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Addition of dextran sulfate to blood cardioplegia attenuates reperfusion injury in a porcine model of cardiopulmonary bypass

^a Department of Clinical Research, University of Bern, Bern, Switzerland
^b Department of Cardiovascular Surgery, University Hospital, Bern, Switzerland
^c Department of Anesthesiology, University Hospital, Bern, Switzerland
^d Department of Cardiology, University Hospital, Bern, Switzerland

Received 5 December 2007; received in revised form 24 April 2008; accepted 5 May 2008.

^_* Corresponding author. Address: University of Bern, Department of Clinical Research, Murtenstrasse 31, 3010 Bern, Switzerland. Tel.: +41 31 632 9669; fax: +41 31 632 8837. (Email: robert.rieben{at}dkf.unibe.ch).

Objective: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Methods: Eighteen pigs (DXS, n = 10; phosphate buffered saline [PBS], n = 8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60 min with BCP containing either DXS (300 mg/10 ml, equivalent to 5 mg/kg) or 10 ml of PBS. Following 30 min reperfusion, pigs were weaned from CPB. During 2 h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. Results: DXS significantly reduced CK-MB levels (43.4 ± 14.8 ng/ml PBS, 35.9 ± 11.1 ng/ml DXS, p = 0.042) and significantly diminished cytokine release: TNFalpha (1507.6 ± 269.2 pg/ml PBS, 222.1 ± 125.6 pg/ml DXS, p = 0.0071), IL1beta (1081.8 ± 203.0 pg/ml PBS, 110.7 ± 79.4 pg/ml DXS, p = 0.0071), IL-6 (173.0 ± 91.5 pg/ml PBS, 40.8 ± 19.4 pg/ml DXS, p = 0.002) and IL-8 (304.6 ± 81.3 pg/ml PBS, 25.4 ± 14.2 pg/ml DXS, p = 0.0071). Tissue endothelin-1 levels were significantly reduced (6.29 ± 1.90 pg/100 mg PBS, 3.55 ± 1.15 pg/100 mg DXS p = 0.030) as well as thrombin–anti-thrombin formation (20.7 ± 1.0 µg/ml PBS, 12.8 ± 4.1 µg/ml DXS, p = 0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81 ± 3% vs 78 ± 3%, p = 0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt _min), pulmonary artery pressure (21 ± 3 mmHg PBS, 19 ± 3 mmHg DXS, p = 0.002) and right ventricular pressure (21 ± 1 mmHg PBS, 19 ± 3 mmHg DXS p = 0.021) were significantly improved with the use of DXS. Conclusions: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.

Key Words: Ischemia • Reperfusion • Complement inhibition • Cytoprotection • Endothelium

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