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(Circulation. 1995;92:334-340.)
© 1995 American Heart Association, Inc.

Articles

Influence of Temperature on Neutrophil Trafficking During Clinical Cardiopulmonary Bypass

Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90[pt 2]:I-202).

Philippe Menasché, MD, PhD; Jacqueline Peynet, MD; Nicole Haeffner-Cavaillon, PhD; Marie-Paule Carreno, PhD; Thierry de Chaumaray, MD; Valentine Dillisse; Bouchaîb Faris, MD; Armand Piwnica, MD; Gérard Bloch, MD; Alain Tedgui, PhD

From the Department of Cardiovascular Surgery and INSERM U-141, Hôpital Lariboisière, and INSERM U-28, Hôpital Broussais, Paris, France.

Correspondence to Dr Philippe Menasché, Department of Cardiovascular Surgery, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris Cédex 10, France.

	Abstract

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Background The adhesion of neutrophils to endothelial cells and their subsequent transendothelial migration play a major role in inflammatory damage elicited by cardiopulmonary bypass (CPB) because these events are linked to the release of cytotoxic proteases and oxidants. However, the patterns of neutrophil trafficking in relation to systemic temperature during clinical CPB have not yet been characterized.

Methods and Results Twenty case-matched patients undergoing warm (31.8±0.4°C) or cold (26.3±0.5°C, P<.0001 versus warm) bypass were studied. Blood samples were simultaneously collected from the right and left atria before, at the end of, and 30 minutes after CPB. Plasma levels of C3a, P- and E-selectins, elastase, and interleukin-8 were determined by immunoassays. The results demonstrate: (1) a rise in C3a, reflecting complement activation, (2) a fall in soluble E-selectin consistent with an increased adhesiveness of activated neutrophils, (3) a rise in soluble P-selectin expected to enhance endothelial adhesion of these neutrophils, (4) a rise in elastase, suggesting an adhesion-triggered neutrophil degranulation, and finally (5) a rise in interleukin-8 that is likely to promote transendothelial migration of adherent neutrophils. All of these changes occurred in the two groups of patients and were significant compared with prebypass values. However, in none of the groups was there a significant difference between right and left atrial values for any of the markers. The single difference between cold and warm bypass patients was a significant reduction of elastase release in the cold group (P<.001 versus the warm group).

Conclusions Clinical CPB is associated with biological changes suggesting the occurrence of neutrophil trafficking. Hypothermia provides only partial protection through a reduced release of elastase. Overall, these results reinforce the rationale for the development of therapeutic strategies targeted at blunting the neutrophil-mediated component of bypass-induced inflammatory damage.

Key Words: cardiopulmonary bypass • cardioplegia • immune system • leukocytes • endothelin

	Introduction

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There is increasing evidence that neutrophil trafficking is an important contributive factor to inflammatory tissue damage.¹ Trafficking refers to adhesion of neutrophils to endothelial cells, followed by their transendothelial migration or, conversely, by their return into the bloodstream. The deleterious effects of neutrophil adhesion and emigration stem from the link between these events and the release of neutrophil-derived cytotoxic products, in particular oxygen free radicals and proteolytic enzymes.^{2 3}

There is an increasing body of evidence indicating that neutrophils play a pivotal role in the inflammatory response elicited by CPB that is responsible for the common development of postoperative organ dysfunction.^{4 5 6} The recent introduction of warm blood cardioplegia has rekindled an interest in the influence of temperature on this inflammatory response because systemic normothermia is an integral part of the "warm heart surgery" strategy.⁷ The present study, therefore, was designed to characterize the patterns of neutrophil trafficking during clinical CPB and to assess the effect of bypass temperature on these patterns. The results were assessed by measuring circulating levels of C3a, P- and E-selectins, elastase, and IL-8. These markers were selected because they allow tracing of the main steps sequentially involved in neutrophil trafficking. Thus, C3a and selectins (P and E) reflect complement and endothelial cell activation, respectively, both of which are required for neutrophil adhesion; elastase release reflects neutrophil degranulation associated with adhesion to the vascular endothelium, and IL-8 is a marker of transendothelial migration of adherent neutrophils. In addition, all of these inflammatory mediators were simultaneously assayed in the right and left atrial blood to determine the potential contribution of the lungs in their generation.

