It is likely that protamine compli- cations are underreported [100, 104]. A comprehensive review of the literature suggests true anaphylactic re- actions to protamine are rare (less than 1% of patients having CPB) [100], and approximately 60% occur before CPB, likely related to other drugs used in preoperative preparation of patients (eg, antibiotics or gelatin solution) [105]. The results from this limited database of anaphy- lactic reactions showed that cardiac surgery proceeded without complications after cardiovascular collapse caused by pre-CPB anaphylactic or anaphylactoid re- actions. Rapid institution of cardiopulmonary bypass may be lifesaving in this setting [106]. Catastrophic cardiovascular reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated. That suggests that methylene blue may be the treatment of choice in this setting but high level evidence to support this intervention is lacking [106]. Evidence to date suggests that the site of protamine administration does not in uence the incidence of protamine-induced pulmonary vasoconstriction, and aspirin ingestion within 1 week of surgery may decrease it [107]. Furthermore, acute right ventricular failure and pulmonary hypertension often precede catastrophic re- actions to protamine [103, 108, 109]. Prostacyclin and bradykinin B2 attenuate the acute pulmonary hyperten- sion in this setting but, again, no high level evidence supports the use of these agents to reverse the early stages of a reaction to protamine [108, 110]. What is known is that serious protamine reactions predispose to operative mortality, and discontinuation of protamine and reinstitution of CPB, if serious protamine reactions occur, may be lifesaving [103, 105]. Studies show that antibodies to the protamine/heparin complex occur commonly after CPB [111, 112]. These antibodies share a number of serologic features with HIT- derived antibodies, including platelet activation. In addition, these protamine/heparin antibodies cross react with protamine-containing insulin preparations [111]. 