Catastrophic cardiovascular adverse reactions to protamine.

The article by Viaro et al1 (September 2002) provides important and interesting data on the side effect profile of protamine. However, their article raises a number of important points that need addressing. First, clinically, when protamine is administered slowly, the vast majority of patients experience a minimal cardiovascular effect. A few individuals show elevated pulmonary artery pressures and develop acute right ventricular dilatation, which is obvious on inspection to a cardiac surgeon. This would seem to indicate an idiosyncratic mechanism, and not a fixed pathway. In the setting of pulmonary hypertension, administering nitric oxide (NO) in the form of nitroprusside is not uncommon, although the use of inhaled NO is more usual. Administering methylene blue would reduce the pulmonary NO level, precipitating a pulmonary hypertensive crisis, necessitating the readministration of heparin and the recommencement of cardiopulmonary bypass, an obvious retrograde step. Second, Viaro et al1 seem to confuse low systemic vascular resistance (SVR), or vasoplegia, postoperatively with a reaction to protamine, utilizing the reaction as an argument for the use of methylene blue. Numerous other factors have been described as a cause of vasoplegia postoperatively.2 The rarity of vasoplegia after off-pump cardiac surgery, when heparin and protamine are utilized in exactly the same way, compared to its incidence after on-pump cardiac surgery would seem to eliminate protamine as a cause. However, we completely agree with their opinion that patients with vasoplagia who are unresponsive to catecholamine administration should receive methylene blue. Third, Viaro et al1 maintain that a low SVR is the main problem with protamine administration. We would have to disagree, since it is well known that the administration of protamine directly into the left side of the heart, usually via a dedicated left atrial line, dramatically reduces the cardiovascular effects of protamine administration. The reasons that this technique has not found widespread adoption are twofold, as follows: infrequent use of direct left atrial lines, and fear of cerebral embolic episodes. This would seem to refute the claim of Viaro et al1 that a low SVR is the main pathophysiologic effect of protamine administration. Fourth, Viaro et al1 quite rightly present conflicting evidence with regard to the possible mechanism of action of protamine and the role of NO. However, two additional important points need to be made. A number of the studies that they quote utilized different organs and even different species, and we already know that the lungs behave differently from species to species and from the systemic circulation. In addition postcardiopulmonary bypass endothelial function is impaired, which means that agents that directly produce/inhibit NO may be effective (eg, nitroprusside); however, agents that rely on endothelial function (eg, glyceryl trinitrate/L-NG-monomethyl-L-arginine) will be ineffective. Finally, the claim that isolated pulmonary vasodilatation may cause systemic hypotension is difficult to understand. As far as we are aware, isolated pulmonary vasodilatation may actually increase cardiac output and BP by increasing left ventricular filling. Of course, in vasoplegia, which Viaro et al1 seem to confuse with “a reaction to protamine,” a low pulmonary vascular resistance does occur, but shunting, as is seen in the systemic circulation in patients with vasoplagia, also occurs.