	Methods

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Study Population
Twenty adult patients undergoing CPB for coronary or valve operation constituted the study population for this study, which was approved by our institutional review committee. The patients were divided into two equal groups according to the core temperature at which CPB was conducted. Ten patients underwent warm CPB (although, in the absence of active warming, their core temperature actually drifted during bypass to a nadir of 31.8±0.4°C). They were case-matched with 10 patients who were cooled to an average of 26.3±0.5°C (P<.0001 versus warm CPB). All patients were weaned from bypass after the core temperature had reached 37°C to 37.5°C. Myocardial protection was achieved with continuous warm blood cardioplegia⁸ and cold crystalloid cardioplegia associated with topical cooling in the warm and cold bypass groups, respectively. Anesthetic and CPB techniques were otherwise similar in the two groups and included, in particular, the use of membrane oxygenators in all patients. Steroids were not used in any patients.

Sample Collection and Measurements
Right and left atrial blood samples were obtained by direct puncture at the following time points: before bypass (immediately after opening of the pericardium), at the end of bypass, and 30 minutes thereafter (after administration of protamine). All samples were immediately centrifuged, stored at -20°C, and assayed for C3a by radioimmunoassay (Amersham Corp) and for P- and E-selectins, elastase, and IL-8 by ELISA (P- and E-selectins and IL-8, British Biotechnology; elastase, Merck Diagnostica). All postbypass data were corrected for hemodilution.

Statistics
Preoperative continuous variables were compared by use of unpaired Student's t tests. Comparisons between groups and within each group were performed by use of two-factor (groupxtime) and one-factor (time) ANOVA, respectively, followed by Dunnett's multiple comparison analysis when significance was indicated. Comparison of data between the two sampling sites was performed by paired Student's t tests at each sampling point. The relation between IL-8 and elastase levels was assessed by Spearman's rank correlation. A probability of less than .05 was considered significant. Results are presented as mean±SEM.

	Results

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Baseline Characteristics
Patients were not randomized but were allocated to warm or cold bypass on the basis of their respective surgeon's practice. However, the case-matching procedure resulted in an equitable distribution of all major clinical characteristics among the two groups (the Table). Likewise, baseline values for all biochemical markers were not significantly different between the two groups.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Comparison of Right Atrial Versus Left Atrial Samples
At all sampling times, right atrial values of the different markers were similar to those simultaneously measured in the left atrial blood. This pattern was found equally in the two groups. Consequently, only right atrial values are reported.

Comparison of Warm Versus Cold CPB
C3a. Baseline values of C3a were 606±57 and 423±63 µg/L in cold and warm CPB patients, respectively (P=NS). Plasma levels of C3a increased approximately sixfold during bypass and continued to rise thereafter, reaching peak values 30 minutes after bypass. Overall, C3a increased significantly (P<.0001) over the study period, but at neither of the two postbypass sampling points did the increase in C3a over prebypass values differ significantly between cold and warm CPB patients.

P-Selectin. There was a significant (P<.0001) increase in P-selectin concentrations over the course of the study. The steepest increase occurred during bypass, after which values tended to level off. The patterns of changes in P-selectin concentrations were not significantly different between the two groups (Fig 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Bar graphs of influence of the temperature of CPB on changes in soluble P-selectin levels. Each group consisted of 10 patients. Error bars indicate SEM.

E-Selectin. E-Selectin levels declined significantly (P<.0001) from baseline values over the bypass period. This decrease was of similar magnitude in the two groups. There was no further change in E-selectin levels between the end of bypass and the 30-minute postbypass study point (Fig 2).

View larger version (21K): [in this window] [in a new window]   Figure 2. Bar graphs of influence of the temperature of CPB on changes in soluble E-selectin levels. Each group consisted of 10 patients. Error bars indicate SEM.

Elastase. Within each group, plasma concentrations of elastase increased significantly (P<.0001) from prebypass values throughout the study period. However, this increase was reduced significantly (P<.001) in cold bypass patients compared with the warm CPB group (Fig 3). The difference in elastase release over time according to temperature was demonstrated further by the significant (P<.0001) interaction between these two factors.

View larger version (21K): [in this window] [in a new window]   Figure 3. Bar graphs of influence of the temperature of CPB on changes in elastase levels. Each group consisted of 10 patients. Error bars indicate SEM.

