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Ann Thorac Surg 1999;68:52-56
© 1999 The Society of Thoracic Surgeons

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Original Articles

Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury

^a Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People’s Republic of China
^b Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People’s Republic of China

Address reprint requests to Dr S. Wan, Division of Cardiothoracic Surgery, Dept of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong
e-mail: swan{at}cuhk.edu.hk

Presented at the 19th Annual San Diego Cardiothoracic Surgery Symposium "Pathophysiology and Techniques of Cardiopulmonary Bypass," San Diego, CA, Feb 18–20, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Proinflammatory cytokines play a key role in the inflammatory cascade after cardiopulmonary bypass and may induce cardiac dysfunction. We compared the production of cytokines and the degree of postoperative myocardial injury in patients with multivessel coronary artery disease undergoing coronary artery bypass grafting through median sternotomy with or without cardiopulmonary bypass.

Methods. Forty-four consecutive patients were studied. Patients were selected for off-pump coronary artery bypass grafting whenever complete revascularization was technically feasible. There were no differences between the two groups with respect to age, sex, symptoms, or functional class. Plasma levels of tumor necrosis factor-, interleukin (IL)-6, IL-8, and IL-10 were measured before the operation, at the end of the procedure, and 2, 4, 8, 24, and 48 hours thereafter. Levels of the MB isoenzyme of creatine kinase and cardiac troponin-I were also measured after the operation.

Results. The number of grafts was 2 ± 0.7 in the off-pump group (n = 18) and 3 ± 0.8 in the cardiopulmonary bypass group (n = 26). There were no deaths or major complications in either group. Levels of tumor necrosis factor- were low in both groups. No significant intergroup differences were noted regarding serial IL-6 measurements. However, IL-8 and IL-10 levels after the operation were lower in the off-pump group (IL-8, 4 ± 1 versus 38 ± 12 pg/mL, p < 0.01; IL-10, 5 ± 2 versus 191 ± 33 pg/mL, p < 0.001). Whereas postoperative creatine kinase-MB values were similar in the two groups, cardiac troponin-I levels were significantly lower in the off-pump group (8 hours, p < 0.005; 24 hours, p < 0.02, respectively). Moreover, cardiac troponin-I values 24 hours after operation correlated strongly with IL-8 levels (r = 0.61, p < 0.005), indicating that the degree of myocardial injury may be related to IL-8 production.

Conclusions. Compared with conventional coronary artery bypass grafting, coronary revascularization without cardiopulmonary bypass is associated with reduced cytokine responses and less myocardial injury.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Cardiopulmonary bypass (CPB) has long been recognized as one of the major causes of a complex systemic inflammatory response, which may contribute to postoperative complications and even multiple organ dysfunction [1]. Therefore, avoiding the use of CPB ("off-pump") during coronary artery bypass grafting (CABG) is believed to be associated with less risk of postoperative morbidity. Indeed, minimally invasive direct CABG has been shown to be beneficial [2], even in high-risk patients with multivessel coronary artery disease [3, 4], and to be associated with reduced myocardial injury [5]. Off-pump CABG through median sternotomy may also result in less incidence of postoperative arrhythmia and pulmonary and neurologic complications compared with the conventional procedure [6].

Recent investigations have indicated that cytokines play a key role in the inflammatory cascade associated with CPB [7]. Proinflammatory cytokines, such as tumor necrosis factor- (TNF-), interleukin (IL)-6, and IL-8, may contribute to myocardial dysfunction [8] and hemodynamic instability after clinical CPB [7]. Moreover, the myocardium is capable of synthesizing TNF-, IL-6, and IL-8 during CPB [9].

To improve our understanding of the potential benefits of off-pump procedures, we conducted a prospective study to compare the production of cytokines in patients undergoing CABG through median sternotomy, with or without CPB.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
With ethical committee approval, 44 consecutive patients with multivessel coronary artery disease undergoing CABG were studied. Written informed consents were obtained in all cases. Patients undergoing redo or emergency procedures, having infectious disease before operation, or preoperatively using steroids were excluded from the study. Patients were selected for off-pump CABG only when complete revascularization was technically feasible. Because the study started at the learning period of our off-pump practice, we had decided that whenever a distal circumflex coronary artery needed to be grafted, the patient should be included in the CPB group. There were no differences between the two groups of patients with respect to age, sex, symptoms, or functional class (Table 1).

