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(Circulation. 1995;92:354-358.)
© 1995 American Heart Association, Inc.

Articles

Hypothermia During Cardiopulmonary Bypass Delays but Does Not Prevent Neutrophil– Endothelial Cell Adhesion

A Clinical Study

Presented at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.

Françoise Le Deist, MD; Philippe Menasché, MD, PhD; Christophe Kucharski, MD; Alain Bel, MD; Armand Piwnica, MD; Gérard Bloch, MD

From the Department of Cardiovascular Surgery, Hôpital Lariboisière, and INSERM U-132, Hôpital Necker-Enfants Malades, Paris, France.

	Abstract

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Background An accurate evaluation of warm heart surgery cannot be limited to the assessment of the myocardial effects of warm blood cardioplegia but should also address the effects of systemic normothermia on the inflammatory response to cardiopulmonary bypass. A major component of this response is the endothelial adhesion of neutrophils, because it is linked to the release of cytotoxic compounds. This study was designed (1) to characterize the bypass-induced changes in the expression of neutrophil adhesion molecules (L-selectin and ß₂-integrins) and (2) to assess the influence of bypass temperature on these changes.

Methods and Results Twenty case-matched patients undergoing open-heart procedures were divided into two equal groups according to the core temperature during cardiopulmonary bypass: warm (33.4±0.3°C) or cold (27.1±0.4°C, P<.0001 versus warm). Arterial blood samples were collected before, during, and 30 minutes after bypass and processed for the expression of L-selectin and ß₂-integrins (CD11a, CD11b, and CD11c) with flow cytometry. Warm bypass was associated with an early and sustained upregulation of CD11b. In contrast, hypothermia resulted in a strikingly less pronounced CD11b upregulation during bypass. However, CD11b expression sharply increased thereafter so that 30 minutes after bypass, it was no longer significantly different between the two groups. Changes in CD11c expression grossly paralleled those described for CD11b. Neither CD11a nor L-selectin changed significantly from baseline values in either group.

Conclusions Clinical cardiopulmonary bypass is associated with a marked upregulation of the neutrophil CD11b and CD11c integrins. Hypothermia delays but does not prevent the increased expression of these adhesion molecules, which could consequently represent logical targets for interventions designed to blunt the neutrophil-mediated component of bypass-induced inflammatory tissue damage.

Key Words: cardioplegia • proteins • cardiopulmonary bypass • surgery

	Introduction

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A thorough evaluation of warm heart surgery cannot be limited solely to the assessment of the myocardial effects of warm blood cardioplegia but rather must also include that of the systemic effects of warm cardiopulmonary bypass (CPB). The clinical relevance of the latter issue stems from the two following observations: (1) Organ dysfunction, which still commonly occurs after open-heart procedures, can in most cases be attributed to an inflammatory response to bypass,^{1 2 3} and (2) the magnitude of this response might be influenced by intraoperative temperature.^{4 5 6}

A large body of experimental evidence currently suggests that activated neutrophils are key mediators of the inflammatory reactions elicited by CPB⁷ through their ability to release tissue-damaging compounds after they have adhered to endothelial cells.^{8 9} This adhesion sequentially involves two classes of neutrophil cell-surface receptors: ß₂-integrins, which comprise three heterodimers (CD11a/CD18, CD11b/CD18, and CD11c/CD18), and L-selectin.^{10 11} The present study was therefore designed with two objectives: (1) to assess the patterns of changes in the expression of these adhesion molecules during clinical CPB and (2) to determine the influence of temperature during bypass on these patterns.

