The first comment of the letter by Poullis and Shackcloth focuses on the following two points: (1) protamine as a fixed pathway, and (2) methylene blue infusion as cause of pulmonary nitric oxide (NO) reduction. Multiple immunologic and nonimmunologic mechanisms have been reported for the pathophysiology of protamine reactions in human, animal, and in vitro models. The life-threatening cardiopulmonary collapse following protamine administration in humans appears to represent true anaphylaxis or allergy, mediated by immunospecific antibodies. Immunospecific antibodies against protamine (ie, allergic mechanisms) are the only logical explanation by Poullis and Shackcloth for the unpredictable protamine cardiovascular effects. Although protamine reactions have been classified according to pulmonary or systemic vascular effects, this does not elucidate the underlying pathophysiologic mechanisms.1–
We focused on the nitric NO pathway in our article, and this approach may have led to the idea of a “fixed pathway.” This was not our intention. We trust in different trigger mechanisms, but we have to consider the direct action of protamine in stimulating endothelial NO release, and the protamine anaphylactic or anaphylactoid properties that also have NO as the final mediator. We do not agree that administering methylene blue would reduce pulmonary NO levels, precipitating a pulmonary hypertensive crisis. Methylene blue does not interfere with NO release, but it blocks guanylyl cyclase, avoiding NO-mediated vasodilatation.2–3
Our clinical and ongoing experimental protocols have proved that methylene blue infusion increases mean arterial pressure without affecting pulmonary artery pressure and cardiac output. This is not the case when we use NO synthesis blockers such as NG-nitro-L-arginine methylester or NG-monomethyl-L-arginine.