"Sirs: I have found you an argument. I am not obliged to find you an understanding."
Dr. Samuel Johnson (1709-1784)
Comments on the study "Methylene blue for vasoplegic syndrome treatment in heart surgery. Fifteen years of questions, answers, doubts and certainties" authored by Full Professor Paulo Roberto Barbosa Evora, published in issue 24.3 of the Brazilian Journal of Cardiovascular Surgery .
The induction of an inflammatory state by endothelial dysfunction and an increased production of nitric oxide (NO) lead to vasodilatation of smooth muscle. These mechanisms would be by the action of NO in opening potassium channels, leading to decrease of calcium concentration and subsequent hyperpolarization with relaxation of vascular smooth muscle [2,3]. When this action becomes excessive, there is persistence of vasodilation and hyporesponsiveness to norepinephrine, characterizing vasoplegic syndrome (VS) .
When we analyze the risk factors for the development of VS, different mechanisms of action are presented to explain the endothelial dysfunction after a stress factor in the vascular wall. Persistent vasodilation by tissue accumulation of ACE inhibitor may be another factor. When seeking the most likely factors that could contribute to the VS, these same studies do not consider the possibility of withdrawal of these drugs in the preoperative period when such drugs are used .
The use of methylene blue (MB) by inhibiting guanylate cyclase and avoiding the increase of cyclic GMP (mediated by the action of NO), allows the action of norepinephrine in vascular tone . The biggest problem found in the use of MB in the treatment of VS is that the majority of published studies refers to researches on clinical cases, variable incidence of VS (8.8 to 44%), and variable results regarding the MB treatment [6,7]. From the difficulty in recognizing a particular etiology, it lacks an experimental model suitable for the use of MB in cardiac surgery, despite its promising initial results.
When the "window of opportunity" (the period between 8 and 16 hours post-stress tissue) is noted carefully, in which the action of MB is more effective, this time of 8 hours coincides with the end of the cardiovascular effects of CPB. The study by Fernandes  also mentions that in some vascular beds (renal and pulmonary) after using the MB, it may occur vascular vasoconstriction, worsening of clinical presentation and death.
In fact, after fifteen years of history, the MB in the treatment of VS presents with many questions, few answers, many doubts and uncertainties.
Curitiba, PR, Brazil
1. Évora PRB, Ribeiro PJF, Vicente WVA, Reis CL, Rodrigues AJ, Menardi AC, et al. Azul de metileno no tratamento da síndrome vasoplégica em cirurgia cardíaca. Quinze anos de perguntas, respostas, dúvidas e certezas. Rev Bras Cir Cardiovasc. 2009;24(3):279-88.
2. Schroeder RA, Kuo PC. Nitric oxide: physiology and pharmacology. Anesth Analg. 1995;81(5):1052-9.
3. Fernandes D. Dinâmica da guanylate ciclase solúvel na sepse: uma janela de oportunidade [Tese de doutorado]. Florianópolis:Universidade Federal de Santa Catarina;2006. 132p.
4. Gomes WJ, Carvalho AC, Palma JH, Gonçalves I Jr, Buffolo E. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg. 1994;107(3):942-3.
5. Levin MA, Lin HM, Castillo JG, Adams DH, Reich DL, Fischer GW. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation. 2009;120(17):1664-71.
6. Mota AL, Rodrigues AJ, Évora PRB. Circulação extracorpórea em adultos no século XXI. Ciência, arte ou empirismo? Rev Bras Cir Cardiovasc. 2008;23(1):78-92.
7. Leite EG, Ronald A, Rodrigues AJ, Evora PR. Is methylene blue of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome during cardiac surgery? Interact Cardiovasc Thorac Surg. 2006;5(6):774-8.
Dear Dr. Hélcio Giffhorn,
First of all, thank you for the interest in our review and by presentation of data in the literature that add interesting aspects to the matter still unresolved, that is the inhibition of guanylate cyclase as a therapeutic resource in vasoplegia resistant to adrenergic action of vasoactive amines. I also thank the citation by Samuel Johnson, which is extremely relevant.
