung function was found among post-CCABG patients (62). In the other study, a shorter time to extubation and shorter stay in intensive care unit was found among OPCAB patients (63). Also, in a study of patients with recent myocardial infarction, a shorter ventilation time was documented for OPCAB-patients compared to CCABG-patients (32).

It has been suggested, that the mechanism behind impaired lung function after CCABG was changes in alveolar gas exchange as a result of increased interstitial oedema. This effect has, however, been specifically addressed by several studies finding that this effect is comparable in OPCAB and CCABG-patients and most significant during the first few postoperative hours (23, 42, 64-65).In a randomized comparison of patients with single- and double-vessel disease, a significantly higher veno-arterial shunting was found after cardiopulmonary by-pass (23). It is still unknown whether this result can be generalized to patients with triple vessel disease where the OPCAB-technique is complicated by the need to manipulate the heart.

### **3.7 Gastro-intestinal complications**

There is evidence from a single, large, randomized trial that the risk of gastro-intestinal complications - including ischaemic bowel, hepatic failure, gastric bleeding, perforated duodenal ulcer, acute cholecystitis, and acute pancreatitis - is higher after CCABG than after OPCAB (66). This study, however, excluded patients needing grafts to the circumflex territory. This selection can be expected to favour OPCAB. Other, larger, randomized trials either do not find this difference or do not report this endpoint (6-7, 12-14).

#### **3.8 Inflammatory response**

A generalized inflammatory response is activated by any sort of surgery, but is aggravated by cardio-pulmonary by-pass. The blood–air interface and the contact between the blood and the artificial surfaces of the CPB circuit play important roles. Cooling and heating as well as ischemia and reperfusion of the myocardium are other factors that tend to activate a systemic inflammatory response.

The inflammatory response includes both humoral and cellular elements. Randomized comparisons between CCABG and OPCAB shows the CCABG patients to have increased serum-levels of a multitude of different substances including tumor necrosis factor-alpha, interleukins 6 and 8, selectin, c-reactive protein, intracellular adhesion molecule – 1, and vascular endothelial growth factor (39,67-72). Also, the expression of a scavenger molecule on monocytes is significantly higher in "on-pump" patients (73). It has been proposed that this inflammatory over-activation can be harmful and lead to organ failure and infections. No definitive coupling has, however been made in coronary artery by-pass patients between inflammatory markers and clinical outcome.

Similarly, oxidative stress is known to be higher in patients undergoing cardiopulmonary by-pass. Theoretically, this may cause tissue damage, but no practical clinical consequence has been proven in patients (74).