	Methods

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Study Population
This study, which was approved by our institutional review committee, comprises 20 cardiac surgical patients who were prospectively assigned to receive warm or cold CPB. Although the assignment of patients was based exclusively on their respective surgeons' practices, there was no significant difference in baseline characteristics between the two groups (Table). In the warm heart surgery group, core temperature, as assessed by a nasopharyngeal probe, was allowed to drift and averaged 33.4±0.3°C during bypass. Retrograde blood cardioplegia was continuously delivered at the same temperature as that of the systemic perfusate.¹² In the cold heart surgery group, the core temperature was lowered to 27.1±0.4°C (P<.0001 versus the warm group) and gradually brought up to 37°C to 37.5°C by the end of bypass. In this group, myocardial protection was provided by single-dose cold (4°C) crystalloid cardioplegia supplemented by topical cooling. CPB was otherwise conducted in a similar fashion in the two groups with a roller pump and membrane oxygenation. Likewise, the same anesthetic regimen, consisting of a combination of fentanyl, flunitrazepam, and pancuronium, was used in all patients.

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

Arterial blood samples were collected shortly after induction of anesthesia, at 5, 10, and 15 minutes of bypass, and 30 minutes after the end of bypass. Prebypass and postbypass samples were drawn from the radial artery catheter; during bypass, samples were drawn from the arterial limb of the oxygenator. All samples were stored on ice for a short period until processing for flow cytometric analysis.

Flow Cytometric Analysis
Aliquots of 25 µL were immediately stained with saturating concentrations of mouse anti-human monoclonal antibodies to CD11a (IOT16, Immunotech), CD11b (Leu 15, Becton Dickinson), CD11c (Leu M5, Becton Dickinson), and L-selectin (TQ1, Coulter Clones) for 20 minutes at 4°C. These antibodies are conjugated to phycoerythrin except for IOT16, which is conjugated instead to fluorescein isothiocyanate. After two washes in PBS, erythrocytes were lysed with fluorescence-activated cell sorter lysing solution (Becton Dickinson) for 10 minutes and, after centrifugation and removal of the supernatant, were washed once with PBS and resuspended in a 1% solution of formaldehyde in PBS. Samples were then kept at 4°C in the dark until analysis.

Flow cytometric analysis of cellular fluorescence was performed on a FACScan cytometer (Becton Dickinson). Green and red amplifier gains were calibrated with fluorescent beads before each experiment to check that relative fluorescence values were comparable between experiments. A total of 5000 events were recorded from each sample and analyzed with LYSIS II analysis software (Becton Dickinson). Neutrophils were gated on the basis of forward and orthogonal light scatter, and fluorescence was measured on a log scale. Data are expressed as the arithmetic mean of linear fluorescence values, which correspond to the average degree of expression of the relevant epitope on the cell surface.

Statistics
Baseline continuous data were compared by unpaired two-tailed t test. Comparison of groups over time was performed by two-way ANOVA with repeated measures. Data were further compared by use of Scheffé's test if ANOVA was significant (P<.05). All values are expressed as mean±SEM.

	Results

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CD11a. CD11a expression did not change significantly from baseline values in either group over the observation period (Fig 1).

View larger version (17K): [in this window] [in a new window]   Figure 1. Bar graph showing influence of temperature of cardiopulmonary bypass (CPB) on changes in expression of neutrophil integrin CD11a. Each group consisted of 10 patients.

CD11b. In the warm group, CD11b expression increased dramatically as early as 5 minutes after the onset of bypass. At this time point, CD11b mean fluorescence values were already significantly higher than prebypass values (163±32 versus 63±13 arbitrary units, P<.03) and tended to level off thereafter. In the cold group, changes in CD11b expression during bypass were less pronounced and more delayed than in the warm group, since a significant difference from baseline levels was attained only after 15 minutes of bypass (85±15 versus 38±6 arbitrary units, P<.01). After bypass, however, CD11b levels showed a sharp increase, so that the difference in mean fluorescence values for this integrin, which was significant between the two groups at 5, 10, and 15 minutes of bypass (P<.004, P<.002, and P<.002, respectively), had disappeared at the 30-minute postbypass time point (Fig 2).

