Cytokine Responses to Cardiopulmonary Bypass: Lessons Learned From Cardiac Transplantation

CURRENT REVIEWS

Cytokine Responses to Cardiopulmonary Bypass: Lessons Learned From Cardiac Transplantation Song Wan, MD, Jean-Louis LeClerc, MD, and Jean-Louis Vincent, MD, PhD Departments of Cardiac Surgery and Intensive Care, University Hospital Erasme, Free University of Brussels, Brussels, Belgium

Background. A growing body of evidence relates the release during cardiopulmonary bypass (CPB) of proinflammatory cytokines, such as tumor necrosis factor-a, interleukin (IL)-6, and IL-8, to the postoperative systemic inflammatory response syndrome. Antiinflammatory cytokines, such as IL-10, however, may also play an important role in limiting these complications. Methods. The English-language literature was reviewed. Emphasis was placed on cytokine responses during clinical CPB for cardiac operations and, in particular, for heart and heart-lung transplantation. Results. The recent data indicate that (1) although cytokine release can be triggered by many factors during CPB, ischemia-reperfusion may play the most important

role; (2) the levels of tumor necrosis factor-a, IL-6, and IL-8 are correlated with the duration of cardiac ischemia and the myocardium is a major source of these three cytokines during CPB; (3) IL-10 levels are correlated with the duration of CPB and the liver is a major source of IL-10 during CPB; and (4) steroid pretreatment is an effective intervention to inhibit the release of proinflammatory cytokines and enhance IL-10 production. Conclusions. The improved knowledge of cytokine responses to CPB may help to develop interventions aimed at reducing postoperative morbidity and mortality. (Ann Thorac Surg 1997;63:269 –76) © 1997 by The Society of Thoracic Surgeons

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profoundly alter the peripheral circulation, reducing vascular tone and thus, resulting in postoperative low systemic vascular resistance [13]. Cytokines also exert a direct damaging effect to the other organs and contribute to the development of multiorgan failure [24]. Finally, the release of cytokines under CPB conditions may be involved in immunologic alterations that can develop in the postoperative period [25, 26]. Once the release of cytokines during CPB has been described, it becomes important to explore the mechanisms involved. A better understanding of this process may lead us to consider some form of intervention. The aim of the present article is to review some important elements implicated in the cytokine response to CPB, with particular reference to patients undergoing cardiac transplantation.

lthough cardiopulmonary bypass (CPB) is fundamental for cardiac operations, it is associated with substantial postoperative morbidity [1]. Complement activation has been incriminated for many years [2, 3], although recent studies question its involvement in the development of acute lung injury after CPB [4, 5]. Considerable interest has been recently focused on the involvement of cytokine network during and after CPB [6 –19]. The release of proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a) [12, 13], interleukin (IL)-1b [13], and IL-8 [14 –16], has been associated with the development of complications after CPB. Interestingly, the antiinflammatory cytokine IL-10 is also released during CPB [17–19]. Hence, the inflammatory response to CPB is an extremely complex phenomenon that is far from completely understood. Table 1 presents a brief overview of some recent clinical studies on cytokine response to CPB. The release of cytokines during CPB can have deleterious effects on the heart and on other organs. The proinflammatory cytokines can significantly alter myocardial contractility [16, 20, 21]. Importantly, these cytokines do not need to circulate, as the myocardium is capable of synthesizing biologically active TNF-a [22, 23]. Local release of TNF in the myocardium may be involved in the postischemic myocardial depression (“stunning”) after CPB [21]. Some of these effects may be mediated by an increased production of nitric oxide within cardiac myocytes [20, 21]. Proinflammatory cytokines may also Address reprint requests to Dr Vincent, Department of Intensive Care, University Hospital Erasme, Free University of Brussels, Route de Lennik 808, B-1070, Brussels, Belgium.

