Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery

Abstract

While experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p<0.001), while post-protamine activated clotting times were similar among groups. The high dosing group revealed increased intrinsic clotting times (236 ± 74 vs 196 ± 64 s; p=0.006) and the maximum post-protamine thrombin generation was less suppressed in the low dosing group (38 ± 40 % vs 6 ± 9 %; p=0.001). Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95 % CI 500-830 ml vs 470 ml; 95 % CI 420-530 ml; p=0.021) when compared to the low dosing group, respectively. More patients in the high dosing group received fresh frozen plasma (11 % vs 0 %; p=0.02) and platelet concentrate (21 % vs 6 %; p=0.04) compared to the low dosing group. Our study confirms in vitro data that abundant protamine dosing is associated with increased postoperative blood loss and higher transfusion rates in cardiac surgery.

2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery

“…165 In a second RCT, a protamine-to-heparin dosing ratio of 1.3 over the total heparin dose was associated with significantly more postoperative bleeding (615 ml, 95% CI 500-830 vs 470 ml, 95% CI 420-530; P ¼ 0.02) compared with a dosing ratio of 0.8, whereas post-protamine ACT levels were comparable among the groups. 154 None of the patients showed signs of heparin rebound. A recent RCT in patients having CABG showed that a protamine-to-heparin dosing ratio o0.6 was associated with significantly more blood loss within 12 h after surgery [420 ml (interquartile range 337-605 ml) vs 345 ml (interquartile range 230-482 ml); P ¼ 0.0041], but no difference in PRBC transfusion was noted (2.3 units vs 2.7 units; P ¼ 0.83) compared to patients subjected to a ratio 40.8.…”

The role of evidence-based algorithms for rotational thromboelastometry-guided bleeding management

“…Therefore, a 1 : 1 ratio between primary heparin dose and protamine dose cannot be recommended. Here, a heparin to protamine ratio of 1 : 0.6-0.8 seems to be more effective [56,61,62]. Additional protamine administration is definitively not beneficial in patients with a prolonged ACT due to a protamine overdose.…”

“…4 Algorithms for ROTEM-guided management CT IN /CT HEP -ratio ≤ 1, but also with a significant and long-acting inhibition of platelet function including the adenosine diphosphate (ADP)-and thrombin receptor-activating peptide (TRAP)-pathway [57][58][59][60]. RCTs confirmed that a protamine overdose is associated with a significant increase in blood loss, transfusion requirements, and need for re-surgery after cardiac surgery [61,62]. Therefore, a 1 : 1 ratio between primary heparin dose and protamine dose cannot be recommended.…”

Point-of-Care Measurement of Activated Clotting Time for Cardiac Surgery as measured by the Hemochron Signature Eliteand the Abbott i-STAT: Agreement, Concordance, and Clinical Reliability

“…Obviously, while the former reading suggests a more than sufficient degree of heparin anticoagulation, the latter clearly is far below our target value of 430 seconds for CPB and, if true, would have put the patient at risk for clot formation within the CPB circuit. In fact, it is not far fetched that some of the reported CPB cases of intracardiac and oxygenator thrombosis [18][19][20][21] may be due to wrong ACT measurements.…”