Ann Thorac Surg 2002;74:139-142
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Duroflo II heparin bonding does not attenuate cytokine release or improve pulmonary function
John Butler, FRCS*a,
Elijah W. Murithi, FRCSa,
Vivek L. Pathi, FRCSa,
Kenneth J.D. MacArthur, FRCSa,
Geoffrey A. Berg, FRCSa
a Department of Cardiac Surgery, Western Infirmary, Glasgow, Scotland, United Kingdom
Accepted for publication March 11, 2002.
* Address reprint requests to Dr Butler, Department of Cardiac Surgery, Western Infirmary, Dumbarton Rd, Glasgow G14 6NT, Scotland, UK
e-mail: gilmour.wendy.wg{at}northglasgow.scot.nhs.uk
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Abstract
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Background. Comparison of the cytokine generation and leukocyte activation properties of Duroflo II heparin bonded bypass circuit (Baxter Healthcare Corp, Compton, UK) and the conventional cardiopulmonary bypass circuit. Attempt to correlate these to pulmonary dysfunction postoperatively.
Methods. Forty patients undergoing elective, isolated coronary artery bypass grafting were randomly allocated to have either plain extracorporeal circuits (group C) or heparin bonded extracorporeal circuits (group H). Full systemic heparinization was used in all patients. The inflammatory response was assessed by measuring plasma levels of interleukin-6, interleukin-8, interleukin-10, and polymorphonuclear elastase. Gas exchange was assessed by measuring the PaO2/FIO2 ratio.
Results. Significant impairment of oxygenation was seen in both groups with the lowest values at the end of the operation before a gradual return to normal during the next 6 hours. There were no differences between the groups in gas exchange or times to extubation. There were significant elevations in all the cytokines, with interleukin-6 levels peaking at 4 hours in group H and 24 hours in group C, before starting to return to normal at 48 hours. The patterns of interleukin-8 and interleukin-10 rise were identical in the two groups. Polymorphonuclear elastase reached a peak at the end of the operation in group H and remained elevated up to 24 hours, whereas levels continued to rise in group C up to 4 hours. There were no significant differences in levels between groups at any time. There were no differences between the groups in blood loss or blood product usage.
Conclusions. Cardiopulmonary bypass induces a systemic inflammatory response with release of cytokines and activation of leukocytes. This correlates with the severe deterioration in pulmonary gas exchange from preoperative levels up to 6 hours postoperatively (p < 0.05). In the presence of systemic heparinization, Duroflo II heparin bonding of the circuits has minor effects on the pattern of evolution of this inflammatory response.
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Introduction
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Despite major advances in perfusion technology, the inflammatory response to cardiopulmonary bypass continues to be a source of morbidity. It is well established that the activation of the cellular components of blood, namely platelets and leukocytes with resultant release of autodigestive enzymes such as polymorphonuclear (PMN) elastase, can have serious effects on many organ systems [1–3]. Other proinflammatory mediators, such as the cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8), complement an endotoxin that can exacerbate the acute phase response to injury [4–6]. Recent evidence indicates that this response can be modulated by the synthesis in the liver of antiinflammatory cytokines such as interleukin-10 (IL-10) [7, 8]. The ultimate clinical outcome therefore may depend on the balance of these opposing effects.
Therapies aimed at attenuating the inflammatory response have involved two major strategies. Pharmacological methods involving the administration of corticosteroids, aprotinin, or antioxidants, and mechanical means such as leukocyte depletion and ultrafiltration have met with varied success. Since the trigger for the inflammatory cascades is felt to be the large artificial surface in contact with blood, improvements in the biocompatibility of these circuits would be expected to ameliorate the response. Covalent or ionic bonding of heparin to the bypass tubing was initially used to reduce the degree of systemic heparinization. A beneficial spin-off of this technology has been the claimed attenuation of the inflammatory response [9, 10].
We designed a randomized study to outline the inflammatory responses to the conventional circuit and Duroflo II heparin bonded circuit (Baxter Healthcare Corp, Compton, UK). Proinflammatory and antiinflammatory cytokines and a product of leukocyte activation were assayed and correlated to pulmonary gas exchange as an index of end-organ damage.