Cardiopulmonary bypass technique
The extracorporeal circuit consisted of a roller pump (Sarns 9000, 3M Health Care, Ann Arbor, MI) and a membrane oxygenator (Turbo; 3M Health Care). Standard systemic heparinization (3 mg/kg) was performed, and an activated clotting time of greater than 480 seconds was maintained during CPB. The pump flow was set at 2.4 L · min^-1 · m^-2. Patients were cooled to 34°C during CPB, and they received intermittent antegrade normothermic blood cardioplegia, which was a mixture of 400 to 600 mL of oxygenated blood with graduated doses of potassium-magnesium solution [10]. On discontinuation of CPB, heparin was neutralized with protamine sulfate.

Off-pump technique
Traction sutures were applied to the pericardial edges, displacing the heart anteriorly. For exposure of the left anterior descending coronary artery or its diagonal branches, additional pericardial traction sutures were inserted anterior to the left phrenic nerve to rotate the heart, and a moist sponge was placed behind its laterodorsal aspect, bringing the coronary artery into the operative field. For exposure of obtuse marginal or right coronary branches, two wet cotton tapes were passed through the transverse sinus with their right ends secured to the surgical drapes. The two loose lengths of tape were then used to lift and rotate the heart toward the surgeon, as well as to stabilize the coronary artery. Patients were heparinized (1 mg/kg) and two 4-0 Prolene (Ethicon, Somerville, NJ) sutures were used to temporarily occlude the coronary artery on either side of the anastomosis site. Heparin was neutralized with protamine sulfate after all anastomoses were completed.

Cytokine and biochemical measurements
Blood samples were collected from each patient before the operation, at the end of the procedure, and 2, 4, 8, 24, and 48 hours thereafter. Samples were immediately cooled to 4°C and centrifuged (3,000 g for 10 minutes at 4°C). Plasma was stored at -70°C until assay. Levels of TNF-, IL-6, IL-8, and IL-10 were determined by means of commercially available enzyme-linked immunosorbent assays (R & D Systems, Minneapolis, MN). Plasma levels of the MB isoenzyme of creatine kinase were measured by a microparticle enzyme immunoassay (IMx STAT System, Abbott Laboratories, Abbott Park, IL). In addition, cardiac troponin-I (cTnI), a highly specific marker of myocardial injury, was also measured using direct chemiluminometric technology (Automated Chemiluminescence System: ACS-180, Chiron Diagnostics, East Walpole, MA).

Statistical analysis
A two-way analysis of variance for repeated measures was used, followed by Mann-Whitney U test for comparison of cytokine and cTnI levels between two groups at each time. The Spearman correlative coefficient test was used to explore the relationship between cytokine levels and postoperative cTnI values. Data were stored and analyzed using standard computer software (StatView Software, Brainpower Inc., Calabasas, CA). Values of cytokines and other biochemical parameters are presented as mean ± standard error of the mean. Clinical data are shown as mean ± standard deviation. Probability values less than 0.05 were considered to indicate statistical significance.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Eighteen patients underwent off-pump CABG and 26 patients underwent CABG with the use of CPB. Duration of CPB and aortic cross-clamping in the CPB group was 92 ± 25 and 49 ± 18 minutes, respectively. Complete revascularization was achieved in all patients. The number of grafts was 2 ± 0.7 in the off-pump group and 3 ± 0.8 in the CPB group. All patients in the off-pump group received intraoperative angiographic assessment [11], and all anastomoses were confirmed widely patent with excellent distal runoff. One patient in each group required reexploration for bleeding after operation. There was no death or major complication in either group.

