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Communications to the Editor |

Catastrophic Cardiovascular Adverse Reactions to Protamine FREE TO VIEW

Michael Poullis; Michael Shackcloth
Author and Funding Information

Affiliations: Cardiothoracic Center, Broadgreen Hospital, Liverpool, UK,  Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

Correspondence to: Michael Poullis, BSc(Hons), MBBS, Department of Cardiothoracic Surgery, Cardiothoracic Center, Broadgreen Hospital, Thomas Dr, Liverpool L14 3PE, United Kingdom



Chest. 2003;124(1):411-412. doi:10.1378/chest.124.1.411
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To the Editor:

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.

Viaro, F, Dalio, M, Evora, PRB (2002) Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated.Chest122,1061-1066. [PubMed] [CrossRef]
 
Poullis, M Vasodilatation after cardiac surgery [letter]. J Thorac Cardiovasc Surg. 2000;;119 ,.:857
 
To the Editor:

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.23 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.

Their second comment focuses on the impression that our article emphasizes the confused concept that protamine infusion is the crucial mechanism of low vascular resistance or vasoplegia. Again, our emphatic statements about the NO pathway and endothelium function may have led to this interpretation. We agree that cardiac surgery vasoplegia has multiple mechanisms, including drug interactions, as Poullis4 discussed in his excellent letter, which was motivated by the article of Argenziano et al5 on vasodilatory shock after cardiac surgery.

Their third comment rejects the notion that low systemic vascular resistance is “the main problem with protamine administration.” In our opinion, this is really the main hemodynamic protamine effect. These effects are closely related to infusion rate. Pulmonary hypertension and systemic hypotension routinely occur in most animal models when protamine or any other polycation is given by rapid injection. Many reports have suggested that there may be advantages to the intra-aortic (IA) administration vs the IV administration of protamine due to the reversal of heparin at the end of cardiopulmonary bypass. The cardiac surgical practice is consistent in presenting similar good results if protamine is infused by the IV or IA route. However, there is significant hypotension when protamine is infused by the IA route.1 NO release is mainly responsible for this effect, because the arterial endothelium is more adapted to this function than is the venous endothelium.

Their fourth comment focuses on the unpredictability of the endothelium function of different organs and animal species, and the unpredictability of NO donors and blockers effects. We completely agree with this comment. We did not emphasize these points, but they are relevant. When low systemic vascular resistance occurs during or after protamine infusion, NO release is a transitory consequence of the constitutive NO-synthase expression. However, if protamine evokes an anaphylactic/anaphylactoid or inflammatory reaction, it causes massive overproduction of NO as consequence of inducible NO-synthase isoform expression.4

We agree that isolated pulmonary vasodilatation may increase cardiac output and BP by increasing left ventricular filling. This is true and happens when using inhaled NO to treat patients with pulmonary hypertension. However, even in the setting of pulmonary hypertension, and considering the possibility of hypovolemia, isolated pulmonary vasodilatation may cause systemic hypotension by volume redistribution.

Finally, we would like to emphasize the three known vasodilatation mechanisms, as follows: guanosine monophosphate-cyclic-dependent, adenosine monophosphate cyclic-dependent, and hyperpolarization-dependent. These three mechanisms are synergistic. Beside these three mechanisms, an arginine vasopressin deficiency also has been reported. From our point of view, a better understanding of this synergism is mandatory. If the vasoplegic hypotension is unresponsive to catecholamines (adenosine monophosphate cyclic), methylene blue (guanosine monophosphate cyclic) infusion would be logical. In our opinion, this synergism is strongly suggested by the faster decrease of catecholamines after methylene blue infusion. Arginine vasopressin deficiency is a particular and individual possibility, because, in general, vasopressin levels remain increased until 48 to 72 h after cardiopulmonary bypass.

References
Bailey, JM, Levy, JH, Hug, CC, Jr Cardiac surgical pharmacology. Edmunds, LH, Jr eds.Cardiac surgery in the adult1997,225-254 McGraw-Hill. New York, NY:
 
Viaro, F, Dalio, MB, Evora, PR Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice?Chest2002;122,1061-1066. [PubMed] [CrossRef]
 
Pearson, PJ, Evora, PR, Ayrancioglu, K, et al Protamine releases endothelium-derived relaxing factor from systemic arteries: a possible mechanism of hypotension during heparin neutralization.Circulation1992;86,289-294. [PubMed]
 
Poullis, M Vasodilatation after cardiac surgery [letter]. J Thorac Cardiovasc Surg. 2000;;119 ,.:857
 
Argenziano, M, Chen, JM, Choudhri, AF, et al Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent.J Thorac Cardiovasc Surg1998;116,973-980. [PubMed]
 

Figures

Tables

References

Viaro, F, Dalio, M, Evora, PRB (2002) Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated.Chest122,1061-1066. [PubMed] [CrossRef]
 
Poullis, M Vasodilatation after cardiac surgery [letter]. J Thorac Cardiovasc Surg. 2000;;119 ,.:857
 
Bailey, JM, Levy, JH, Hug, CC, Jr Cardiac surgical pharmacology. Edmunds, LH, Jr eds.Cardiac surgery in the adult1997,225-254 McGraw-Hill. New York, NY:
 
Viaro, F, Dalio, MB, Evora, PR Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice?Chest2002;122,1061-1066. [PubMed] [CrossRef]
 
Pearson, PJ, Evora, PR, Ayrancioglu, K, et al Protamine releases endothelium-derived relaxing factor from systemic arteries: a possible mechanism of hypotension during heparin neutralization.Circulation1992;86,289-294. [PubMed]
 
Poullis, M Vasodilatation after cardiac surgery [letter]. J Thorac Cardiovasc Surg. 2000;;119 ,.:857
 
Argenziano, M, Chen, JM, Choudhri, AF, et al Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent.J Thorac Cardiovasc Surg1998;116,973-980. [PubMed]
 
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