Antithrombin-heparin covalent complex reduces microemboli during cardiopulmonary bypass in a pig model

Abstract

Transcranial Doppler-detected high-intensity transient signals (HITS) during cardiopulmonary bypass (CPB) surgery have been associated with postoperative neurocognitive dysfunction, suggesting microemboli in the brain could be a contributing factor. HITS occur despite administration of unfractionated heparin (UFH). This study was done to determine whether antithrombin-heparin covalent complex (ATH), a more potent anticoagulant than heparin, can reduce HITS during CPB. In a pig CPB model, ATH, UFH, or UFH ؉ antithrombin (AT) was intravenously administered to female Yorkshire pigs after sternotomy. Twenty minutes later, hypothermic CPB was initiated and continued for 1.25 hours, then normothermia was re-established for 45 minutes. Protamine sulfate was given to neutralize the anticoagulants, and pigs were allowed to recover. HITS were monitored using an arterial flow probe placed over the carotid artery. Compared with UFH (300 or 1000 U/kg), ATH reduced the number of HITS during CPB in a dose-dependent manner. AT (3 mg/kg) ؉ UFH (300 U/kg) resulted in an intermediate HITS rate between UFH and ATH (2 mg/kg in terms of AT). Examination of brain sections for emboli formation confirmed that, similar to HITS, number of thrombi decreased in direct proportion to ATH dosage. These results support the hypotheses that the majority of HITS represent thromboemboli and that ATH reduces emboli formation during CPB. IntroductionMany important advances in cardiac surgery were made in past decades including procedures such as cardiopulmonary bypass (CPB), coronary artery bypass grafting, and cardiac repair or replacement surgery. 1,2 There is some evidence of adverse neurological effects associated with cardiac surgery, particularly with CPB. Neurocognitive dysfunction is a common complication of cardiac surgery. [3][4][5][6] The etiology of neurocognitive dysfunction is controversial, but there is evidence suggesting that microemboli may be a contributing factor. Some studies have been performed using transcranial Doppler ultrasound to detect microemboli as high-intensity transient signals (HITS) during cardiac surgery. 7,8 In these studies, HITS were associated with neurocognitive deficits, especially with respect to memory loss. Of the possible sources of microemboli, including air, thrombi, and fat from cellular or particulate matter promoted by the bypass pump, thromboemboli are thought to be an important contributor to the neurocognitive dysfunction that occurs after CPB. 9,10 Currently, unfractionated heparin (UFH) is the standard agent used for anticoagulation during CPB. Although UFH provides sufficient anticoagulation to prevent clotting within the bypass circuit, clinical application of UFH is limited by its pharmacokinetic and biophysical properties. UFH has a short, dose-dependent intravenous half-life and an unpredictable anticoagulant effect, mainly due to variable nonspecific plasma and cell surface protein binding. 11,12 UFH is also unable to inactivate surface-bound coagulation factors, such as fibrin-bound thro...

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