Key points
- We recommend to consult your poison centre with the use of this antidote.
- Onset of action is about 5 minutes; duration of action is about 2 hours.
- Administered alone, protamine exerts an anticoagulant effect. However, when administered in the presence of heparin (a strongly acidic substance) a stable salt is formed, resulting in loss of anticoagulant activity for both agents.
- A larger than necessary (> 6 mg/kg) dose of protamine can therefore have an anticoagulant effect and inhibit platelet formation. It is generally better to administer a lower dose than a higher one.
+ Synonyms and other terms
- Protamine sulfate
+ Indications
- Overdose of unfractionated heparin (UFH; standard heparin) with bleeding.
- Overdose of low molecular weight heparin (LMWH; dalteparin, enoxaparin, nadroparin, tinzaparin ) with bleeding.
+ Dosage
+ Pediatric Dose
WARNING: The dose of protamine to be administered should be calculated based on the remaining amount of anticoagulant to be neutralized.
Unfractionated (standard) heparin:
- Available activated partial thromboplastin time (APTT):
- APTT 150-200 secs: No protamine.
- APTT 200-300 secs: 0.6 mg/kg protamine (max 50 mg/dose) by IV infusion over 10 min.
- APTT 300-400 secs: 1.2 mg/kg protamine (max 50 mg/dose) by IV infusion over 10 min.
Repeat the APTT 5-15 min after the end of the IV infusion and 2 hrs later (possibility of rebound with heparin) to assess whether an additional dose is required.
- APPT unavailable; heparin dose known (continuous IV infusion):
- Consider the elimination half-life of standard heparin is about 1 hr.
- Calculate the amount of heparin to neutralize:
- Include all bolus doses and the continuous infusion in the calculation.
- [All the units administered in the last hour] + [half the units administered 2 hrs ago] + [a quarter of the units administered 3 hours ago]
- Example: For a patient receiving a continuous IV infusion of standard heparin of 1500 units/h with a 5000 unit bolus 3 hrs ago, should neutralize: [1500 units in the last hour] + [750 units 2 hrs ago] + [1250 units (bolus) + 375 units (infusion) 3 hrs ago] = 3875 units to neutralize.
- Determine the dose of protamine to administer:
- [Quantity of heparin to neutralize] x [1 mg protamine/100 units of heparin]
- Maximum 50 mg of protamine per dose
- E.g.: To neutralize 3875 standard heparin units, administer approx. 39 mg of protamine.
- Administer the dose by IV infusion over 10 min.
- APPT unavailable; heparin dose known (administer by direct IV only):
- See table below.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
TIME SINCE THE INJECTION OF HEPARIN DIRECT IV | DOSE OF PROTAMINE RECOMMENDED FOR EACH 100 UNITS OF STANDARD HEPARIN |
Shorter than 30 minutes | 1 mg |
30 - 60 minutes | 0.5 to 0.75 mg |
60 - 120 minutes | 0.375 to 0.5 mg |
Longer than 120 minutes | 0.25 to 0.375 mg |
- APTT unavailable; heparin dose unknown:
- Administer an empirical dose of 25-50 mg of protamine IV infusion over 10 min.
- Adjust the dose if necessary, depending on effect.
Repeat the APTT 5 to 15 min after the end of the IV infusion and 2 hours later (possible rebound with heparin) to assess whether an additional dose is required.
- Standard heparin administered subcutaneously:
- 1-1.5 mg of protamine per 100 standard units heparin.
- Administer the dose by IV infusion over 10 min.
Low Molecular Weight Heparin (LMWH):
- If shorter than 8 hours since last dose of LMWH:
- 1 mg of protamine per mg of enoxaparin or for every 100 anti-Xa units of LMWH.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
- An additional dose corresponding to half of the initial dose may be necessary if the APTT remains high when measured 2 to 4 hours after the first infusion.
- If longer than 8 hours and less than 12 hours since last dose of LMWH:
- 0.5 mg of protamine per mg of enoxaparin or for every 100 anti-Xa units of LMWH.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
- It may be necessary to repeat the same dose if the APTT remains high when measured 2 to 4 hours after the first infusion.
- If longer than 12 hours since the last dose of LMWH:
- Administration of antidote may not be necessary; check with the Poison Control Center whether administration of low doses of protamine would be appropriate.
+ Adult Dose
WARNING: The dose of protamine to be administered should be calculated based on the remaining amount of anticoagulant to be neutralized.
Unfractionated (standard) heparin:
- Available activated partial thromboplastin time (APTT):
- APTT 150-200 secs: No protamine.
- APTT 200-300 secs: 0.6 mg/kg protamine (max 50 mg/dose) by IV infusion over 10 min.
- APTT 300-400 secs: 1.2 mg/kg protamine (max 50 mg/dose) by IV infusion over 10 min.
Repeat the APTT 5-15 min after the end of the IV infusion and 2 hrs later (possibility of rebound with heparin) to assess whether an additional dose is required.
- APPT unavailable; heparin dose known (continuous IV infusion):
- Consider the elimination half-life of standard heparin is about 1 hr.
- Calculate the amount of heparin to neutralize:
- Include all bolus doses and the continuous infusion in the calculation.
- [All the units administered in the last hour] + [half the units administered 2 hrs ago] + [a quarter of the units administered 3 hours ago]
- Example: For a patient receiving a continuous IV infusion of standard heparin of 1500 units/h with a 5000 unit bolus 3 hrs ago, should neutralize: [1500 units in the last hour] + [750 units 2 hrs ago] + [1250 units (bolus) + 375 units (infusion) 3 hrs ago] = 3875 units to neutralize.
