Chapter 228. Protamine

Pharmacology. Protamine is a cationic protein obtained from fish sperm that rapidly binds to and inactivates heparin. The onset of action after intravenous administration is nearly immediate (30–60 seconds) and lasts up to 2 hours. It also partially neutralizes low-molecular-weight heparins (LMWHs) and can act as an anticoagulant by inhibiting thromboplastin.

Indications

1. Protamine is used for the reversal of the anticoagulant effect of heparin when an excessively large dose has been administered inadvertently. Protamine generally is not needed for the treatment of bleeding during standard heparin therapy because discontinuance of the heparin infusion is generally sufficient.

2. Protamine may be used for the reversal of regional anticoagulation in the hemodialysis circuit in cases in which anticoagulation of the patient is contraindicated (ie, active GI or CNS bleeding).

Contraindications

1. Do not give protamine to patients with known sensitivity to the drug. Patients with diabetes who have used protamine insulin may be at the greatest risk for hypersensitivity reactions.

2. Protamine reconstituted with benzyl alcohol should not be used in neonates because of suspected toxicity from the alcohol.

Adverse effects

1. Rapid intravenous administration is associated with hypotension, bradycardia, and anaphylactoid reactions. Have epinephrine (See Epinephrine), diphenhydramine (See Diphenhydramine), and cimetidine or another histamine2 (H2) blocker (See Cimetidine and Other H2 Blockers) ready. Reaction may be prevented by avoiding high infusion rates of more than 5 mg/min.

2. A rebound effect caused by heparin may occur within 8 hours of protamine administration.

3. Excess doses may lead to anticoagulation and the risk for bleeding.

4. Use in pregnancy. FDA Category C (indeterminate). A maternal hypersensitivity reaction or hypotension can result in placental ischemia. However, this does not preclude its acute, short-term use for a seriously symptomatic patient (See Introduction in Section III).

Drug or laboratory interactions. No known drug interactions other than the reversal of the effect of heparin.

Dosage and method of administration

1. Administer protamine by slow intravenous injection over at least 1–3 minutes, not to exceed 50 mg in a 10-minute period.

2. The dose of protamine depends on the total dose and the time since the administration of heparin.

   1. If immediately after heparin administration, give 1–1.5 mg of protamine for each 100 units of heparin.

   2. If 30–60 minutes after heparin administration, give only 0.5–0.75 mg of protamine for each 100 units of heparin.

   3. If 2 hours or more after heparin administration, give only 0.25–0.375 mg of protamine for each 100 units of heparin.

   4. If heparin was being administered by constant infusion, give 25–50 mg of protamine.

3. If the patient is overdosed with an unknown quantity of heparin, give an empiric dose of 25–50 mg over 15 minutes (to minimize hypotension) and determine the activated partial thromboplastin time (aPTT) after 5–15 minutes and for up to 2–8 hours to determine the need for additional doses.

4. For an overdose of a low-molecular-weight heparin

   1. Dalteparin or tinzaparin. Give 1 mg of protamine for every 100 anti–factor Xa international units of dalteparin and tinzaparin. If 8–12 hours has elapsed since ...