1Nuffield Department of Anaesthetics, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. 2Department of Haematology, Churchill Hospital, Headington, Oxford OX3 9LJ, UK*Corresponding author
Accepted for publication: July 13, 2001
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Abstract |
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Br J Anaesth 2001; 87: 8447
Keywords: blood, anticoagulants, heparin; blood, antithrombin; surgery, cardiovascular
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Introduction |
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Patients with unstable angina are commonly managed with i.v. heparin therapy and often present for urgent coronary revascularization. In such patients, the management of their anticoagulation for cardiopulmonary bypass (CPB) can be difficult. The AT-3 concentration can be increased either by giving fresh frozen plasma or AT-3 concentrate3 9 or more heparin can be given until an acceptable degree of anticoagulation is achieved.5 7 10 The former is expensive and time-consuming. The latter method, which is the more usual clinical approach, is difficult to monitor, and patients given greater doses of heparin have a greater risk of postoperative bleeding and blood transfusion.9 11 It is uncertain what constitutes adequate anticoagulation in these patients.
In our department we monitor heparinization peroperatively with activated coagulation time (ACT) and we obtain an ACT of 400 s or greater for CPB. However, we accept a lower ACT in patients who show marked heparin resistance (i.e. failure to obtain clinically adequate ACT despite apparently sufficient heparin).
We assessed heparin resistance in our patients, the relationship between this and indices of coagulation and anticoagulation, and verified that accepting a lower ACT did not increase subclinical coagulation or harm the patient. We feel this will clarify the management of this patient group and prevent the potential complications and disadvantages associated with further doses of heparin or the use of fresh frozen plasma or AT-3 concentrate.
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Methods |
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All blood samples were taken either from the arterial cannula after the removal of 15 ml of blood and fluid from the connecting catheter or directly from the bypass circuit. Anaesthesia was induced with fentanyl (15 µg kg1) and a sleep dose of either thiopentone or etomidate, and pancuronium (0.1 mg kg1); anaesthesia was maintained with halothane. Arterial and internal jugular cannulae were inserted and connected to an infusion of saline (0.9% w/v) with sodium heparin 1 U ml1 (Leo Laboratories, Princes Risborough, UK) running at 3 ml h1 to maintain cannula patency. Before cannulation of the aorta, sodium heparin was given i.v. at a dose of 300 IU kg1. Cannulation was performed and the patient commenced on CPB. Blood was analysed for ACT (Hemochron 401; Technidyne Corporation, Edison, NJ, USA), haematocrit, heparin concentration, AT-3, thrombinantithrombin complex (TAT-c), prothrombin fragment F1+2 (PF1+2) and D-dimers after induction of anaesthesia but before sternotomy, and 5 and 20 min after establishing CPB. If the first dose of heparin did not achieve an ACT of greater than 400 s at 5 min of CPB, a further 5000 IU of heparin was given; if this still did not achieve an ACT of greater than 400 s, this was accepted and no further heparin was administered.
Assays
Prothrombin fragment F1+2, TAT-c and D-dimers were all measured using commercial ELISA kits from Dade Behring (Walton Manor, Milton Keynes, UK); the kits were Enzygnost F1+2 micro, Enzygnost TAT micro and Enzygnost D-dimer micro respectively. Antithrombin was measured with a chromogenic kit (Coamatic Antithrombin; Chromogenics, Quadrateck, Epsom, UK). Heparin concentration was measured using a heparin anti-Xa assay (Organon-Teknika, Boxtel, Netherlands) with appropriate dilutions of patients samples. All the tests were performed according to the manufacturers instructions.
Statistics
Results are mean (SD). Paired and unpaired Students t tests were used throughout except for the numbers of patients in each group requiring second doses of heparin, which were analysed with the 2 test. Linear regression analysis by the least-squares method was performed for each measurement with ACT as a continuous independent variable. Significance was set at P<0.05.
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Results |
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Three patients in group C and 10 in group H had an ACT<350 s at either 5 or 20 min. When these two subgroups were compared within their parent group, the pre-CPB AT-3 in those patients of group C who subsequently had ACT<350 s was significantly lower than those with all ACT>350 s [83.4 (15.7)% in ACT>350 s and 48.8 (15.3)% in ACT<350 s; P<0.01]. There was no significant difference between the measurements of activation of coagulation between the subgroups. No patients had an ACT<300 s.
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Discussion |
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In contrast to other groups,2 3 8 12 we did not show a decreased response to initial heparin dose in patients receiving i.v. heparin therapy before cardiac surgery, although at 20 min of CPB the ACT was significantly less in the heparin group, which may indicate an overall increased requirement for heparin.
The AT-3 concentration was lower at all times in the heparin infusion group, but this only reached statistical significance 5 min after CPB. The AT-3 concentration was lower in the few control patients who had an ACT of less than 350 s after heparinization at either 5 or 20 min of CPB, but this difference was not seen between the two heparin groups with ACT greater than or less than 350 s. Therefore, our findings, based on relatively small numbers, cannot statistically support the theory that long-term heparin infusion decreases AT-34 or that this is responsible for the heparin resistance, as those patients with ACT<400 s in both the control and heparin groups had AT-3 concentrations greater than those who showed no heparin resistance. There was no correlation between AT-3 and heparin concentrations in either group.
In no case was the degree of activation of coagulation pathways greater in patients given heparin infusions than in patients in the control group. Both TAT-c and D-dimers increased over the operative period in both groups, which is the response seen to all surgery, not just that involving CPB.13 TAT-c was greater in the subgroup of heparin-infused patients who had ACT <400 s compared with those with ACT >400 s; however, this was not supported when the arbitrary division was taken as 350 s, or in the control group using either subdivision. This cannot be seen to be evidence of activation of coagulation.
The choice of ACT above which anticoagulation for CPB is considered to be adequate to prevent coagulation has always been controversial. Bull and colleagues1 suggested that below 300 s coagulation was activated and suggested a choice of 480 s as a safeguard, so that the value of 300 s was never reached. By measuring markers of activation of coagulation, Young and colleagues14 demonstrated that below 348 s activation was seen in rhesus monkeys, and rounded this figure up to 400 s. Gravlee and colleagues11 measured the activation of coagulation in humans and stated that ACTs greater than 350 s were not associated with any greater activation of coagulation. This is often interpreted to mean that the ACT should never fall below 400480 s and a lower value is unacceptable. This encourages the practice of giving greater doses of heparin with all the attendant disadvantages of increased postoperative blood loss. We confirmed that, even when the ACT fell to less than 350 s no activation of coagulation was seen. Perfusionists, blinded to the ACT and patient group, reported no clotting in their pumps or problems with the oxygenators and there were no differences in the postoperative outcomes of the two groups at 24 h (data not shown). Perhaps the way to avoid the peaks of anticoagulation in these cases is to accept the lower ACT but to measure it more frequently. This study supports the theory that a heparin dose of 300 IU kg1 provides a safe level of anticoagulation for CPB even in patients on heparin infusions.
ACT measurements are a convenient and hence common but crude measure of heparin anticoagulation. The divergence of results mentioned above suggests that it is not as useful as once considered. Heparin levels have been used to monitor heparinization in patients treated for deep vein thrombosis, but their use in CPB has not been widespread.15 We have confirmed the findings of other workers11 that the heparin concentration showed no significant difference between the groups at any time and did not correlate with the ACT. Possibly the time has come to move away from these older tests in favour of more sophisticated monitoring of heparinization and anticoagulation status.
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Acknowledgement |
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References |
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