- Determine the dose of protamine to administer:
- [Quantity of heparin to neutralize] x [1 mg protamine/100 units of heparin]
- Maximum 50 mg of protamine per dose
- E.g.: To neutralize 3875 standard heparin units, administer approx. 39 mg of protamine.
- Administer the dose by IV infusion over 10 min.
- APPT unavailable; heparin dose known (administer by direct IV only):
- See table below.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
TIME SINCE THE INJECTION OF HEPARIN DIRECT IV | DOSE OF PROTAMINE RECOMMENDED FOR EACH 100 UNITS OF STANDARD HEPARIN |
Shorter than 30 minutes | 1 mg |
30 - 60 minutes | 0.5 to 0.75 mg |
60 - 120 minutes | 0.375 to 0.5 mg |
Longer than 120 minutes | 0.25 to 0.375 mg |
- APTT unavailable; heparin dose unknown:
- Administer an empirical dose of 25-50 mg of protamine IV infusion over 10 min.
- Adjust the dose if necessary, depending on effect.
Repeat the APTT 5 to 15 min after the end of the IV infusion and 2 hours later (possible rebound with heparin) to assess whether an additional dose is required.
- Standard heparin administered subcutaneously:
- 1-1.5 mg of protamine per 100 standard units heparin.
- Administer the dose by IV infusion over 10 min.
Low Molecular Weight Heparin (LMWH):
- If shorter than 8 hours since last dose of LMWH:
- 1 mg of protamine per mg of enoxaparin or for every 100 anti-Xa units of LMWH.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
- An additional dose corresponding to half of the initial dose may be necessary if the APTT remains high when measured 2 to 4 hours after the first infusion.
- If longer than 8 hours and less than 12 hours since last dose of LMWH:
- 0.5 mg of protamine per mg of enoxaparin or for every 100 anti-Xa units of LMWH.
- Maximum 50 mg/dose.
- Administer the dose by IV infusion over 10 min.
- It may be necessary to repeat the same dose if the APTT remains high when measured 2 to 4 hours after the first infusion.
- If longer than 12 hours since the last dose of LMWH:
- Administration of antidote may not be necessary; check with the Poison Control Center whether administration of low doses of protamine would be appropriate.
+ Renal Impairment
No data suggests that the dose should be modified for short-term use.
+ Hepatic Impairment
No data suggests that the dose should be modified for short-term use.
+ Hemodialysis Patient
No data suggests that the dose should be modified for short-term use.
+ Pregnancy
- Safety has not been established.
- Do not hesitate to use protamine during pregnancy if the expected toxic effects pose a significant risk of morbidity or mortality.
- No data suggests that the dose should be modified for short-term use.
+ Obese or Overweight Patient
No data suggests that the dose should be modified for short-term use.
+ Adverse effects
- Related to rate of injection: anaphylactoid reaction with hypotension, bradycardia, erythema, urticaria, dyspnea.
- Unrelated to rate of injection: anaphylaxis, ventricular fibrillation, asystole, non-cardiac pulmonary edema.
- Risk factors for adverse reaction to protamine: injection rate, history of diabetes treated with NPH insulin or protamine zinc, fish allergy (theoretical) or vasectomy (theoretical).
+ Monitoring
- Activated partial thromboplastin time (APTT) 5 to 15 min after protamine infusion and 2 hours later (possibility of rebound with heparin) to assess whether an additional dose is required.
- anti-Xa activity.
- Assay for anti-Xa activity may not be available everywhere; APTT, which measures anti-IIa activity, can generally be used to assess the degree of anticoagulation with LMWH.
- Vital signs: BP and HR.
- Anaphylactoid reactions.
+ End of treatment
- Bleeding stopped.
- Significant adverse effects.
+ Special Notes on Administration
Intravenous Route (IV)
- Direct IV:
- Prefer slow IV infusion to direct IV route whenever possible.
- Maximum rate of 5 mg/min, without exceeding 50 mg per 10 min period.
- Too rapid administration may cause hypotension or pseudo-anaphylactoid reaction.
- IV infusion over 10 minutes:
- Preferred administration.
- Administer the IV dose from the concentrated 10 mg/ml IV solution (max 50 mg/dose) for at least 10 minutes using a volumetric pump.
- The dose may be diluted in 25 to 100 ml of compatible solution in order to facilitate administration of the antidote.
Subcutaneous Route (SC)
- Not applicable.
Intramuscular Route (IM)
- Not applicable.
Intraosseous Route (IO)
- No data available.
Compatibility
Partial list only. Consult the pharmacist on duty at your health care facility.
- Compatible solutes: NS, D5W.
- Y-site compatibility: imipenem and cilastatin.
- Y-site incompatibility: ampicillin, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, penicillin G, piperacillin.
Stability
- Keep the vials at room temperature between 15°C and 30°C.
- Vials for single use with no preservatives.
- No data on the stability of dilute solutions; prepare and administer immediately.
+ Available products
+ Amount required to treat a person weighting 70kg during 24 hours
- At least 250 mg.
+ References
Howland, Mary Ann, Protamine, In Goldfrank's Toxicologic emergencies, Chapter A16, 10th edition, Mc Graw Hill Education, USA 2015, 839-842