© 1997 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

The Role of Endotoxin Release Cardiopulmonary bypass can trigger the release of endotoxin [6, 27–30], which can act as a powerful trigger for release of cytokines such as TNF-a [6, 30, 31]. Circulating endotoxin can appear immediately after the beginning of CPB [27] and the gut is its most likely source, as CPB has been shown to impair gut barrier function and lead to increase gut permeability [32, 33]. Although endotoxin is a potent trigger of the inflammatory cascade of mediators, the role of endotoxin in the release of cytokines during CPB is not straightforward. For instance, Dauber and associates [34] found that bypass-induced coronary and pulmonary vascular injury correlated with peak circulating TNF levels, but not with endotoxin levels, 0003-4975/97/$17.00 PII S0003-4975(96)00931-9

Artery PA/artery Artery

Vein 7 ? 5 Artery 7 Artery 6 LA/RA 1 artery 2 1 8 Artery 6 PA/PV/ 2 1 10 CS 1 artery Artery 5 Artery 8 CS 2 RA/skeletal 2 muscle Artery 5 Artery 6 ? 5

LA/RA Artery

PA

Artery

Artery Artery PA/CS/ artery Artery Artery/hepatic vein

Jansen et al, 1992 [6] Butler et al, 1992 {8] Jorens et al, 1993 [7]

Steinberg et al, 1993 [9] Kalfin et al, 1993 [10]a Finn et al, 1993 [14] Kawamura et al, 1993 [15] Gu et al, 1993 [58] Millar et al, 1993 [55] Hennein et al, 1994 [16]

Te Velthuis et al, 1995 [30] Steinberg et al, 1995 [56] Engelman et al, 1995 [63]a

Menasche´ et al, 1995 [53]a Teoh et al, 1995 [65]a

McBride et al, 1995 [44]

Tabardel et al, 1996 [17]

Wan et al, 1996 [18] Wan et al, 1996 [50] Wan et al, 1996 [23]

Normothermic CPB;

b

? ? In 50% of patients No In 50% of patients ?

TNF-a, IL-1b, IL-6 TNF-a, IL-1b, IL-6, IL-8 IL-8 IL-8 mRNA TNF-a TNF-a, IL-1b, IL-6, IL-8 IL-1b, IL-8

TNF-a, IL-8, IL-10 IL-4, IL-10

TNF-a, IL-6, IL-8, IL-10 TNF-a, IL-6, IL-8, IL-10 TNF-a, IL-6, IL-8, IL-10

TNF-a, IL-1, IL-8, IL-12, IL-10b IL-1b, TNF-a, IL-8, IL-10

IL-8 TNF, IL-6, IL-8

IL 5 interleukin;

IL-10 correlated with hypothermia Liver release IL-10, but not IL-4

IT 5 ischemic

Longer IT, greater TNF/IL-6/IL-8 release Earlier steroids—TNF/IL-8 (2) but IL-10 (1) Myocardium release TNF-a, IL-6, IL-8

Steroid-pretreatment increase IL-10

Pro- and antiinflammatory cytokine balance

Intraoperative IL-8 release in CPBa Benefits of steroid-pretreatment in CPBa

Elderly patients— higher TNF-a/endotoxin Heparin-bonded circuits reduce IL-6/IL-8 Steroid-pretreatment inhibit inflammation

Higher cytokines-CPBa—vasodilatation IL-6/IL-8 elevated Higher IL-8 in HTx—myocardial injury IL-8 production from the myocardium

Nonsignificant elevation, except IL-6 Cell-associated IL-1/IL-8 expression Only IL-8 increased, correlated with CPB time IL-6/IL-8 correlated with IT and CK-MB Heparin-coated circuits reduce TNF Hemofiltration may remove TNF Correlated with IT and cardiac function

Endotoxin induce TNF-a release IL-6 was detected, but not IL-1 Lower IL-8, same degree of lung injury

Lower TNF— better clinical outcome

IL-1 was detected, but not TNF

Main Results and Comments

HTx 5 heart transplantation;

No In all patients

In 66% of patients In HTx group In all patients No

No No ? In all patients

IL-1b, IL-2, IL-4, IL-6, TNF-a IL-1b, IL-8 (in leukocytes) IL-a, IL-1b, TNF-a, IL-8 IL-6, IL-8, TNF-a TNF-a TNF, IL-6, IL-8 TNF-a, IL-6, IL-8

Interleukin-1 receptor antagonist and TNF soluble receptor-1 and -2 were also measured.

