Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery?
OBJECTIVE
Heparin rebound, the reappearance of anticoagulant activity after adequate neutralization with protamine, is thought to contribute to excessive postoperative bleeding after cardiac surgery. We have previously demonstrated that a significant amount of heparin is bound nonspecifically to plasma proteins and is incompletely neutralized by protamine. The aim of this study was to investigate whether clinically important bleeding attributable to heparin rebound can be eliminated by infusion of small amounts of additional protamine for 6 hours postoperatively and whether this treatment can reduce mediastinal blood loss.


METHODS
Three hundred patients undergoing elective cardiac surgery were randomized to receive either a continuous infusion of protamine sulphate (25 mg/h for 6 hours) postoperatively or saline placebo. Serial blood samples were obtained to measure thrombin clotting time and anti-factor Xa activity. Heparin bound nonspecifically to plasma proteins was measured after displacement with a chemically altered heparin with low affinity to antithrombin. Mediastinal blood loss and transfusion requirements were recorded.


RESULTS
Heparin rebound was demonstrated in every patient in the placebo group as reflected by increased thrombin clotting time, anti-factor Xa activity, and protein-bound heparin between 1 and 6 hours after surgery. In contrast, heparin rebound was eliminated in the protamine infusion group. The thrombin clotting time was normalized and both heparin concentration and protein-bound heparin were almost undetectable (P <.001). There was a modest 13% reduction in postoperative bleeding but this did not reduce blood transfusions. No adverse events were attributable to the extra protamine.


CONCLUSIONS
Postoperative protamine infusion was able to almost totally abolish heparin rebound. In the context of this study, protamine infusion resulted in reduced postoperative bleeding but the magnitude was insufficient to alter transfusion requirements.
Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
Kevin H T
KH
Teoh
Edward
E
Young
Mary Helen
MH
Blackall
Robin S
RS
Roberts
Jack
J
Hirsh
D000925:Anticoagulants / Q000009:adverse effects* / Q000378:metabolism; D016063:Blood Loss, Surgical / Q000706:statistics & numerical data; D001798:Blood Proteins / Q000378:metabolism; D001803:Blood Transfusion / Q000706:statistics & numerical data; D002315:Cardiopulmonary Bypass; D004311:Double-Blind Method; D005260:Female; D006493:Heparin / Q000009:adverse effects* / Q000378:metabolism; D006494:Heparin Antagonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care; D011479:Protamines / Q000627:therapeutic use*; D011485:Protein Binding; D013997:Time Factors
D000925:Anticoagulants; D001798:Blood Proteins; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin