Protamine Reaction

Protamine reaction is an adverse response to protamine sulphate given to reverse heparin, ranging from hypotension to anaphylaxis and catastrophic pulmonary hypertension.

Epidemiology. Reactions occur in about 0.2% to 3% of administrations. Severe reactions occur in about 1 in 1,000 to 1 in 3,000.

Types. Type 1: rapid injection hypotension from histamine and nitric oxide release (common). Type 2: immediate anaphylaxis (IgE or IgG). Type 3: non-cardiogenic pulmonary oedema and catastrophic pulmonary vasoconstriction (complement mediated, thromboxane release) with right heart failure. Type 4: delayed pulmonary hypertension.

Risk factors. Previous exposure to protamine (insulin containing protamine, such as neutral protamine Hagedorn), fish allergy (weak), vasectomy, high dose, rapid injection, left atrial or pulmonary artery administration, cardiac surgery, and diabetes on NPH insulin.

Pathophysiology.

Protamine binds heparin, and the protamine heparin complex activates complement, releasing thromboxane A2 and leukotrienes that cause pulmonary vasoconstriction and right ventricular failure. Antibodies cause anaphylaxis.

Within minutes of injection: hypotension, flushing, bradycardia, bronchospasm, rising pulmonary artery pressure, right ventricular dilatation, falling end tidal carbon dioxide, pulmonary oedema, and cardiovascular collapse.

Red flags.

• Rising pulmonary artery pressure and falling blood pressure.
• Bronchospasm or airway swelling.
• Cardiac arrest.

Clinical. Echocardiography shows a dilated, failing right ventricle. Measure tryptase for anaphylaxis (1 hour, 3 to 6 hours and baseline). Allergy testing later. Check activated clotting time to confirm heparin reversal.

Differential diagnosis.

• Anaphylaxis to other agents.
• Pulmonary embolism.
• Cardiac tamponade.
• Left ventricular failure.
• Haemorrhage.
• Air embolism.

Stop protamine at once, give 100% oxygen and call for help. Hold bypass or resume it if the situation is unstable (reheparinisation and return to bypass in severe pulmonary vasoconstriction).

• Adrenaline: 10 to 100 microgram IV titrated, then 0.02 to 0.2 microgram/kg/min; monitor ECG and arterial pressure; avoid excess in ischaemia.
• Noradrenaline: 0.05 to 0.5 microgram/kg/min; maximum 1 microgram/kg/min; monitor arterial pressure; central access.
• Inhaled nitric oxide: 20 to 40 ppm for pulmonary hypertension; continue until haemodynamics improve (hours to days), wean slowly; monitor methaemoglobin and pulmonary pressures.
• Milrinone: 25 to 50 microgram/kg IV over 10 minutes, then 0.375 to 0.75 microgram/kg/min; maximum 1.13 mg/kg daily; monitor blood pressure and arrhythmia; reduce in renal impairment.
• Fluids and calcium (calcium chloride 10 mL of 10% IV), bronchodilators and hydrocortisone 200 mg IV.

Prevention. Give protamine slowly (over 10 minutes or longer, 1 mg for each 100 units heparin, not exceeding 5 mg/min), peripherally into a peripheral vein, and avoid in high risk patients where alternatives exist. Test dose is not reliable. Have vasopressors ready. Consider heparin neutralisation only for the heparin in the circulation.

Monitoring. Arterial pressure, pulmonary pressure, ECG, saturation, activated clotting time and bleeding.

Referral and escalation. Cardiac surgery, cardiac anaesthesia and critical care. Allergy referral at 4 to 6 weeks and document protamine reaction in the notes.