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Ann Thorac Surg 1996;61:1038-1039
© 1996 The Society of Thoracic Surgeons

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Correspondence

Eosinophil Granulocyte Activation and Heparin-Coated Cardiopulmonary Bypass

Oslo Heart Center Pilestredet 32 0027 Oslo Norway

To the Editor:

I read with great interest the recent article entitled ``Eosinophil granule proteins in cardiopulmonary bypass with and without heparin coating'' by Nilsson and associates [1]. They studied activation of eosinophil granulocytes expressed by release of eosinophil cationic protein and eosinophil protein X in patients undergoing cardiopulmonary bypass with either a Carmeda Bio-Active Surface (Carmeda, Stockholm, Sweden) coated system or ordinary uncoated equipment. The systemic heparin doses were reduced to 50% and 75% of normal doses in two heparin-coated groups. They demonstrated significantly less release of the eosinophil proteins in the patients treated with heparin-coated cardiopulmonary bypass, which was interpreted as evidence of improved biocompatibility of the heparin-coated circuit. However, like in several other reports on heparinized CPB [2--4], their study design implicated changing of two parameters at the same time, namely, the presence of heparin-coated surfaces and reducing the amount of systemic heparin. Therefore, their conclusion may be questioned, as the influence of lowering the level of circulating heparin remained unknown.

My colleagues and I have made a similar study on neutrophil activation [5], investigating the effects of both the concentration of circulating heparin and the surface-bound heparin by including three groups of patients: two groups have heparin-coated (Duraflo II; Baxter-Bentley Laboratories, Irvine, CA) cardiopulmonary bypass, one group given low-dose heparin (activated clotting time >250 seconds) and the second group having normal high-dose heparin (activated clotting time >480 seconds). A third control group was perfused with ordinary uncoated circuits and full heparin dose. We were able to demonstrate that neutrophil activation was decreased only in patients receiving reduced doses of heparin, indicating that reduced activation was more related to the lower level of circulating heparin than to the presence or absence of heparin-coated surfaces.

To evaluate the influence of systemic heparin on eosinophil granulocytes, we went back to duplicate deep frozen (-70°C) plasma samples from the three patient groups mentioned above and analyzed the concentrations of eosinophil cationic protein. The analyses were performed by the same laboratory as in Dr Nilsson's study (Department of Clinical Chemistry, Uppsala University Hospital, Uppsala, Sweden, headed by Prof P. Venge). The results turned out to be very similar to those recognized for neutrophil activation. Figure 1 shows the time-dependent changes of the three groups and Figure 2 demonstrates the total amounts of eosinophil cationic protein release, which were significantly reduced in the low-heparin group compared with the control group (p = 0.002) and with the full heparin dose group (p = 0.02). There were no significant differences between the full heparin dose group and the control group, both receiving the same amount of intravenous heparin. Consequently, these data confirm that eosinophil granulocyte activation is profoundly influenced by the amount of systemic heparin.

View larger version (19K): [in this window] [in a new window]   Fig 1. . Time-dependent changes in eosinophil cationic protein level in the three groups. (CPB = cardiopulmonary bypass; X-clamp = cross-clamp.)

View larger version (21K): [in this window] [in a new window]   Fig 2. . Total release of eosinophil cationic protein during cardiopulmonary bypass in the three groups. Eosinophil cationic protein release was significantly reduced in the low heparin dose versus the control group (**p = 0.002) and versus the full heparin dose group (*p = 0.02). There were no significant differences between the full heparin dose group and the control group. Median values and quartiles are shown.