Levels of TNF- were detected in 13 patients (50%) in the CPB group and in 3 patients (17%) in the off-pump group transiently after reperfusion to the myocardium. However, they were equally low in both groups. The mean values of TNF- never exceeded 10 pg/mL in either group throughout the study period. Levels of IL-6 increased in both groups after the operation. Nevertheless, no significant differences were noted between the two groups regarding serial IL-6 measurements (Fig 1). Levels of IL-8 were significantly elevated in the CPB group after the operation, but not in the off-pump group (Fig 1). Production of IL-10 shortly after operation was also markedly increased in the CPB group but remained low in the off-pump group (Fig 1).

View larger version (16K): [in this window] [in a new window]   Fig 1. Plasma levels of interleukin (IL)-6, IL-8, and IL-10 in patients undergoing coronary artery bypass grafting through median sternotomy with or without cardiopulmonary bypass (CPB). Data are mean ± standard error of the mean. (BS = before operation; End = the end of operation; 2h, 4h, 8h, 24h, 48h = time points after the end of operation.)

View larger version (18K): [in this window] [in a new window]   Fig 2. Plasma levels of the MB isoenzyme of creatine kinase (CK-MB) in patients undergoing coronary artery bypass grafting through median sternotomy with or without cardiopulmonary bypass (CPB). Data are mean ± standard error of the mean.

View larger version (17K): [in this window] [in a new window]   Fig 3. Plasma levels of cardiac troponin-I (cTnI) in patients undergoing coronary artery bypass grafting through median sternotomy with or without cardiopulmonary bypass (CPB). Data are mean ± standard error of the mean. (Sampling time points: see legend of Fig 1.)

View larger version (17K): [in this window] [in a new window]   Fig 4. Relationship between cardiac troponin-I (cTnI) values 24 hours after operation and interleukin-8 (IL-8) levels 4 hours after operation in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Although systemic levels of TNF- were low in both groups in the present study, TNF- could be detected more frequently in the CPB group than in the off-pump group, which is in agreement with some recent observations suggesting TNF- may be involved in inducing the adverse effects of CPB [7, 12]. The systemic level of TNF- may not actually reflect its local concentration in the myocardium, which is a major source of TNF- after reperfusion [9]. The exact role of TNF- in myocardial injury associated with CPB, therefore, still needs to be further defined.

To date, the role of IL-6 in the inflammatory reactions after cardiac operations is far from completely understood. Interleukin-6 is thought to be a marker rather than a critical mediator of injury [7], and recent data even indicated that IL-6 might have antiinflammatory effects through direct suppression of TNF- and IL-1, as well as through the induction of their natural antagonists [13]. Conversely, however, IL-6 is also thought to play a role in neutrophil-mediated myocardial ischemia-reperfusion injury [14]. In patients undergoing off-pump single-vessel coronary grafting through median sternotomy, similar IL-6 production was noted as in those undergoing multivessel CABG with CPB [15]. Our observations also support the hypothesis that CPB is not the only trigger of IL-6 release during multiple coronary grafting. Production of IL-6 might be influenced by the degree of surgical trauma (ie, surgical incision) as well as by CPB-related factors. Nevertheless, IL-6 is unlikely to be a potent mediator inducing myocardial injury.

Interleukin-8 is a crucial chemokine known to attract and activate neutrophils [16] as well as T lymphocytes, and to control their trafficking [17]. In animal models, the release of IL-8 is induced only after reperfusion of the ischemic myocardium [18, 19]. Clinical studies have also documented that the myocardium is a major source of IL-8 during reperfusion after a longer duration of ischemia [20, 21], or after acute myocardial infarction [9, 22]. Furthermore, administration of anti–IL-8 antibodies in rabbits prevents pulmonary [23] or cardiac [24] ischemia-reperfusion injury, or acid-induced lung injury [25]. Inasmuch as neutrophil activation is an important early step in ischemia-reperfusion injury, the lower myocardial injury seen after off-pump procedures could be explained by the lower IL-8 production associated with the procedure. In the present study, the strong correlation between IL-8 and cTnI levels confirms that IL-8 is a critical mediator in inducing myocardial injury. Whether neutralizing IL-8 could result in improved myocardial preservation during CPB, as suggested by some experimental studies [23, 24], warrants clinical investigation.

