Protamine Administration Considerations
Administer protamine sulfate at 1 mg per 100 units of heparin given in the previous 2-3 hours (maximum 50 mg single dose), delivered slowly over 10 minutes to prevent life-threatening hypotension and anaphylactoid reactions. 1
Dosing Algorithm
Time-Based Dose Adjustments
The protamine dose must be reduced based on time elapsed since heparin administration, as heparin is metabolized with an approximate half-life of 30 minutes: 2
- Within 30 minutes: Full dose of 1.0 mg per 100 units heparin 1
- 30-60 minutes prior: Reduce to 0.5-0.75 mg per 100 units 3
- 60-120 minutes prior: Reduce to 0.375-0.5 mg per 100 units 3
- >2-3 hours: Protamine likely not needed 1
Critical pitfall: Never calculate protamine based on total cumulative heparin dose—only use the dose given in the preceding 2-3 hours. 1
Low Molecular Weight Heparin (LMWH) Reversal
For enoxaparin reversal, use a different calculation: 4
- Within 8 hours: 1 mg protamine per 1 mg enoxaparin (max 50 mg) 4
- 8-12 hours: 0.5 mg protamine per 1 mg enoxaparin (max 50 mg) 4
Note that protamine only partially reverses LMWH anticoagulation. 4
Administration Protocol
Infusion Rate
Always administer by slow IV injection over 10 minutes minimum—rapid administration causes severe hypotension, bradycardia, and anaphylactoid reactions that can be fatal. 1, 2 Resuscitation equipment and anaphylaxis treatment must be immediately available before administration. 2
Post-Administration Monitoring
Measure aPTT or ACT 5-10 minutes after protamine administration to confirm adequate reversal. 1 If ACT/aPTT remains elevated, administer additional protamine at 0.5 mg per 100 units of heparin. 1
High-Risk Populations
Insulin-Dependent Diabetics
Patients receiving NPH (neutral protamine Hagedorn) insulin have dramatically increased risk of severe anaphylactoid reactions—3% incidence versus 0.2% in non-insulin users. 5 These reactions carry 36% mortality in vascular surgery patients with cardiac disease. 5 Consider avoiding routine protamine reversal in this population when clinically feasible. 5
Other High-Risk Groups
Increased hypersensitivity risk occurs in: 4
- Fish allergy patients
- Prior protamine exposure
- Vasectomized or infertile men
- Previous protamine-insulin use
Context-Specific Modifications
Prophylactic Heparin
Do NOT routinely reverse prophylactic subcutaneous heparin—only consider reversal if aPTT is significantly prolonged with active bleeding. 1 Prophylactic doses rarely require reversal. 1
Cardiac Surgery with Cardiopulmonary Bypass
For CPB duration <90 minutes, use fixed-dose ratio method of 1.0-1.3 mg per 100 units. 1 Recent evidence suggests even lower ratios (0.56:1) may be sufficient, reducing protamine-related complications. 6
Important Safety Considerations
Paradoxical Anticoagulation
Protamine itself has weak anticoagulant properties at high doses, which can paradoxically worsen bleeding. 4, 7 This reinforces the importance of avoiding overdosing. 6
Rebound Anticoagulation
The heparin-protamine complex may dissociate as protamine is metabolized or attacked by fibrinolysin, potentially freeing heparin and causing delayed bleeding. 7 Monitor patients for several hours post-reversal.
Maximum Dose Limit
Never exceed 50 mg in any 10-minute period, regardless of heparin dose. 1, 2 This absolute limit prevents severe adverse reactions.