Pediatric Adults, routine op

HTx/routine op HTx, HLTx Adults, routine op

Adults, routine op

Adults, routine op

Adults, routine op Adults, routine op

Adults, routine op Adults, routine op Adults, routine op

In 50% of patients No No In 50% of patients No No ? ? In all patients ? No

TNF-a TNF-a IL-1, IL-6 IL-8

No

Steroid Administration

IL-1, TNF

Cytokine Measurements

CK-MB 5 creatine kinase-MB; CPB 5 cardiopulmonary bypass; CS 5 coronary sinus; HLTx 5 heart-lung transplantation; time; LA/RA 5 left/right atrium; op 5 operation; PA/PV 5 pulmonary artery/vein; TNF 5 tumor necrosis factor.

a

10 7

10 10 7

7

7

3 8

op

op op

op op

Adults, routine op Adults, routine op HTx/routine op Pediatric

Adults, routine Adults, routine Pediatric Adults, routine Adults, routine Pediatric Adults, routine

Adults, routine op Adults, routine op Adults, routine op

Adults, routine op

Adults, routine op

Patient Characteristics

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Seghaye et al, 1996 [19] Wan et al (in press) [49]

Menasche´ et al, 1994 [13]a Frering et al, 1994 [41]a Oz et al, 1995 [46] Burns et al, 1995 [47]

9

Artery 8 8 6

8

No. of Samples

Vein

Sampling Site

Haeffner-Cavaillon et al, 1989 [11] Jansen et al, 1991 [12]

Reference

Table 1. Some Studies on Cytokine Responses During Clinical Cardiopulmonary Bypass

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although both of them were associated with peripheral pump– oxygenator bypass.

The Role of Complement Activation Complement activation during CPB has also been suggested as contributing to the release of cytokines [9 –11]. Complement is activated during CPB by blood–air interfaces or blood–material interaction and formation of heparin–protamine complexes, through either the alternate pathway (after the onset of CPB) or the classic pathway (after the administration of protamine). The degree of complement activation depends on the degree of surgical trauma and the duration of CPB [2, 3]. Ivey and co-workers [35] recently found that IL-8 generation during reperfusion of the ischemic myocardium may be indirectly dependent on complement fragment C5a production. However, IL-8 can be induced only after reperfusion of the ischemic myocardium in rabbits [35] and dogs [36], as well as in humans [37]. The precise role of complement activation as a trigger of cytokine release (including IL-8) under CPB conditions is still unclear.

The Role of Ischemia-Reperfusion and the Relationship With Myocardial Injury Most cases of CPB are associated with aortic crossclamping, which results in global myocardial ischemia, whereas the release of the aortic cross-clamp results in myocardial reperfusion. Lindal and colleagues [38] recently showed in patients undergoing CPB that ischemia is associated with ultrastructural evidence of myocytic and microvascular injury, which seems to be reversible in nature, but subsequent reperfusion leads to more severe myocardial damage. Colletti and co-workers [39] clearly showed in a rat model that hepatic ischemia-reperfusion, in the absence of endotoxin, can induce TNF-a production that further results in pulmonary and hepatic injury. Kukielka and associates [40] recently demonstrated that IL-6 synthesis by the canine myocardium is accelerated by reperfusion. Jansen and colleagues [12] first reported that TNF concentration can be detected only after release of the aortic cross-clamp during clinical CPB. Consistently, the important role of ischemia-reperfusion is supported by some other observations relating the magnitude of proinflammatory cytokine response to the duration of ischemia [15, 16, 18]. Kawamura and co-workers [15] studied 11 patients undergoing valvular operations and found IL-6 and IL-8 levels to be correlated with the duration of aortic cross-clamping and the degree of myocardial injury as reflected by the creatine kinase-MB isoenzyme values. Hennein and colleagues [16] showed in 22 patients undergoing coronary artery bypass grafting (CABG) that the duration of aortic cross-clamping was the only independent predictor of postoperative TNF-a and IL-6 levels. These investigators reported a direct relationship between IL-6 and IL-8 levels and the development of left ventricular wall dyskinesia in the postoperative period [16]. In 10 patients undergoing normother-