View larger version (34K): [in this window] [in a new window]   Figure 2. Bar graph showing influence of temperature of cardiopulmonary bypass (CPB) on changes in expression of neutrophil integrin CD11b. Each group consisted of 10 patients.

CD11c. The patterns of changes in CD11c expression in the two groups grossly paralleled those described for CD11b (Fig 3). Furthermore, analysis of postbypass samples disclosed in six patients of each group the presence of a second population of cells with low fluorescence for CD11b and/or CD11c.

View larger version (23K): [in this window] [in a new window]   Figure 3. Bar graph showing influence of temperature of cardiopulmonary bypass (CPB) on changes in expression of neutrophil integrin CD11c. Each group consisted of 10 patients.

L-selectin. In neither of the two groups were mean fluorescence values for L-selectin, measured during or after bypass, significantly different from control levels, nor were they different between the two groups (Fig 4).

View larger version (57K): [in this window] [in a new window]   Figure 4. Bar graph showing influence of temperature of cardiopulmonary bypass (CPB) on changes in expression of neutrophil L-selectin. Each group consisted of 10 patients.

	Discussion

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Molecular Mechanisms of Neutrophil–Endothelial Cell Adhesion
The adhesion of neutrophils to endothelial cells and their subsequent transendothelial migration are coordinately regulated by molecules that belong to three structurally distinct families: the selectin family, the integrin family, and the immunoglobulin superfamily.

There are three selectins: L-, P-, and E-selectins. L-selectin, which is expressed on the surface of all leukocytes, mediates a loose binding of unactivated neutrophils to endothelial cells. These adhesive bonds are not strong enough to overcome the dispersal forces generated by flowing blood, but they allow neutrophils "rolling" along the vessel wall to be in prolonged contact with activating stimuli that cause, among other things, upregulation of ß₂-integrins.^{10 11} P- and E-selectins are expressed on endothelial cells and also contribute to neutrophil adhesion but with different time frames (P-selectin is mobilized within minutes of stimulation, whereas E-selectin expression peaks after 4 to 6 hours).^{11 13} A common feature of the three selectins is to recognize the same sialyl Lewis-x oligosaccharide ligand.¹⁴

ß₂-Integrins are heterodimers that share the same ß₂-subunit (CD18) and have immunologically distinct -subunits (CD11a, b, and c), which allows identification of three complexes: CD11a/CD18 (or LFA-1), CD11b/CD18 (or MAC-1), and CD11c/CD18 (or p150,95).¹⁵ These three molecules are basally expressed on quiescent neutrophils, but only CD11b and CD11c can be mobilized from intracellular pools in response to various inflammatory mediators,¹⁶ although qualitative changes in surface expression of CD11b/CD18 might be as important as a quantitative increase for enhanced adherence to endothelium.¹⁷ Namely, ß₂-integrins serve to strengthen neutrophil–endothelial cell adhesive interactions initiated by L-selectin, whose shedding parallels CD11b upregulation.^{18 19 20} Whereas CD11c reacts with different ligands, in particular the complement cleavage product iC3b,²¹ CD11a and CD11b recognize primarily members of the immunoglobulin superfamily.^{7 15 21}

The member of the immunoglobulin superfamily that seems to be the most relevant to neutrophil adhesion is the intercellular adhesion molecule-1 (ICAM-1). Although constitutively expressed on the endothelial cell surface, this molecule is markedly upregulated by cytokines, with a peak expression occurring 24 hours after stimulation.¹⁵ Actually, the CD11b/CD18–ICAM-1 receptor ligand interaction is currently viewed as the key mechanism of neutrophil shear-resistant "cementing" to the vascular wall.¹³ This adhesion of neutrophils primes them for free radical production⁸ and degranulation.⁹ Neutrophil-mediated tissue damage is further amplified as a transendothelial cell chemotactic gradient (largely driven by interleukin-8)¹⁹ makes adherent neutrophils detach and migrate into the interstitium, where they can injure parenchymal cells directly.²²