It is noteworthy that cytokines are likely to act both individually and within a complex network of interrelated and interacting signals [7]. The lower release of IL-10 during off-pump operation may be related to the reduced production of IL-8. Therefore, the balance between the proinflammatory and antiinflammatory responses may be even more crucial in reducing the damaging effects of CPB.

The cTnI values in our study were somewhat higher than those in the previous reports [5, 26], which may be related to different assay technology and kits used. The ACS method applied in the present study detects free cTnI in addition to the complex forms. Because there was no electrocardiographic or creatine kinase-MB evidence for postoperative myocardial infarction, the diagnostic cutoff cTnI values measured by ACS are yet to be determined. A detailed analysis of free cTnI generation during CABG is currently ongoing in our institution.

Finally, it should be noted that apart from CPB itself, the intergroup differences might also be influenced by different surgical maneuvers (ie, cold cardioplegic arrest and global ischemia in the CPB setting). The purpose of the present study was to improve our understanding of the rationale behind off-pump CABG, rather than to advocate a specific technique. Our study was not randomized, nor was the sample size large enough to document any clinical outcome variables, such as time on ventilator or length of intensive care unit stay. As the off-pump technology evolves, a randomized larger trial would be required to address these issues.

In conclusion, avoiding the use of CPB during multivessel CABG reduces cytokine response, as manifested by the lower release of IL-8 and IL-10. Less myocardial injury is also observed after off-pump operation, which is directly related to the less pronounced IL-8 production.

	Acknowledgments

 
This study was supported by Research Grant Council Earmarked grant (CUHK 280/96M), Hong Kong.

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				P. Biglioli, A. Cannata, F. Alamanni, M. Naliato, M. Porqueddu, M. Zanobini, E. Tremoli, and A. Parolari Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress Eur. J. Cardiothorac. Surg., August 1, 2003; 24(2): 260 - 269. [Abstract] [Full Text] [PDF]

				P. Giomarelli, S. Scolletta, E. Borrelli, and B. Biagioli Myocardial and lung injury after cardiopulmonary bypass: role of interleukin (IL)-10 Ann. Thorac. Surg., July 1, 2003; 76(1): 117 - 123. [Abstract] [Full Text] [PDF]

				N. B. Aydin, H. Gercekoglu, B. Aksu, V. Ozkul, T. Sener, I. Kiygil, T. Turkoglu, S. Cimen, F. Babacan, and M. Demirtas Endotoxemia in coronary artery bypass surgery: A comparison of the off-pump technique and conventional cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2003; 125(4): 843 - 848. [Abstract] [Full Text] [PDF]

				M. Czerny, D. Zimpfer, J. Kilo, R. Gottardi, D. Dunkler, E. Wolner, and M. Grimm Coronary reoperations: recurrence of angina and clinical outcome with and without cardiopulmonary bypass Ann. Thorac. Surg., March 1, 2003; 75(3): 847 - 852. [Abstract] [Full Text] [PDF]

				A. M. Calafiore, M. Di Mauro, C. Canosa, G. Di Giammarco, A. L. Iaco, and M. Contini Early and late outcome of myocardial revascularization with and without cardiopulmonary bypass in high risk patients (EuroSCORE>=6) Eur. J. Cardiothorac. Surg., March 1, 2003; 23(3): 360 - 367. [Abstract] [Full Text] [PDF]

				G. S. Musleh, N. C. Patel, A. D. Grayson, D. M. Pullan, D. J.M. Keenan, B. M. Fabri, and R. Hasan Off-pump coronary artery bypass surgery does not reduce gastrointestinal complications Eur. J. Cardiothorac. Surg., February 1, 2003; 23(2): 170 - 174. [Abstract] [Full Text] [PDF]

				J. H. Levy and K. A. Tanaka Inflammatory response to cardiopulmonary bypass Ann. Thorac. Surg., February 1, 2003; 75(2): S715 - 720. [Abstract] [Full Text] [PDF]