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mic CPB, however, Frering and associates [41] failed to observe any significant correlation between IL-6 and IL-8 levels and either the CPB time or the aortic crossclamping time. To further define the influence of the duration of myocardial ischemia on the degree of cytokine release after CPB, we compared the blood cytokine levels in patients undergoing CABG with those undergoing heart transplantation (HTx), in whom the duration of ischemia was much longer. Levels of TNF-a, IL-6, and IL-8, which increased after reperfusion of the myocardium, were much higher in the HTx group than in the CABG group [18]. Moreover, we recently extended these findings to a larger population, including recipients of heart-lung transplantation (HLTx) who had had an even longer ischemic time. Blood sampling schedule, cytokine determination, and data analysis were the same as described previously [18]. Steroids were only given in the HTx and HLTx group, starting 90 minutes after declamping. In contrast to a previous report [16], TNF-a levels did not correlate with the duration of ischemia in the current study at any time point. However, IL-6, IL-8, and IL-10 levels 1 to 2 hours after aortic declamping correlated significantly with the duration of ischemia. Figure 1 shows this correlation 90 minutes after declamping. Peak creatine kinase-MB isoenzyme levels after operation, reflecting the degree of myocardial injury, also correlated with the duration of ischemia (Fig 2). We found a positive correlation between creatine kinase-MB isoenzyme levels and IL-6 levels 90 minutes and 2 hours after declamping, but this correlation was relatively weak (r 5 0.54 and 0.56, respectively, both p , 0.02). Thus, the degree of cytokine production is also related to the degree of myocardial injury during CPB, although this relation remains relatively weak. This observation is not surprising as myocardial injury can be related to regional circulatory disturbances independent of cytokines. Myocardial injury is uncommon in septic shock, although cytokine release can be massive in these conditions.

The Role of Interleukin-10 and the Organ Source of Cytokines The observation of a release of IL-10 during CPB is interesting. Interleukin-10 is known to either directly inhibit the release of proinflammatory cytokines [42, 43], or indirectly exert antiinflammatory effects by triggering the release of IL-1 receptor antagonist and TNF soluble receptors 1 and 2 [44]. However, the production of IL-10 may also be enhanced by proinflammatory cytokines such as TNF-a [45]. We could not find any obvious relation between the levels of IL-10 and the other mediators. In the latter study, we observed that IL-10 levels correlated strongly with the duration of ischemia (Fig 1), but such observation was not apparent in our previous study [18]. This positive relation may have been brought out by the longer duration of CPB in HLTx than in HTx. This begs the question of the source of these cytokines during CPB. Although it is logical to consider the myocardium as an important source, other organs also expe-

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Fig 2. Relationship between peak creatine kinase-MB isoenzyme (CK-MB) values after operation and the ischemic duration in patients undergoing coronary artery bypass grafting (CABG, n 5 20), heart transplantation (HTx, n 5 11), or heart-lung transplantation (HLTx, n 5 5).

Fig 1. Relationship between plasma interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) levels 90 minutes after aortic declamping and the ischemic duration in patients undergoing coronary artery bypass grafting (CABG, n 5 20), heart transplantation (HTx, n 5 11), or heart-lung transplantation (HLTx, n 5 5).

