Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

Area of Science:

• Cardiovascular Surgery
• Anesthesiology
• Pharmacology

Background:

• Protamine dosing post-cardiopulmonary bypass (CPB) typically uses a fixed ratio based on pre-CPB heparin dose.
• Mathematical models of heparin clearance offer a potential method to improve protamine dosing precision and coagulation outcomes.
• This study investigated a 2-compartment model for protamine dosing versus a fixed ratio.

Purpose of the Study:

• To evaluate if protamine dosing based on a mathematical model improves thromboelastography (TEG) parameters compared to a fixed ratio.
• To determine if the model-based approach reduces the administered protamine dose.
• To assess the impact on postoperative outcomes such as transfusion requirements and drainage.

Main Methods:

• An adaptive randomized controlled trial (NCT03532594) with 228 participants was conducted.
• Participants were randomized to receive protamine dosed by a heparin clearance model or a fixed ratio (1 mg protamine/100 IU heparin).
• The primary endpoint was kaolin TEG r-time 3 minutes post-protamine administration; secondary endpoints included transfusion needs and drainage.

Main Results:

• The model-based group showed a significantly shorter mean kaolin TEG r-time post-CPB (6.58 vs. 8.08 minutes; p=0.0016).
• The post-protamine TEG more closely resembled pre-CPB parameters in the model group (ratio 0.96 vs. 0.75; p<0.001).
• The model group received a lower median protamine dose (180 vs. 280 mg; p<0.001) with no significant difference in transfusion or drainage.

Conclusions:

• Mathematical model-guided protamine dosing improves TEG parameters and reduces protamine dose compared to fixed ratios post-CPB.
• This approach did not increase postoperative drainage or red blood cell transfusion requirements in this low-risk cohort.
• Further research may explore generalizability to diverse patient populations and complex clinical scenarios.