The relevance of these events to CPB is that neutrophil–endothelial cell adhesive interactions are dependent not only on the inflammation-induced expression of specific cell surface receptors but also on blood flow–induced shear forces. One would thus expect neutrophil sequestration to be enhanced during the weaning phase of bypass, when initially low reperfusion flow rates, and consequently low shear stresses, may promote, particularly in lungs, both L-selectin–mediated rolling²³ and subsequent integrin-mediated firm adhesion.²⁴

Interpretation of Results
The two major findings of this study are that CPB is associated with an upregulation of the neutrophil adhesion molecules CD11b and CD11c and that hypothermia delays but does not prevent the increased expression of these two integrin subunits.

The observation that CD11a expression did not change significantly during or after CPB has been made previously in a simulated extracorporeal circuit²⁵ and is not surprising, since CD11a is involved primarily in the adhesion of lymphocytes,²⁶ as evidenced by the efficacy of monoclonal antibodies against CD11a in preventing allograft rejection.²⁷ Conversely, CD11a plays a more limited role in the adhesion of activated neutrophils, which is consistent with our findings and is further supported by the previous observation that anti-CD11a monoclonal antibodies are unable to block neutrophil adhesion.²⁸ The early and marked upregulation of CD11b after the institution of bypass supports similar findings previously made in humans^{29 30} and could be equally predicted from the capacity of this integrin determinant to be strongly expressed in response to inflammatory mediators like the complement-derived anaphylatoxin C5a,²⁹ platelet-activating factor,³¹ leukotriene B₄,²³ and interleukin-8,³² all of which have been identified in circulating blood during clinical bypass.^{33 34} Our finding that CD11c was also upregulated, although to a lesser extent, during bypass is consistent with the translocation of this adherence receptor from intracellular pools to the cell surface in response to the same stimuli as CD11b.¹⁶ The finding that peak expression of CD11b and CD11c occurred shortly after the onset of bypass makes it unlikely that between-group differences may have been biased by the slightly (although not significantly) longer bypass times associated with hypothermic perfusion.

In vitro, upregulation of CD11b is paralleled by a downregulation of L-selectin of similar magnitude.^{18 19 20} This pattern was not found in the present study, in which L-selectin expression remained unchanged throughout the observation period in the two groups. A likely explanation for this discrepancy is that loss of L-selectin has been observed in neutrophils that had actually extravasated in interstitial tissue.¹⁸ This population of cells is obviously missed by flow cytometric analysis of circulating blood elements. Finn and coworkers²⁵ similarly reported that after 2 hours of bypass in a mock extracorporeal circuit, more than half the neutrophils still had normal expression of L-selectin together with a greatly increased expression of CD11b/CD18. In any case, the lack of significant changes in L-selectin expression does not argue against the occurrence of neutrophil adhesion during bypass, since, in vivo, the concentration of interleukin-8 required to cause neutrophil margination in the lungs is much lower than that required for inducing shedding of L-selectin.³⁵

The use of hypothermia significantly reduced the expression of CD11b and CD11c during bypass compared with normothermia. This result is in keeping with the previously documented effect of temperature on complement activation^{4 5} and on the expression of neutrophil cell-surface receptors in response to complement-activated products.⁴ However, the present study also shows that hypothermia was unable to prevent a postbypass increase in the expression of CD11b and CD11c, so that 30 minutes after the end of bypass, mean fluorescence values yielded by these two integrin determinants were no longer significantly different between the warm and cold groups. Similar observations have been made in a mock circuit by Elliott and Finn,⁷ who reported upregulation of expression of CD11b/CD18 by rewarming from hypothermic bypass conditions. Put together, these data suggest that the rewarming phase that precedes discontinuation of bypass is probably sufficient to elicit an upregulation of neutrophil adhesion molecules. This hypothesis is in agreement with the observation that hypothermia during bypass prevents leukocytosis as long as it is maintained but that white blood cell counts sharply increase when the body temperature is restored to 35°C to 36°C; the magnitude of postbypass leukocytosis is then equivalent to that seen after normothermic bypass.³⁶ In a similar fashion, hypothermia has been shown to delay but not to significantly reduce the postbypass peak concentration of acute-phase reactants such as C-reactive protein.³⁷ It is unlikely that in the present study, potential late differences between the cold and warm groups were missed, because data were not collected beyond 30 minutes after bypass, since it has been shown that CD11b values measured at this time point are similar to those measured 24 hours later.³⁸