IL-8. There was an overall significant (P<.0001) increase in IL-8 levels during the study. Although peak values were reached 30 minutes after the end of bypass (Fig 4), post hoc comparisons indicated that the significant rise in IL-8 values occurred during bypass, with no further change between the end of bypass and the 30-minute postbypass time mark. There was no significant difference in IL-8 levels between the warm and cold bypass groups at any sampling point. In the cold CPB group, there was a significant correlation between IL-8 and elastase levels (r=.639, P<.01); a similar relation was not found in the warm CPB group (r=.108, P=.68).

View larger version (22K): [in this window] [in a new window]   Figure 4. Bar graphs of influence of the temperature of CPB on changes in IL-8 levels. Each group consisted of 10 patients. Error bars indicate SEM.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The two major findings of the present study are that (1) CPB is associated with the release of inflammatory mediators reported to be involved in neutrophil trafficking and (2) hypothermia confers only partial protection against this event.

Patterns of Neutrophil Trafficking During CPB
Neutrophil trafficking encompasses adhesion to endothelial cells followed by transendothelial migration (Fig 5).

View larger version (104K): [in this window] [in a new window]   Figure 5. Schematic of neutrophil-endothelial cell interactions. S Lex indicates Sialyl Lewis X determinant; ELAM-1, endothelial leukocyte adhesion molecule–1; and FREE RAD, free radicals.

In this study, changes in the expression of two adhesion-promoting endothelial receptors (P- and E-selectins) could be documented clearly. The increase in P-selectin (also known as GMP-140 or CD62P) is not unexpected because this molecule is rapidly expressed on the surface of endothelial cells and platelets in response to mediators such as histamine, thrombin, and free radicals,⁹ which have been shown to be released during clinical CPB.¹⁰ Although the expression of P-selectin on endothelial cells is reported to be transient, low levels of oxidants can induce a sustained expression over several hours,⁹ which could account for our findings of persistently high levels of this selectin until 30 minutes after the end of bypass. We agree that our data do not allow identification of the respective contributions of endothelial cells and platelets to the rise in circulating P-selectin levels. Actually, these two sources are likely to be relevant to the pathophysiology of bypass, since platelet-bound P-selectin mediates the formation of neutrophil-platelet aggregates that may impede microcirculatory flow¹¹ whereas endothelium-bound P-selectin contributes to the initial step of neutrophil trafficking, that is, neutrophil rolling on endothelial cells.¹² However, the decrease in neutrophil-platelet conjugates reported to occur at the onset of bypass in pediatric patients¹³ suggests that vascular adhesion of neutrophils dependent on endothelial P-selectin may predominate over their binding to activated platelets.

At least two additional endothelial molecules are involved in this neutrophil adhesion process: ICAM-1 and E-selectin (also called endothelial leukocyte adhesion molecule–1 or CD62E). Both are markedly upregulated by cytokines such as TNF and IL-1,¹⁴ which in turn are produced by monocytes/macrophages on stimulation of these cells by mediators such as complement-derived fragments.¹⁵ The occurrence of these events during clinical bypass is demonstrated by our data on C3a, which confirm the widely established fact that CPB causes complement activation,^{16 17} and by previous observations of elevated levels of TNF,^{18 19} IL-1,^{15 19 20 21} and ICAM-1^{22 23} after open-heart procedures. However, because ICAM-1 can be expressed by a wide variety of cells,^{14 24 25} we elected in the present study to assess the changes in circulating levels of E-selectin, which is only shed by activated endothelial cells.^{9 25}

On the basis of these considerations, a rise in soluble E-selectin levels was anticipated. Actually, the opposite was found: soluble E-selectin decreased from baseline values during bypass. There is no obvious explanation for this phenomenon. However, one possibility is that soluble E-selectin, which has been shown to act as a chemoattractant,²⁶ competes with membrane E-selectin for their common neutrophil ligands, thereby contributing to reducing adhesion of neutrophils to the endothelium.²⁷ This hypothesis tends to be supported by additional in vitro experiments suggesting that soluble E-selectin may bind to its ligands released from activated neutrophils (data not shown), thereby reducing the amount of these ligands available for interaction with their endothelial cell surface counterreceptors. Taken together, these results are consistent with an increased adhesive potential of activated neutrophils whose margination through an endothelial E-selectin–dependent interaction would be attenuated by the inhibitory function of soluble E-selectin until the latter mechanism is overwhelmed. This might occur as the expression of endothelial E-selectin increases until it peaks 4 to 6 hours after cytokine stimulation.⁹ This would explain why an increase in blood levels of soluble E-selectin caused by the subsequent shedding of the endothelial form may have been missed in this study because of the time frame of the sampling protocol. Interestingly, a similarly "protective" antiadhesion effect has been attributed to the soluble forms of two other endothelial cell surface receptors, P-selectin²⁸ and ICAM-1.²⁴

