SEE Volume 42A Sample Question

Due to a protamine shortage, the pharmacy department at your institution asks if using an initial fixed dose of 250 mg of protamine for heparin reversal during adult cardiac surgery would be appropriate. A recent study compared the administration of a fixed 250 mg dose of protamine to that of a dose based on a protamine to heparin ratio of 1 mg:100 U in patients undergoing cardiac surgery. According to this study, which of the following statements is MOST likely true?

(A) No difference was found in the initial activated clotting time after reversal between the 2 groups. ✔

(B) No difference was found in the total amount of protamine administered for heparin reversal between the 2 groups. X

(C) Cumulative chest tube drainage during the first 24 hours after surgery was higher in the 250-mg dosing group. X

Read the discussion below.

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Discussion

Reversal of heparin during cardiac surgery has traditionally involved the administration of an initial protamine dose based on a protamine to heparin ratio of 1 mg:100 U. However, use of this dosing approach may result in the administration of excessive amounts of protamine, which may lead to increased bleeding. Excessive protamine also results in unnecessary costs and medication usage, issues that are particularly relevant in view of recent nationwide drug shortages of protamine and current emphasis on delivering cost-effective medical care.

A recent single-center randomized clinical trial compared 2 approaches for determining the initial protamine dose for heparin reversal during adult cardiac surgery: a fixed dose of 250 mg of protamine (fixed-dose group) versus a protamine dose based on a protamine to heparin ratio of 1 mg:100 U (ratio-based group). The choice of 250 mg as the fixed dose was based on the size of the larger protamine vial. The study included patients undergoing elective cardiac surgery with cardiopulmonary bypass who had an initial calculated heparin dose of 27,500 U or greater (350 U/kg/total body weight). Additional heparin after the initial calculated dose was administered as needed to achieve a pre-bypass activated clotting time (ACT) greater than 450 seconds. The initial protamine dose in the ratio-based group was based on the total amount of heparin administered pre-bypass. In both groups, additional protamine was administered after the initial protamine dose if the ACT was at least 20% above baseline or at the discretion of the surgeon or anesthesiologist if the ACT was above baseline but did not meet the 20% criteria.

The primary study outcome was the ACT after the initial protamine dose. Secondary outcomes included the administration of additional protamine after the initial dose, the total dose of protamine administered, and total chest tube drainage during the first 24 hours after surgery.

A total of 130 patients were enrolled in the study and randomized to the fixed-dose or ratio-based group (65 patients in each group). Five patients were subsequently removed from the study because of an unanticipated need for circulatory arrest, leaving 62 participants in the fixed-dose group and 63 participants in the ratio-based group. As hypothesized, the initial dose of protamine was lower in the fixed-dose group than in the ratio-based group (250 mg vs 335.6 mg; mean difference [MD], –85.6; 95% CI, –97.8 to –73.5).

The main study results were as follows (Table 1):

• The mean ACT after the initial protamine dose was not found to be different between the fixed-dose and ratio-based groups (123.6 seconds vs 125.6 seconds; MD, –2.0; 95% CI, –7.2 to 3.3).
• The odds of having an ACT greater than 10% above baseline after the initial protamine dose was not affected by the group assignment (adjusted odds ratio, 0.73; 95% CI, 0.31 to 1.71).
• The percentage of patients receiving additional protamine after the initial dose did not differ between the fixed-dose and ratio-based groups (29.0% vs 31.7%).
• The amount of additional protamine did not differ between the fixed-dose and ratio-based groups (13.5 mg vs 16.3 mg; MD, –2.9; 95% CI, –11.8 to 6.0).
• The total amount of protamine administered for heparin reversal was lower in the fixed-dose group than in the ratio-based group (263.5 mg vs 352.0 mg; MD, –88.5; 95% CI, –102.6 to –74.4).
• The total protamine to heparin ratio (total protamine dose/total heparin dose before bypass) was lower in the fixed-dose group than in the ratio-based group (0.79 vs 1.05; MD, –0.26; 95% CI, –0.30 to –0.22).
• Chest tube drainage during the first 24 hours after surgery was not found to be different between the fixed-dose and ratio-based groups (673.1 mL vs 750.3 mL; MD, –77; 95% CI, –220 to 65).

Table 1. Outcomes comparing the fixed and heparin ratio-based protamine dose groups. Used with permission, from Jain P, Silva-De Las Salas A, Bedi K, Lamelas J, Epstein RH, Fabbro M II. Protamine dosing for heparin reversal after cardiopulmonary bypass: a double-blinded prospective randomized control trial comparing two strategies. Anesthesiology. 2025;142(1):98-106. doi:10.1097/ALN.0000000000005256

In summary, this randomized clinical trial showed that an initial fixed dose of 250 mg of protamine may be as effective for reversing heparin during adult cardiac surgery with cardiopulmonary bypass as traditional protamine dosing based on a protamine to heparin ratio of 1 mg:100 U. Furthermore, this fixed-dose approach resulted in the administration of a lower total dose of protamine, potentially reducing costs and drug wastage.

Reference

1. Jain P, Silva-De Las Salas A, Bedi K, Lamelas J, Epstein RH, Fabbro M II. Protamine dosing for heparin reversal after cardiopulmonary bypass: a double-blinded prospective randomized control trial comparing two strategies. Anesthesiology. 2025;142(1):98-106. doi:10.1097/ALN.0000000000005256

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