Furthermore, in the two groups, analysis of postbypass samples disclosed two populations of cells, one of which was weakly fluorescent for CD11b and/or CD11c, thereby reflecting the low expression of the corresponding epitopes. These cells are phenotypically similar to young cells released from the bone marrow,³⁹ which largely account for the postbypass increase in white blood cell counts.³⁶ The fact that this pattern of expression was equally distributed among warm and cold bypass patients is consistent with the previously mentioned observation that the magnitude of postbypass leukocytosis is unaffected by the temperature that has prevailed during the preceding period of extracorporeal circulation.

Clinical Implications
In this study, the postoperative clinical outcomes were not different between the two patient groups. In particular, the times to extubation were similar (17±2 and 15±3 hours in warm and cold bypass patients, respectively). This result is consistent with the observation that although the kinetics of changes in the expression of CD11b and CD11c were different between the two groups, the ultimate extent of these changes was similar in warm and cold bypass patients. That the upregulation of these two integrins was not reflected by the occurrence of adverse postoperative events could simply be due to the small size of our patient population and/or the use of poorly sensitive clinical end points, and we acknowledge that it does not exclude the possibility that normothermically perfused tissues may have incurred a greater degree of subclinical damage due to their longer exposure time to adhesion-promoting molecules. This hypothesis tends to be supported by our previous findings that, compared with cold bypass, warm bypass is associated with greater cytokine production,⁶ subsequently higher circulating levels of cytokine-induced endothelial ligands (ICAM-1) for neutrophil adhesion receptors,⁴⁰ and greater release of elastase,⁴⁰ a highly injurious enzyme liberated by adhesion-promoted degranulation.⁹ Notwithstanding the putative protection afforded by hypothermia with regard to delaying the expression of neutrophil integrins during CPB, several experimental studies reasonably allow the implication of these molecules in the pathogenesis of postbypass inflammatory damage, in particular in lungs, in which neutrophil sequestration correlates with increased expression of CD18 on these cells,⁴¹ but also in the heart itself. Consequently, benefits should reasonably be expected from appropriate pharmacological blockade of neutrophil integrin expression. This hypothesis is supported by the observation that monoclonal antibodies against the common ß-subunit of integrins (anti-CD18) reduce myocardial stunning in a rabbit model of heterotopic heart transplantation.⁴² Likewise, new anti-inflammatory drugs that inhibit integrin upregulation (leumedins) have been shown to improve the recovery of both cardiac⁴³ and pulmonary⁴⁴ function in pig models of CPB. Of greater clinical relevance are the recent reports that glucocorticoids³⁸ and the adenosine-regulating agent acadesine⁴⁵ can blunt CD11b/CD18 expression in patients undergoing open-heart operations, an effect probably mediated by a reduced cytokine release and an increased accumulation of endogenous adenosine (a known inhibitor of neutrophil adhesion), respectively. The rationale for this type of intervention is reinforced by the results of the present study, which, by demonstrating that neutrophil integrin upregulation occurs during clinical bypass regardless of the temperature of the systemic perfusate, supports the idea that these adhesion molecules would constitute logical targets for therapeutic interventions designed to attenuate the deleterious effects of extracorporeal circulation.

	Acknowledgments

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

	Footnotes

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

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