References

1. Nilsson L, Peterson C, Venge P, Borowiec JW, Thelin S. Eosinophil granule proteins in cardiopulmonary bypass with and without heparin coating. Ann Thorac Surg 1995;59:713–6.[Abstract/Free Full Text]
2. Fosse E, Moen O, Johnson E, et al. Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1994;58:472–7.[Abstract/Free Full Text]
3. Pekna M, Hagman L, Haldèn E, Nilsson UR, Nilsson B, Thelin S. Complement activation during cardiopulmonary bypass: effect of immobilized heparin. Ann Thorac Surg 1994;58:421–4.[Abstract/Free Full Text]
4. Borowiec J, Thelin S, Bagge L, Nilsson L, Venge P, Hansson HE. Heparin-coated circuits reduce activation of granulocytes during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;104:642–7.
5. Øvrum E, Mollnes TE, Fosse E, et al. High and low heparin dose with heparin-coated cardiopulmonary bypass: activation of complement and granulocytes. Ann Thorac Surg 1995;60:1755–61.[Abstract/Free Full Text]
6. Øvrum E, Mollnes TE, Fosse E, et al. Complement and granulocyte activation in two different types of heparinized extracorporeal circuits. J Thorac Cardiovasc Surg (in press).

Reply

Departments of Thoracic Surgery Clinical Chemistry University Hospital S-751 85 Uppsala Sweden

To the Editor:

We welcome Dr Øvrum's contribution to the discussion about biocompatibility in cardiopulmonary bypass. In his study, using the Duraflo II heparin coating (Baxter-Bentley Laboratories, Irvine, CA) the systemic heparin dose affected the plasma level of eosinophil cationic protein (ECP), whereas using heparin coating or not had no influence. We do not think, however, that these results can be transferred directly to other heparin surfaces. We studied the Carmeda Bio-Active Surface (CBAS) developed by Carmeda, Stockholm, Sweden, in which heparin is covalently bound to the surface after an amination procedure [1]. The Duraflo II surface is composed of ionized heparin, which demonstrates a certain leakage into the circulation [2]. In our work [3] we could demonstrate a very high affinity of ECP to the CBAS. Binding of released ECP to the heparinized surface therefore is the most likely explanation of the pronounced reduction in ECP plasma level compared with the uncoated control group. In combination with heparin coating we used two levels of systemic heparinization, 75% and 50% of full dose respectively, and found no difference in ECP levels. We admit that inclusion of a group with full-dose heparin would have been better to clarify the specific question of the effect of systemic heparinization on ECP level. Our study design, however, was determined by clinical considerations where reduction of the heparin dose is a natural consequence of using heparin-coated equipment.

Regarding the effect of the systemic heparinization on other granulocyte proteins we have found that myeloperoxidase level is significantly reduced during cardiopulmonary bypass in coronary bypass patients using the CBAS, also with full systemic heparinization (Fig 1). In an in vitro cardiopulmonary bypass [4] using uncoated and CBAS-coated circuits, the myeloperoxidase level was very much reduced in the CBAS group although addition of heparin to the blood in the perfusate was the same. Myeloperoxidase did not bind to the CBAS, so these results were interpreted as decreased contact activation of the granulocytes.

View larger version (17K): [in this window] [in a new window]   Fig 1. . Myeloperoxidase level during and after cardiopulmonary bypass (CPB). Black bars = heparin-coated group; white bars = control group. (*p < 0.05 when compared with initial value. #p < 0.05 when compared with control group.)

References

1. Larm O, Larsson R, Olsson P. A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue. Biomater Med Device Artif Organs 1983;11:161–73.
2. Edmunds LH. Surface-bound heparin-panacea or peril? Ann Thorac Surg 1994;58:285–6.[Free Full Text]
3. Nilsson L, Peterson C, Venge P, Borowiec JW, Thelin S. Eosinophil granule proteins in cardiopulmonary bypass with and without heparin coating. Ann Thorac Surg 1995;59:713–6.[Abstract/Free Full Text]
4. Videm V, Nilsson L, Venge P, Svennevig JL. Reduced granulocyte activation with a heparin-coated device in an in vitro model of cardiopulmonary bypass. Artif Organs 1991;15:90–5.[Medline]

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This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Eivind Øvrum Leif Nilsson Jan W. Borowiec Stefan Thelin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Øvrum, E. Articles by Thelin, S. Search for Related Content PubMed PubMed Citation Articles by Øvrum, E. Articles by Thelin, S.