rience ischemia-reperfusion and therefore, may also release cytokines. To define the source of these cytokines, we recently introduced a coronary sinus catheter in patients undergoing CABG. Cytokine levels were simultaneously measured in arterial blood, coronary sinus blood, and mixed venous blood. We found that the myocardium, but not the lungs, is a major source of TNF-a and IL-6 [23]. Furthermore, the heart may also release IL-8 during more severe injury [18, 23, 46]. In fact, Burns and colleagues [47] recently reported that activated local IL-8 gene expression in the myocardium is associated with pediatric CPB. Neither the heart nor the lung, however, is the source of IL-10 [23]. We hypothesize that other organs such as the liver are primarily responsible for IL-10 release during CPB. Le Moine and colleagues [48] reported that the ischemic liver can be an important source of IL-8 and IL-10. In their study, IL-10 levels did not correlate with the duration of ischemia of the liver allografts [48]. Our previous study also found that IL-10 production was similar after HTx and CABG [18], suggesting the mechanism of IL-10 release is different with those proinflammatory cytokines. Accordingly, we recently measured IL-10 levels simultaneously in hepatic venous blood and arterial blood in steroid-pretreated patients undergoing CPB. We observed that the liver is a main source of IL-10 shortly after reperfusion during CPB [49]. By further including data from our previous study [50] of group II patients (6 HTx and 4 HLTx patients), who also received steroid pretreatment, arterial IL-10 levels 1 hour after aortic declamping in these patients were significantly correlated with the duration of CPB (Fig 3).

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Fig 3. Correlation between arterial interleukin-10 (IL-10) levels and the duration of cardiopulmonary bypass (CPB) 1 hour after aortic declamping in steroid-pretreated patients undergoing routine cardiac operations (coronary artery bypass grafting and aortic valve replacement [CABG1AVR]), heart transplantation (HTx), and heart-lung transplantation (HLTx).

The Importance of Temperature The importance of temperature on the degree of mediator release during CPB has been addressed in several studies. Hypothermic (28° to 30°C) conditions have been shown to be associated with a lower cytokine release [13]. Lichtenstein and associates [51] reported that warm aerobic arrest of the heart is safe and effective even in high-risk patients with aortic cross-clamping time longer than 3 hours, and these patients were easily weaned from CPB without inotropic support. However, a randomized clinical study indicated that normothermic (37°C) CPB is associated with a higher incidence of low systemic vascular resistance [52]. Menasche´ and colleagues noted that the production of TNF-a, IL-1b, and IL-6 [13], but not of IL-8 [53], were significantly higher after normothermic CPB than hypothermic CPB. This temperature-dependent release of cytokines was incriminated in greater need for vasopressor support after normothermic CPB [13]. An earlier study [11] also found that IL-1 production is correlated with the increase in patients’ body temperature. On the other hand, Seghaye and colleagues [19] recently reported that hypothermia could also modulate IL-10 release. However, another clinical study [41] did not confirm that differences in temperature during CPB could influence either the production of cytokines (TNF-a, IL-1b, IL-6, and IL-8) or the systemic vascular resistance.

Anticytokine Strategies During Cardiopulmonary Bypass At least some of the anticytokine strategies developed in the sepsis syndrome [54] may also be considered under

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CPB conditions, with the aim to reduce postoperative complications. Millar and associates [55] noted that removal of TNF-a and IL-6 by hemofiltration may have beneficial effects in children undergoing CPB. Steinberg and colleagues [56] found that heparin bonding of the bypass circuits can reduce the release of IL-6 and IL-8, but another Steinberg and associates [9] reported that heparin-coated CPB circuits have no effect on complement activation or cytokine production. Heparin-coated circuits with reduced doses of heparin are not likely to totally prevent the damaging effects of CPB [57]. It may be necessary, however, to maintain standardized systemic heparinization with the use of heparin-coated circuits. Such a protocol has been shown to decrease complement and TNF generation [58] and thereby improve the postoperative recovery of patients [59]. On the other hand, steroid administration has been a topic of intense investigation, which will be summarized in the next section. Aprotinin may present another option to reduce inflammatory response to CPB. Hill and coworkers [60] recently found that low-dose aprotinin was as effective as steroids in inhibiting CPB-induced release of TNF-a.

