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Heparin Antidote — Vascular / Cardiac Surgery

Protamine Sulphate

Brand names: Protamine Sulphate Injection

Protamine sulphate is the specific intravenous antidote used to neutralise the anticoagulant effect of unfractionated heparin, for example after cardiopulmonary bypass or when reversing therapeutic heparinisation.

Auto-extracted from the source labelling — not yet independently clinician-verified. These values were distilled from the UK SPC (or the US label where noted) but have not had a clinician sign-off. Confirm against the current SmPC before prescribing.

Adult dose

Dose: NEUTRALISATION OF UNFRACTIONATED HEPARIN, INTRAVENOUS: dose is calculated from the heparin to be neutralised, not from body weight. US label verbatim: 'Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.' The dose must then be reduced for heparin already cleared: 'Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin. For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.'
Route: Intravenous — 'Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period'. 'Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used. Diluted solutions should not be stored since they contain no preservative.'
Frequency: Single slow intravenous injection over 10 minutes, with further dosing guided by coagulation studies — 'The dosage of protamine sulfate should be guided by blood coagulation studies.' The label gives no fixed repeat interval.
Max: Maximum 50 mg per dose. US label verbatim: 'Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg.'
Source: US FDA prescribing information (openFDA/DailyMed), Protamine Sulfate Injection USP, Fresenius Kabi USA LLC, label date 2024-03-18. NO UK SPC WAS FETCHED — verify every figure against the UK SPC before publication. INDICATION SCOPE: the dose above is neutralisation of UNFRACTIONATED HEPARIN. THE LOW-MOLECULAR-WEIGHT HEPARIN FIGURES ON THE LIVE PAGE ARE NOT IN THIS SOURCE — '1 mg per 100 anti-Xa units of LMWH', '1 mg per 1 mg enoxaparin', the '~60–80% anti-Xa reversal' figure and the statement about fondaparinux appear nowhere in the fetched label and must not be carried forward without their own source. Likewise the live page's 'rate <5 mg/min' is not in this label; what the label states is the 10-minute injection period and the 50 mg per-dose ceiling. COMPATIBILITY: 'Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.' 'Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration.' TRUNCATION: the label's WARNINGS and PRECAUTIONS sections were NOT retrieved in this bundle (only DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and a truncated ADVERSE REACTIONS), so the safety fields below are incomplete — in particular the fish-allergy, prior-protamine-exposure, vasectomy and NPH-insulin risk factors named on the live page are absent from what was fetched and are unverified here.

Dose adjustments

Renal

Not stated — the fetched label sections (DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, ADVERSE REACTIONS) contain no renal dose adjustment, and WARNINGS/PRECAUTIONS were not retrieved. The dose is determined by the quantity of heparin to be neutralised and by blood coagulation studies, not by renal function. Verify against the UK SPC.

Hepatic

Not stated — no hepatic dose adjustment appears in any fetched section of this bundle. Verify against the UK SPC.

Dose auto-extracted from US FDA prescribing information (openFDA / DailyMed) — cross-check; US labelling may differ from UK — not yet clinician-verified. Always confirm against the product SmPC and your local formulary before prescribing.

Contraindications

  • 'Protamine sulfate is contraindicated in patients who have shown previous intolerance to the drug.' (This is the ENTIRE contraindications section of the fetched label — the fish-allergy, previous-protamine-sensitivity and vasectomy items on the live page are NOT in this source and are unverified here.)

Side effects

  • 'The intravenous administration of protamine sulfate may cause a sudden fall in blood pressure and bradycardia.'
  • 'Other reactions include transitory flushing and feeling of warmth, dyspnea, nausea, vomiting and lassitude.'
  • 'Back pain has been reported in conscious patients undergoing such procedures as cardiac catheterization.'
  • Anaphylaxis 'that resulted in severe respiratory distress, circulation collapse and capillary leak. Fatal anaphylaxis has been reported in one patient with no prior history of allergies'
  • Anaphylactoid reactions 'with circulatory collapse, capillary leak, and noncardiogenic pulmonary edema; acute pulmonary hypertension'
  • 'Severe and potentially irreversible circulatory collapse associated with myocardial failure and reduced cardiac output can also occur.'
  • High-protein, noncardiogenic pulmonary oedema
  • NOTE: the ADVERSE REACTIONS section was truncated at the source-fetch limit, so this is not a complete list

Monitoring

  • COAGULATION STUDIES GOVERN THE DOSE — 'The dosage of protamine sulfate should be guided by blood coagulation studies' (stated twice in the DOSAGE AND ADMINISTRATION section, both times cross-referring to WARNINGS).
  • TIME SINCE HEPARIN must be established before dosing, because the required protamine dose falls rapidly as heparin is cleared ('if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient').
  • HAEMODYNAMIC MONITORING during the injection: intravenous administration 'may cause a sudden fall in blood pressure and bradycardia', so monitor blood pressure and heart rate throughout the 10-minute injection and be prepared for anaphylaxis, anaphylactoid reactions, capillary leak, noncardiogenic pulmonary oedema and acute pulmonary hypertension.
  • NOTE: the WARNINGS and PRECAUTIONS sections referenced repeatedly by the dosing text were NOT retrieved in this bundle, so this monitoring set is incomplete — read them in the UK SPC.

Clinical monograph

How it works

It is a strongly basic protein that binds ionically to acidic heparin molecules, forming an inactive stable complex and thereby abolishing heparin's antithrombin-mediated anticoagulant activity; it only partially reverses low molecular weight heparins.

Prescribing in practice

  • Give by slow intravenous injection — rapid administration can cause severe hypotension, bradycardia, flushing and acute pulmonary hypertension, so titrate against the heparin dose still circulating and avoid excess (protamine itself has weak anticoagulant activity in overdose).
  • Patients exposed to protamine-containing insulins, those with fish allergy, and men who have had a vasectomy are at higher risk of hypersensitivity and anaphylaxis, so have resuscitation facilities available.
  • It only incompletely neutralises low molecular weight heparins and does not reliably reverse fondaparinux, so confirm which anticoagulant is being reversed before dosing.

Monitoring

Monitor activated partial thromboplastin time (or activated clotting time intra-operatively) to confirm reversal, alongside blood pressure, heart rate and signs of anaphylaxis during and after the injection.

Counselling the patient

  • Explain this is given by a clinician to switch off the effect of a blood-thinner.
  • Report any breathlessness, flushing, rash or feeling faint immediately.

Evidence & guidelines

Its use as the heparin antidote is long-established standard practice supported by the SPC, surgical anticoagulation protocols and UK guidance.

Reference: MHRA SPC Protamine Sulphate; British Society for Haematology LMWH Guidelines; Cardiac Surgery Anticoagulation Protocols; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

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