Regardless of the precise endothelial molecules involved in neutrophil adhesion, additional evidence for the occurrence of this event comes from our findings of elevated elastase levels at the end of bypass, since margination of neutrophils is linked to their degranulation.³ In fact, a rise in blood level of elastase has been demonstrated repeatedly in patients undergoing open-heart surgery^{22 29 30 31 32} and is likely to play an important role in bypass-induced tissue injury in view of the membrane-damaging effects of this enzyme^{32 33} and the presumably limited protection afforded by naturally circulating antiproteases because of their restricted access to the microenvironment between adherent neutrophils and endothelial cells.³⁴

Neutrophils that have adhered can return into the bloodstream or emigrate into the interstitium, where they amplify inflammatory damage by injuring parenchymal cells directly through the release of proteases and oxidants in their close vicinity.³⁵ Emigration has also been reported to be a critical determinant of protein vascular leakage.¹¹ An important regulator of this transendothelial traffic is IL-8, which, in this study as in others,^{21 32 36} was found to increase significantly during bypass. The interpretation of this increase is not straightforward. Whereas soluble blood-borne IL-8 may behave as an inhibitor of neutrophil-endothelial cell interactions,^{37 38 39} endothelium-bound IL-8 released in response to mediators such as TNF-, IL-1ß, or endotoxin⁴⁰ (all of which have been identified during CPB in humans^{15 18 19 20 21} ) can actually promote neutrophil transmigration by virtue of its ability to both upregulate a specific class of neutrophil adhesion molecules, termed ß2 integrins,^{40 41} and create a transendothelial cell chemotactic gradient.^{38 40} ß2 Integrins, which largely account for endothelial adhesion of neutrophils through interactions with ICAM-1,¹¹ are also required for transmigration,^{11 14 41} as illustrated by the relation between the increased expression of their common CD18 subunit on neutrophils and the intrapulmonary sequestration of these cells.⁴² Thus, in the specific setting of CPB, the previous documentation of an upregulation of neutrophil integrins^{22 43 44} together with the rise in elastase levels argue in favor of an adhesion- and transmigration-promoting role of IL-8.

Overall, these results demonstrate that clinical bypass is associated with biological changes that are likely to set the stage for neutrophil trafficking. Interestingly, in neither of the two groups was there a significant difference between right and left atrial values of the different markers that were assayed. This suggests that, at least within the time frame of our sampling protocol, the lung was a target for rather than a source of inflammatory mediators. This hypothesis is consistent with previous findings that transpulmonary gradients of these mediators occur at the onset of pulmonary reperfusion and are abolished rapidly thereafter.⁴⁵

Effects of Hypothermia
The fact that the values of all markers except elastase were not significantly different between the two groups probably indicates that the rewarming phase inherent to the practice of cold CPB is sufficient for eliciting an inflammatory response that, by the time of weaning from bypass, is of a magnitude similar to that seen in patients who have been exposed to warm bypass throughout. This assumption is supported by the previous report that the increase in C3a levels correlates with the duration of rewarming.⁴⁶ It should be specified that whenever a difference between the two groups did not reach the preset threshold of statistical significance (P<.05), the power of the negative comparison was assessed for the variable under study. In all cases, the 1–ß values were found to be lower than 80%, except for the comparison between C3a values 30 minutes after bypass, which yielded a 1–ß value of 85%. Thus, it is unlikely that significant differences between groups with regard to P- and E-selectins, IL-8, and even C3a may have been missed only because of the small size of the study populations.