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Patients and methods
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Forty patients, aged 40 to 75 years, undergoing elective, isolated coronary artery bypass grafting were randomized to receive a conventional or a Duroflo II heparin bonded bypass circuit. The surgeon, anesthetist, and staff involved in the postoperative care of the patients were blinded to the type of circuit used. Exclusion criteria included administration of corticosteroids or nonsteroidal antiinflammatory agents, or intravenous heparin infusion.
Computer generated random numbers were used to allocate 20 patients to receive the Duraflo II heparin bonded circuit and a further 20 to a nonheparin bonded circuit (also manufactured by Baxter Healthcare Corp). A standard anesthetic technique using fentanyl, propofol and pancuronium was used for all patients. All patients underwent nonpulsatile perfusion at 32°C, with aortic and two-stage atrio-caval venous cannulation (Sarns, Terumo, Oxford, UK) and membrane oxygenators. A pulmonary artery vent was used routinely. The oxygenators, cannulas, all tubing, and connectors were heparin bonded to achieve "tip to tip" bonding. Full systemic heparinization with 300 iu/kg was used, and the activated clotting time was maintained at more than 400 seconds (Hemochron, model 401; International Technodyne Corp, Meteuchen, NJ). Cardiotomy suction was used in both groups to scavenge shed blood. Myocardial protection was done with antegrade St Thomas’ crystalloid cardioplegia and topical hypothermia.
Blood samples were withdrawn from indwelling cannulas at induction of anesthesia, skin closure, and at 2, 4, 6, 24, and 48 hours postoperatively. Ethamine diamine tetraacetic acid (EDTA) samples were centrifuged at 4°C, and the plasma was stored at -70°C for bulk analysis. Cytokine and PMN elastase levels were determined by enzyme linked immunosorbent assay using standard commercial kits (Quantikine; R & D Systems, Minneapolis, MN and 12589 PMN elastase, IMAC; Merck Diagnostica, respectively). The limit of sensitivity of each assay was as follows: IL-6, 0.70 pg/mL; IL-8, 1.5 pg/mL; IL-10, 2 pg/mlL; and PMN elastase, 20 ng/mL.
Blood gas analysis was performed on heparinized blood using the blood gas analyzer (Ciba-Corning, model 288 [Crawley, Sussex, UK]). The arterial PO2 was divided by the FIO2 to provide a simple index of gas exchange.
Data were analyzed before and after correction for hemodilution. Results for uncorrected data are expressed as median (interquartile range) unless otherwise stated. Within group differences were assessed by Friedman’s two-way analysis of variance and between group differences by the Kruskal-Wallis test. Analyses were performed using the Arcus Quickstat Biomedical software package (Addison Wesley Longman trading as Research Solutions [Cambridge, UK]).
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Results
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Demographic and operative data for the two groups are displayed in Table 1.
There were no significant differences between the two groups in any of these factors. There were no significant differences between the groups in blood loss during the first 12 hours or blood product usage. There was a gradual increase in temperature in both groups, peaking at 6 hours postoperatively. The temperatures were comparable for the two groups, until 48 hours when the plain extracorporeal circuit group (group C) had significantly higher temperatures (37.4°C vs 36.9°C; p < 0.0005).
The oxygen gradients (PaO2/FIO2) fell significantly below baseline at the end of the operation in both groups (p < 0.0001). There was a gradual recovery of PaO2/FIO2 in both groups by 6 hours, though they remained significantly below baseline even at this stage p less than 0.05 (Table 2).
Times to extubation in the two groups were identical (heparin bonded extracorporeal circuit [group H], 12.7 ± 3.1; plain extracorporeal circuit [group C], 12.9 ± 2.9).
Cytokine profiles for the two groups are shown in Figure 1.
There were no statistically significant correlations noted between the PaO2/FIO2 and levels of biochemical markers at any time in either group.
IL-6 levels rose significantly in both groups by the end of the operation and continued to rise up to 4 hours postoperatively (group C, 248 pg/mL, p < 0.0008; group H, 295 pg/mL, p < 0.0008). Levels in group H then fell at 24 hours to 237 pg/mL (p = 0.15), whereas group C continued to rise to 284 pg/mL (p < 0.0002; 2 to 24 hours). There were no significant differences between the groups at any stage.