Steroid Administration Before Cardiopulmonary Bypass Corticosteroids have been administered in cardiac operations for many years [61, 62], but their exact mechanism of action has not been well defined. Steroid administration before CPB has been found to reduce complement activation [29, 63], although this effect has not always been observed [12]. Steroids may also prevent cytokine release. Jansen and colleagues [12] reported that steroid administration before CPB can effectively reduce TNF-a production after reperfusion. These effects were associated with a lower incidence of postoperative hemodynamic instability [12]. High TNF-a levels have been recently related to an altered left ventricular performance in patients after CPB [30]. Engelman and co-workers [63] showed that steroid pretreatment can markedly inhibit the production of IL-1b and IL-8. Tabardel and associates [17] reported that steroid administration before CPB can also increase the release of IL-10. Enhancing the production of IL-10 may bring some beneficial effects not only by inhibiting the release of other proinflammatory cytokines [42, 43], but also by diminishing the immunocyte hyperstimulation under CPB conditions [64]. By inhibition of TNF-a, IL-6, and IL-8, steroid pretreatment can prevent peripheral vasodilation after warm heart operations [65]. However, it has been suggested that steroids may increase endotoxin release [29], which might counterbalance some of their effects. We [50] recently documented that administration of steroids before HTx and HLTx procedures, instead of as usual at the end of CPB, can significantly inhibit TNF-a and IL-8 production but greatly increase the release of IL-10. These results are in agreement with previous studies stressing the crucial importance of the timing of anticytokine interventions [54]. Steroids have also been

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reported to negatively regulate IL-6 production [65]. Interleukin-6 levels are thought to reflect the degree of inflammatory injury after CPB [24]. Interestingly, IL-6 release is not significantly influenced by the timing of steroid administration [50]. Our study also included HLTx patients, and the lung allograft is able to release TNF-a, IL-2, and interferon-g [66, 67]. We noted that IL-8 levels increased much higher in HLTx patients than in HTx patients [50]. A possible explanation is that the longer duration of CPB and ischemia in HLTx than in HTx was associated with a higher cardiac, as well as pulmonary, release of cytokines. The immunomodulating effects of steroids may have beneficial influences on allograft survival in HTx and HLTx patients. In particular, the release of IL-10 may provide benefits for prolonging allograft survival and induce tolerance [68], although a recent study suggested that IL-10 may serve a function in the immune regulation of the infiltrate at sites of inflammation, rather than in immune suppression of the rejection process [69]. Intragraft infusion of another important antiinflammatory cytokine IL-4, but not IL-10, may prolong graft survival [70]. It was recently suggested that steroid pretreatment can increase IL-4 production in vitro [71]. We observed, however, that IL-4 was not significantly released in steroid-pretreated patients during CPB [49]. Further investigations are certainly warranted to explore the pathophysiology involved and thereby improve therapy.

Summary The release of proinflammatory cytokines during and after CPB may play an important role in the deleterious effects of CPB to the heart and other organs. The mechanisms are primarily related to ischemia-reperfusion of the myocardium and also other organs, including the lung, the gut, and the liver. The production of proinflammatory cytokines is correlated with the duration of cardiac ischemia, as the myocardium is a main source of these cytokines during CPB. The production of antiinflammatory cytokine IL-10 is correlated with the duration of CPB and the liver was found to be a major source of IL-10 during CPB. There is also some association between the release of proinflammatory cytokines and the degree of myocardial injury after CPB. A number of anticytokine strategies, including procedures such as hemofiltration, heparin coating of the CPB circuits, or pharmacologic interventions, may be considered to reduce morbidity after CPB. Among these, steroid administration before both hypothermic or normothermic CPB may be a simple, safe, and effective intervention to influence the cytokine responses in open heart operations, not only by inhibiting proinflammatory cytokines TNF-a and IL-8, but also by enhancing the release of antiinflammatory cytokine IL-10. A better understanding of the cytokine responses to CPB may lead to other interventions aimed at reducing the incidence and the severity of postoperative complications by modulating the inflammatory reactions associated with CPB.

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This study was supported by Fondation pour la Chirurgie Cardiaque, Belgium.

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20. 21. 22.

23.

24. 25. 26.

27. 28.

29.

30.

31. 32. 33.

34.

35.

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