Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial.
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.
Michael I
MI
Meesters
Dennis
D
Veerhoek
Fellery
F
de Lange
Jacob-Willem
JW
de Vries
Jan R
JR
de Jong
Johannes W A
JW
Romijn
Hilde
H
Kelchtermans
Dana
D
Huskens
Robin
R
van der Steeg
Pepijn W A
PW
Thomas
David T M
DT
Burtman
Laurentius J M
LJ
van Barneveld
Alexander B A
AB
Vonk
Christa Boer, Professor of Anaesthesiology, Department of Anaesthesiology, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands, Tel.: +31 20 4443830, Fax: +31 20 4444385, E-mail: c.boer@vumc.nl.
Christa
C
Boer
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D016063:Blood Loss, Surgical / Q000517:prevention & control; D001803:Blood Transfusion; D002315:Cardiopulmonary Bypass; D001026:Coronary Artery Bypass / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage*; D006494:Heparin Antagonists / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011479:Protamines / Q000008:administration & dosage* / Q000009:adverse effects*; D016037:Single-Blind Method; D013916:Thrombelastography
D000925:Anticoagulants; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin
Heparins; blood products; coagulation factors; surgery; thrombin