Methylene blue for the treatment of refr”>American Journal of Emergency Medicine 31 (2013) 753

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American Journal of Emergency Medicine

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Correspondence

Methylene blue for the treatment of refractory anaphylaxis without hypotension?

To the Editor,

I am responding to the case report submitted by Bauer et al [1], who discussed the use of methylene blue (MB) for the treatment of refractory anaphylaxis without hypotension. First of all, I wish to thank Bauer et al [2] for recognizing that my suggestion of inhibiting the cyclic guanosine monophosphate (cGMP) system using MB represented a pioneering option in anaphylaxis treatment. We have been working with MB for the last 20 years, mainly focusing on its uses for vasoplegic syndrome in cardiac surgery. The first use of MB in a patient with agonal respiration, brought about by an acute reaction to ionic radiocontrast, was an example of pure serendipity [3].

Of the 10 total patients we have treated in this manner, MB reversed only the main signs of anaphylaxis in 3 normotensive patients, suggesting the usefulness of this compound in Anaphylactic reaction without Cardiovascular collapse. We reported this incident casually, without emphasizing the importance of only using MB for anaphylaxis without cardiovascular collapse; this distinction is the main message of the case report of Bauer et al. Interestingly, the authors emphasize that the Joint Taskforce on Practice Parameters recommends MB “if anaphylaxis is associated with hypotension” [4], reinforcing this concern.

In 2009, we published a personal statement targeting MB for the treatment of vasoplegic syndrome in heart surgery, including 15 years (now 18 years) of questions, answers, doubts, and certainties [5]. Among several qualities of MB, 4 are applicable to anaphylactic shock:

(1) it is safe at the recommended dose (the lethal dose is 40 mg/kg);

(2) the use of MB does not cause endothelial dysfunction; (3) the MB effect appears in patients with nitric oxide up-regulation; and (4) MB is not itself a vasoconstrictor-by blocking the cGMP pathway, it releases the cyclic adenosine monophosphate pathway, facilitating the epinephrine vasoconstrictor effect. We think that MB acts through this “crosstalk” mechanism. Therefore, we agree with Bauer et al. that the use of MB as a drug of first choice, or its sole use in the treatment of anaphylactic shock, excluding any other treatments, is not a rational therapeutic option. Kofidis and colleagues [6] wrote that this drug deserves attention because of its “catecholamine-saving effect” that prevents possible malperfusion.

The medical history of MB begins with its synthesis in 1876, carried out in Germany by Henrich Caro. Paul Ehrlich won the Nobel Prize and was honored with the title Father of Chemotherapy, stressing that the he became famous for, among other things, using MB in the treatment of malaria. Methylene blue has been used for

many years in clinics, for example, in the treatment of methemoglo- binemia and as a urinary antiseptic. It has not shown, to date, any contraindication rendering its use unsafe. Because MB has been used to treat various clinical conditions, new indications for its use do not require the rigorous ethical and scientific processes applied to new drugs. Anaphylaxis and anaphylactic shock are Medical emergencies; it is therefore extremely difficult or impossible to conceive that a randomized study comparing MB with other agents would be consistent with ethical principles.

In conclusion, determining appropriate methods of blocking the cGMP pathway in anaphylactic shock depends on laboratory studies and, mostly, on the accumulation of reported cases that can generate meta-analyses. I apologize for this personal letter, but I believe that the role of the cGMP system in anaphylaxis is underestimated [7], and I am taking the opportunity given by the study of Bauer et al. to publicize this belief.

Paulo Roberto B. Evora

Department of Surgery and Anatomy Ribeirao Preto Faculty of Medicine University of Sao Paulo

Ribeirao Preto, Sao Paulo, Brazil E-mail address: [email protected]

http://dx.doi.org/10.1016/j.ajem.2013.01.033

References

1. Bauer CS, Vadas P, Kelly KJ. Methylene blue for the treatment of refractory anaphylaxis without hypotension. Am J Emerg Med 201331:264.e3-5.
2. Evora PR, Roselino CH, Schiaveto PM. Methylene anaphylactic shock. Ann Emerg Med 1997;30:240.
3. Evora PR, Ribeiro PJ, de Andrade JC. Methylene blue administration in SIRS after cardiac operations. Ann Thorac Surg 1997;63:1212-3.
4. Lieberman P, Nicklas RA, Oppenheimer J. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126(477):80.e1-42.
5. Evora PR, Ribeiro PJ, Vicente WV, Reis CL, Rodrigues AJ, Menardi AC, et al. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc 2009;24:279-88.
6. Kofidis T, Struber M, Wilhelmi M, Anssar M, Simon A, Harringer W, et al. Reversal of severe vasoplegia with single-dose methylene blue after Heart transplantation. J Thorac Cardiovasc Surg 2001;122:823-4.
7. Evora PR, Rodrigues AJ, Vicente WV, Vicente YA, Basseto S, Basile Filho A, et al. Is the cyclic GMP system underestimated by intensive care and emergency teams? Med Hypotheses 2007;69:564-7.

   ? Conflict of interest: None.

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