IL-8 levels rose significantly in both groups peaking at 4 hours. There were no significant differences between the groups at any stage.
Levels of the antiinflammatory cytokine IL-10 were significantly elevated in both groups peaking by the end of the operation. Levels then fell though remaining elevated above baseline at 24 hours. There were no statistically significant differences between the groups.
PMN elastase levels rose significantly by the end of the operation in both groups (p < 0.0002). In group C, levels continued to rise, peaking at 2 to 4 hours (p < 0.04). In group H, levels peaked at the end of the operation and remained at that level for up to 24 hours. There were no significant differences between the groups at any stage.
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Comment
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The bonding of heparin to all the blood contacting surfaces during cardiopulmonary bypass was developed to enhance biocompatability and attenuate the postperfusion syndrome [11–13]. In ionic bonding, heparin is first linked to a quaternary ammonium salt carrier and the hydrophilic molecular complex bound to the synthetic surface. This leaves the antithrombin III binding site of heparin exposed [14]. These circuits have been used safely with reduced levels of heparin or no heparin at all [15–18]. However some investigators suggest that bound heparin has little effect on anticoagulant activity and that low dose heparin may even upregulate the neutrophil adhesion molecule CD11B and enhance the acute phase response [19, 20]. Furthermore the reports using heparin bonded circuits without systemic heparin have maintained higher flows than normal on bypass making quantification of blood trauma impossible. Therefore we elected to perform our study with full systemic anticoagulation. This may account for the identical blood loss and blood product usage in the two groups and may require a further study using lower dose systemic heparin to show any benefit of heparin bonding.
Under the conditions of this randomized, controlled study there were no differences between the two groups in clinical outcome. This finding would be in agreement with a similar randomized study of patients undergoing cardiac reoperations in which intubation times and hospital stay were identical [21]. Both extubation times and PaO2/FIO2 were not found to differ between the groups in our study. The degree of pulmonary dysfunction seen immediately postoperatively was as great in group H as it was in group C. This may have been due to the period of cardiopulmonary bypass used in this study being too short to demonstrate a difference. It may be that heparin bonding may be of benefit only in high risk subgroups, such as women and those requiring longer cardiopulmonary bypass times [22]. A larger study of such patients is warranted to establish whether heparin bonding can produce clinical improvement as demonstrated in pediatric cardiopulmonary bypass [23]. Another possible explanation may be that the IL-10 response may exert a similar controlling influence on both groups. It may require steroid pretreatment in a further study to clarify this issue [7].
The intense activation of the cytokine systems by cardiopulmonary bypass is well demonstrated in this study. The continued rise of IL-6 up to 24 hours postoperatively in group C in contrast to the trend in group H in which levels peaked at 4 hours postoperatively was a minor difference between the groups. This may indicate that the continued production of IL-6 may be attenuated by Duroflo II heparin bonding with amelioration of the severity of the acute phase response. This may not be significant in this study, but it may become relevant when longer cardiopulmonary bypass times are required. This would be consistent with the significantly elevated temperatures in group C between 24 and 48 hours. As IL-6 levels have been shown to correlate with severity of surgical trauma, it can be argued that the pyrexia may not be evident in these patients due to the cooling on cardiopulmonary bypass and the after drop in temperature seen immediately postoperatively.
The IL-8 responses in both groups were identical. This would be expected as the main stimulus for release of IL-8 is ischemia reperfusion and these were equal in the two groups [24]. Our findings would be consistent with a recent study in which neither albumin pre-priming nor heparin bonding were found to affect the levels of IL-6 or IL-8 in 200 randomized pediatric patients [25].
It is interesting that the PMN elastase levels in group C continued to rise up to 2 to 4 hours postoperatively. In contrast the levels in group H peaked at the end of the operation. Again, this may be an insignificant difference in this study, but it may show a greater divergence if a longer bypass run was used.
In conclusion, no major differences in cytokine or elastase levels were seen between the two groups. However, there were trends in the profiles of these mediators that may require much longer bypass runs to become apparent than those used in our standard clinical practice. There were no differences in gas exchange between the groups, although both showed severe impairment in the immediate postoperative period.
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Abstract
Introduction
= Control group; 
= heparin-bonded group; PMN = polymorphonuclear; Pre = preoperative.)