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on-pump cardiac surgery , especially with deep hypothermic circulatory arrest and or requiring post-operative mechanical circulatory support [ ECMO , Impella , etc .] are likely to have continuing or worse ATIII deficiency , likely contributing to HR [ 45 ].
In patients who were already known to have HR in the preoperative period and or demonstrated HR in the intra-operative period and require post-operative therapeutic anticoagulation must be managed closely with multidisciplinary involvement , taking into account the urgency of anticoagulation and level of haemostasis following the surgery . Given the feasibility of reliably reversing UFH , it may be advisable to start with UFH , using both aPTT and anti-Xa for monitoring , to reliably reach therapeutic levels and identify HR early . In cases with a high risk of thrombotic complications , e . g ., mechanical valves , LVAD , BiVAD , etc ., and in cases where the risk of bleeding is deemed sufficiently low , early initiation of oral anticoagulant therapy may be advisable .
Alternatives for anticoagulation
Direct thrombin inhibitors are an alternative to heparin . Some of the most common are Bivalirudin , Lepirudin and Argatroban . These bind bivalently to thrombin directly , specifically to catalytic and anion-binding exosite of circulating and clot-bound thrombin inhibiting clot formation . The advantage of these over heparin is that they do not require antithrombin to exert their anticoagulant effect and their benefit can also be seen in HIT patients because DTIs do not bind to PF4 . The disadvantage however is the lack of a reversal agent leaving the clearance of these drugs from plasma being a combination of renal mechanisms , proteolytic cleavage or liver clearance depending on which DTI is used . This results in them having a half-life impacted by temperature , renal and liver function making the half-life challenging to predict .
There have been multiple studies out there comparing DTI with anticoagulation monitoring . Several laboratory tests are available to monitor DTI activity ; aPTT , ACT , thrombin time , dilute thrombin time ( DTT ) and Ecarin clotting time ( ECT ) [ 46 – 50 ].
Lepirudin is a DTI which has been shown to be safe . A study by Benoit et al . showed the safe use of Lepirudin with ECT monitoring in a HIT patient on CPB . Whole blood hirudin concentration during CPB was aimed to be above 4 mg / ml �1 . During the case , 0.1 mg / kg / h lepirudin was given preoperative , 0.2 lg / kg �1 bolus just before CPB , and 0.2 lg / kg �1 in the priming solution . Complementary boluses of 5 and 10 mg during the procedure were then given according to the ECT . Whole blood hirudin concentration was 3.8 – 5.8 lg / ml �1 with a total lepirudin administration of 44 mg . The case was done successfully and no thrombotic events were observed [ 51 ]. Another study done by Greinacher et al . looked at 82 patients with HIT . Eight of these needed CPB where Lepirudin was the anticoagulant and ECT was used for monitoring . An initial bolus of 0.25 mg / kg was given and then subsequently 5 mg boluses as needed when the ECT showed Lepirudin values of < 2500 ng / ml . Again , there were no adverse clotting events in any of these patients [ 52 ]. These studies show that it is safe to use dosing of 0.5 / 0.25 mg / kg for lepirudin with 5 mg top-ups at ECT measurements of 2500 – 4000 ng / ml to run CPB .
In reality , not every hospital has access to ECT testing , for those places there have been case reports where ACT has been used successfully [ 46 , 47 , 53 , 54 ]. A study done by Zucker et al . looked at 10 patients . Various ACTs ( ACTT ( Modified ACT ), Celite , Kaolin , ACT +) and ECT levels were investigated against plasma Bivalirudin concentration . Dosing was fixed to ( 1.0 mg / kg bolus followed by a 2.5 mg / kg / h infusion for all patients . The ACTT and the ECT showed greater sensitivity to bivalirudin ( 28.5 s / lg / ml bivalirudin ) compared with the other ACTs evaluated ( 14 s / lg / ml ), this was especially true at low concentrations of bivalirudin (< 10 lg / ml ), with the ECT and ACTT showing slopes near 40 , and the ACT slopes varying from 18 to 27 sec / microg / ml . Although ACTs were still sensitive to Bivalirudin concentration [ 53 ].
Another case study done was by Boysan et al . using Bivalirudin during CPB . They used the same 1.0 mg / kg bolus followed by a 2.5 mg / kg / h infusion . Top-ups of 0.5 mg / kg were added as necessary and the patient had no thrombotic events using ACT , their ACT levels were always above 300 s but often did not reach 400 . As a result , they decided to stop renal clearance of Bivalirudin to aid the ACT [ 46 ].
Nikolaides also did a case report using Bivalirudin . The same dosing strategies as above were initially implemented but they later found with their 100 kg patient this dose was not enough to raise the ACT as required so they gave a total of 250 mg of Bivalirudin as a loading dose and then increased their infusion to 5 mg / kg / h . Using this method with ACT was successful and the case was completed without any adverse effects . This shows that anticoagulation management should be considered patient specific and the dosing should not be blindly followed for every patient . Anticoagulation is multifaceted and there would be an increase in risk and safety without looking at Anticoagulation monitoring indicators [ 47 ].
Nafamostat mesilate ( NM ) is a synthetic protease inhibitor which has been shown to inhibit factor XII , fibrinolysis , platelet aggregation , and blood-foreign surface interaction . It has been used previously in open heart surgery and reduced bleeding [ 55 ]. NM is another drug which has been used in conjunction with Heparin in heparin-resistant patients undergoing CPB . A study done by Kikura et al . looked at 870 cardiac surgery patients , 190 of which had HR , these received a bolus of NM 10 – 20 mg plus 25 – 50 mg / h of NM with 100 u / kg of intravenous heparin every 1.5 – 2 h to maintain ACTs of > 480 s . Ischemic strokes were only found in 1 patient ( 0.5 %) in patients receiving NM as opposed to 10 patients ( 1.5 %) in patients without [ 56 ]. Other studies have shown successful CPB cases using the same combination of NM and LMWH in infective endocarditis patients with a high risk of cerebral bleeds [ 5 , 57 – 59 ]. More studies will have to be done to find out if this strategy is a good alternative treatment in HR patients and may potentiallybesafetouseroutinelyinCPB .
Conclusion
HR during cardiac surgery poses significant risks , leading to adverse outcomes . Advances in understanding its mechanisms