The HEPDOSE pilot study: the use of the PRODOSE algorithm to reverse the effects of the administration of initial high dose unfractionated heparin.

Introduction Objectives: The use of the individualised, pharmacokinetic PRODOSE algorithm for reversing unfractionated heparin (UFH) after cardiopulmonary bypass (CPB) demonstrated a 36% protamine dose reduction compared with the standard regimen (1 mg protamine / 100U pre-CPB heparin) without increased bleeding (1). We aimed to investigate the validity of this algorithm when used on 3 different initial UFH doses. Methods Design: Prospective study Setting Tertiary care cardiac centre Participants 60 elective adult patients undergoing cardiac surgery on CPB Interventions After ethics approval, 60 well matched patients were allocated into three groups to receive an initial dose of 300, 400 or 500 IU per kilogram of UFH prior to the commencement of CPB. Sampling was performed after induction of anaesthesia, and after heparin reversal with protamine using the PRODOSE algorithm. Samples were analysed for the ratio of ROTEM CT INTEM / HEPTEM (I:H CT ratio) anti-Xa levels. Results Measurements and Main Results: The total mean administered heparin dose in the 300IU/kg, 400IU/kg and 500IU/kg groups were 39,975 (36,528-43,421) IU, 43,195 (36,940-49,449) IU and 47,900 (44,807-50,992) IU, respectively (p=0.039). There was no difference in baseline I:H CT ratio (p=0.16) or anti Xa levels (p=0.13) between the groups. The protamine:heparin ratio for reversal post CPB was 0.6 in all three groups. After reversal the I:H CT ratio was 0.997 (0.866-1.02) in the 300U/kg group, 1.038 (0.969-1.042) in the 400U/kg group and 1.03 (0.979-1.063) in the 500U/kg group (p=0.16). There was no statistically significant difference between pre-heparin and post-reversal I:H CT ratio in any of the groups. There was no significant difference in anti-Xa levels (p=0.270) between the groups. There was no difference in overall 24-hour blood loss (p=0.68) or packed red blood cell transfusion (p=0.922). Discussion Conclusion: A primary outcome of an I:H CT ratio of < 1.25 is indicative of complete heparin reversal after CPB. Our study shows that using the PRODOSE pharmacokinetic algorithm to calculate the required protamine dose is feasible and safe over a broad range of pre-CPB heparin doses. This is supported by the secondary outcomes of similar anti Xa levels, blood loss and blood usage in all three groups.