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  1. Pharmacology. Protamine is a cationic protein obtained from fish sperm that rapidly binds to and inactivates heparin by forming a stable salt. 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.

  2. 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 (i.e., active GI or CNS bleeding).

    3. Protamine may be used for the reversal of low-molecular-weight heparins (LMWHs). However, its effect may be partial and unpredictable and is generally reserved for cases with emergent and clinically significant bleeding.

  3. Contraindications

    1. Black Box Warning. 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.

  4. Adverse effects

    1. Black Box Warning. Rapid intravenous administration and high doses are associated with hypotension, bradycardia, and anaphylactoid reactions. Have epinephrine, diphenhydramine, and cimetidine or another histamine2 (H2) blocker 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 (Introduction).

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

  6. Dosage and method of administration

    1. Administer protamine by slow intravenous injection, not to exceed 50 mg in a 10-minute period or 5 mg/min.

    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 60–120 minutes after heparin administration, give only 0.375-0.5 mg of protamine for each 100 units of heparin.

      4. If more than 2 hours after heparin administration, give only 0.25-0.375 mg of protamine for each 100 units of heparin.

      5. 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 10 minutes (to minimize hypotension) and determine the ...

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