The observation that IL-8 levels were similar in the two groups may seem to be at variance with our previous findings of increased TNF and IL-1ß production in patients exposed to warm bypass,¹⁹ since these two cytokines are required for IL-8 production.³² However, the cytokine-induced synthesis of IL-8 is thought to involve transcription and translation and, as such, probably requires 2 to 4 hours.^{36 47} Consequently, it is unlikely that new synthesis fully accounts for the dramatic rise in IL-8 levels seen in our two groups after an average period of 110 minutes of bypass. As a similar pattern of release has been observed in a simulated extracorporeal circuit (which is obviously devoid of endothelial cells),³⁶ it is sound to postulate that this IL-8 primarily originates from circulating cells, that is, red blood cells,¹ which act as a sink for circulating IL-8,⁴⁷ and/or neutrophils themselves.⁴⁸ From this standpoint, one would not expect to see a difference between the two groups (which were, in particular, similar with regard to hematocrit at all sampling points). Indeed, peak levels of IL-8 have been reported to occur approximately 3 hours postoperatively,³² so that our intraoperative measurements do not exclude a later increase in IL-8 of greater magnitude in warm than in cold bypass patients as a consequence of the temperature dependency of TNF and IL-1 production.

The significantly greater increase in elastase seen in the warm bypass group probably should be interpreted in light of the bypass-induced changes in the expression of neutrophil adhesion molecules. Thus, we have previously shown⁴⁴ that during cold bypass, the neutrophil CD11b and CD11c integrins are significantly less upregulated than in patients undergoing warm CPB. Only at the end of bypass does the expression of these adherence receptors increase, probably as a consequence of rewarming, so that postbypass differences between groups are no longer noticeable. The fact remains, however, that compared with tissues that are cooled during bypass, those that remain warm are exposed for a longer period of time to adhesion-promoting molecules. This could account for the higher levels of elastase yielded by warm patients in the present study since, as previously mentioned, neutrophil adhesion is linked to degranulation.³ This hypothesis is supported by three major lines of evidence. First, the time course of elastase release parallels that observed for CD11b expression,²² and it is therefore sound to predict an earlier rise in elastase during bypass in patients who undergo an early intraoperative upregulation of this integrin. Second, elastase levels measured both in adults^{22 30} and in children³² exposed to cold bypass start to rise sharply at the time of rewarming, which is consistent with the ability of hypothermia to delay the onset of adhesion-mediated neutrophil degranulation. Third, both in the present study and in another study,³² a significant correlation between IL-8 and elastase levels was found in cold bypass patients, whereas this correlation was not present in the warm bypass group. This suggests involvement in the latter group of an additional IL-8–independent factor of neutrophil degranulation. Conceivably, this factor could be the temperature-dependent lengthening of the period of neutrophil integrin–mediated endothelial adhesion. It should be noted finally that differences in elastase levels between cold and warm bypass patients were not skewed by the administration of aprotinin, which is known to reduce elastase release,⁴⁹ since this drug was distributed equally between the two groups.

Clinical Implications
There were no differences in patient clinical outcomes between the two groups. This negative finding does not preclude the potential clinical relevance of our biochemical findings. The magnitude of elastase release during bypass has been reported to be correlated significantly with the occurrence of multiple organ failure after pediatric heart surgery⁶ ; therefore, it cannot be ruled out that the use of a larger patient population and of more sensitive end points would have unmasked a similar relation between increased elastase levels and postoperative adverse events in the warm bypass group. Likewise, it is possible that the effect of temperature might have been sensitized by a greater spread between the two groups, that is, by actively keeping the warm patients at 37°C while cooling patients in the hypothermic group to 25°C. Notwithstanding the influence of temperature, the results of the present study establish the likelihood of neutrophil trafficking during clinical CPB. In view of the experimentally demonstrated protective effects of a pharmacological blockade of this phenomenon by drugs⁵⁰ or monoclonal antibodies,⁵¹ our data provide a sound rationale for evaluating the feasibility of some of these interventions in humans in an attempt to further reduce postoperative mortality and morbidity related to the neutrophil-mediated component of bypass-induced inflammatory damage.

	Selected Abbreviations and Acronyms

 

CPB = cardiopulmonary bypass ICAM-1 = intercellular adhesion molecule–1 IL-1 = interleukin-1 IL-8 = interleukin-8 TNF = tumor necrosis factor

	Acknowledgments

 
This work was supported by a grant (CRC 931809) from the Délégation à la Recherche Clinique de l'Assistance Publique-Hôpitaux de Paris.

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