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Ann Thorac Surg 1996;61:781-782
© 1996 The Society of Thoracic Surgeons
North Queensland Clinical School, University of Queensland, Townsville, Australia
The activated/automated clotting time (ACT) is familiar to surgeons, anesthetists, and perfusionists. In one form or another, it is used to monitor the presence (and adequacy) of anticoagulation during cardiopulmonary bypass. Since the reports by Bull and associates [1–3], there have been few studies to determine the correct level for the ACT. Minimum times acceptable in many practices range from 300 to 480 seconds. Despite heparin regimens in current use, there is biochemical evidence of thrombin generation (indicating activation of clotting cascade) [4, 5] and increased fibrinolytic activity. This can be measured with markers such as thrombin-antithrombin III complex, prothrombin fragment 1.2, and fibrinopeptide A. The heparin doses used in these studies are then unable to prevent the intrinsic pathway (due to contact with foreign surfaces) and the extrinsic pathway (via tissue factor) from some degree of activation. In addition, other pathways lead to activation of the remainder of the plasma protein cascades as well as cellular perturbation, which result in fibrinolysis, platelet dysfunction, and endothelial dysfunction (Bidstrup BP, unpublished data).
One solution may be to adopt higher heparin levels. Several reports provide some data to support this. Kestin and colleagues [6] showed that there was little evidence of platelet activation in a protocol that used 4 mg/kg heparin as a loading dose. Platelets showed a lack of P-selectin expression in blood obtained from a bleeding time wound. There was no evidence of platelet activation as determined by flow cytometric analysis. Kestin and colleagues concluded that the changes seen were due to the lack of agonist (thrombin). Others have recently reported lower levels of markers of thrombin activation with higher heparin levels [7]. Despite this, there is concern that higher levels of heparin may result in increased postoperative bleeding. The ability to accurately titrate protamine reversal requirements using one of the commercially available kits, (HMS, Medtronic Inc, Parker, CO; RxDx, International Technidyne, New Jersey, NJ) should alleviate this problem.
Others have evaluated a lowering of heparin dose in an attempt to reduce bleeding [8]. This has often been in conjunction with heparin-coated cardiopulmonary bypass circuits [9]. Despite the early promise, standard heparin doses are usually used [10] except where a clinical reason for decreasing heparin dose, such as the presence of heparin-induced thrombocytopenic syndrome, is present.
Patients previously or recently exposed to heparin may also exhibit heparin resistance, a phenomenon characterized by low ACT after usual dosing and attributed to lowered circulating antithrombin III levels. Dietrich and co-workers [11] evaluated these patients and found there was evidence of increased coagulation activation at the end of bypass. More recently, they reported that preoperative anticoagulation with warfarin did not increase postoperative blood loss [12].
The use of higher circulating heparin levels requires the ability to monitor levels and the effect with reasonable precision using methods with which we are currently familiar. The use of the ACT can be subjected to many variables such as hemodilution, platelet count, and type of activating agent, as well as operator idiosyncrasies. The celite ACT has been shown to be nonlinear with respect to heparin levels when it exceeds 500 seconds. This is further exacerbated when serine proteinase inhibitors such as aprotinin or FUT 175 are added to the circulation during cardiopulmonary bypass [13, 14].
Kaolin as an activating agent may not be subject to such variations, especially if the methodology is controlled carefully (sample size and admixture of components) [15]. In this issue of the Annals, Despotis and associates [16] have shown that there is good correlation in individual patients of circulating heparin levels with the activated clotting time, although the variation was somewhat greater when the ACT exceeded 500 seconds using a high-range cartridge (Medtronic). The use of these tests will allow the maintenance of a consistent level of anticoagulation and the opportunity to determine the clinical and biochemical effects of high heparin doses.
The use of high heparin doses may result in lower antithrombin III levels at the end of cardiopulmonary bypass, resulting in better hemostasis. A further advantage of higher circulating levels at the initiation of cardiopulmonary bypass may be to overcome heparin resistance. Further work is needed to discern the clinical effect of high heparin levels, using markers such as those described by Boisclair and colleagues [17, 18]. The results of these studies will need to be correlated carefully with changes in clinical outcomes. More research is needed in these areas to determine which will become our best practice.
Footnotes
Address reprint requests to Dr Bidstrup, North Queensland Clinical School, University of Queensland, PO Box 1805, Townsville QLD, Australia 4810.
References
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