Protamine reaction

Protamine is a polyvalent cation derived from salmon sperm that binds to and effectively inactivates heparin. The heparin-protamine complexes are then removed by the reticuloendothelial system. Protamine remains the heparin reversal agent of choice in cardiac surgery. Effective dosing for complete heparin reversal is typically 1-1.3 mg of protamine per 100 units of heparin given. It should only be given after the hemodynamics are stable following the termination of CPB when there is a low likelihood of reinitiating bypass. The incidence of adverse protamine reactions is ~10% in adults and <3% in children.

Adverse reactions include hypotension, elevated pulmonary artery pressures (PAP), right heart failure (RVF), bronchoconstriction, noncardiogenic pulmonary edema, anaphylactic and anaphylactoid reactions, and heparin rebound.

Hypotension can be isolated with normal filling pressures and normal airway pressure or accompanied by an elevated PAP, bronchoconstriction with elevated airway pressures, acute RVF, or a combination thereof. Initial hypotension is typically mild; however, the secondary manifestations of hypotension may lead to global cardiovascular collapse. Noncardiogenic pulmonary edema is most likely with concomitant blood product administration. Heparin rebound refers to a re-prolongation of ACT 1-8 hours after heparin neutralization that generally normalizes with the administration of more protamine.

Adverse effects from protamine administration, including anaphylactic and anaphylactoid reactions are believed to be caused by mast cell degranulation, endothelial release of NO with subsequent increased levels of cGMP, protamine-induced platelet aggregation with release of vasoactive substances, protamine induced reductions in myocardial contractility, and potentially pulmonary histamine release. Further, high levels of thromboxanes and C5a anaphylatoxins initiated by protamine-heparin complexes may also play a role.

Risk factors for having an adverse reaction include regular use of NPH insulin, fish allergy (non-shellfish), having a vasectomy, and history of a prior protamine reaction. History of pulmonary hypertension does not appear to be a risk factor for protamine induced pulmonary hypertension.

Treatment for adverse reactions include giving the protamine slowly over a period of >5 minutes, giving a fluid bolus, and vasoactive medications for mild hypotensive reactions. Albuterol may be helpful for bronchospasm. A severe reaction may require a return to CPB with readministration of heparin. If there is documented history of a protamine allergy consider non-heparin based CPB or off-pump procedures, or possibly non-protamine reversal methods such as PF4, heparinase, or no reversal at all. Administration of H1/2 blockers has not proven to be beneficial.