In response to your comments I would like to comment on two aspects: the interpretation of the "window of opportunity" and the possibility of morbidity and mortality related to renal and respiratory functions, described by Fernandes .
In relation to the window of opportunity, You affirms "When we look more closely at the "window of opportunity" (the period between 8 and 16 hours post-stress tissue), in which the action of MB is more effective, this time of 8 hours coincides with the late cardiovascular effects of the CPB". There is a major mistake in this interpretation, because the period from 8 to 16 hours is a period in which the action of MB is less effective
, due to low expression of guanylate cyclase. When I did not know this experimental detail, I came to think of other mechanisms such as the already mentioned hyperpolarization-dependent potassium channels, and deficiency of vasopressin. The lesson given by the description of this "window of opportunity" is the possibility of late use of MB (up to 18-20 hours), when it occurs the synthesis "de novo" of guanylate cyclase. Thus, it is possible to hypothesize that the ineffectiveness of MB is due to hypoactivity of guanylate cyclase, which is probably due to the excessive production of NO by iNOS expression. In the next paragraph I reproduce the text of the original study.
"Recently, a doctoral thesis very well prepared was defended at Federal University of Florianopolis. This thesis has been published and brings some very important data to attempt to answer this question . A model of sepsis in mice allowed the authors to demonstrate, in a period of 24 hours divided into three periods of eight hours, that there is a dynamic action of guanylate cyclase in such a way as to create a "window of opportunity" for the effectiveness of MB to help restore systemic vascular resistance. This phase coincides with the increased expression of iNOS. Between 8 and 16 hours, the expression of guanylate cyclase is absent, probably due to excessive production of nitric oxide and thus, in this phase the MB can not act
. Later, between 16 and 24 hours there would be a synthesis "de novo" of guanylate cyclase, becoming the MB effective."
As the statement that in certain vascular beds (renal and pulmonary) after using the MB, there may be vascular vasoconstriction, worsening of clinical presentation and death, I can not effectively comment very much about such statements . Due to the fact that this model of sepsis is in rats, in my opinion, it is not enough cause for concern. Our studies in pigs and analysis of the literature on human patients attest to the safety of the use of MB. Although there is mention of the use of doses up to 10 mg/kg, I have never surpassed, in my personal experience, the dose of 6 mg/kg.
I echo your words when You said that, in fact, the MB in the treatment of VS has a history of 15 years with many questions, few answers, many doubts and uncertainties. But one certainty I have: it is a measure with wide margin of safety and it can be a life-saving therapy [2,3].
Finally, I suggest to the readers of this response to read two reviews that, in my opinion, have the best "state of the art" on the use of MB in the treatment of vasoplegic syndrome [4,5].
Paulo Roberto B. Evora
1. Renault JA, Costa-Val R, Rossetti MB, Houri Neto M. Comparação entre exercícios de respiração profunda e espirometria de incentivo no pós-operatório de cirurgia de revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2009; 24(2):165-72. [MedLine] View article
2. Guizilini S, Gomes WJ, Faresin SM, Carvalho ACC, Jaramillo JI, Alves FA, et al. Efeitos do local de inserção do dreno pleural na função pulmonar no pós-operatório de cirurgia de revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2004;19(1):47-54. View article
3. Renault JA, Costa-Val R, Rossetti MB. Fisioterapia respiratória na disfunção pulmonar pós-cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2008; 23(4):562-9. [MedLine] View article
4. Westerdahl E. Effects of Deep Breathing Exercises after Coronary Artery Bypass Surgery. Acta Universiatis Upsalaliensis. Dissertations from Faculty of Medicine. 2004.
5. Pasquina P, Merlani P, Granier JM, Ricou B. Continuous positive airway pressure versus noninvasive pressure support ventilation to treat atelectasis after cardiac surgery. Anesth Analg. 2004;99(4):1001-8.