The Story of Nitric Oxide, Sepsis and Methylene Blue: A Comprehensive Pathophysiologic Review

Am J Med Sci. 2020 Oct;360(4):329-337. doi: 10.1016/j.amjms.2020.06.007. Epub 2020 Jun 6.


Methylene blue (MB) is considered to be the first synthetic medication ever used in humans. There are many indications for MB, including vasoplegic shock. Nitric oxide (NO), the central mediator of sepsis, promotes vasoplegia by enhancing the guanylate cyclase cyclic guanosine monophosphate second messenger system, the effect of which is attenuated by MB. Therefore, the use of MB represents a unique pharmacologic approach towards treating the underlying pathophysiology of vasoplegia in sepsis. There are numerous reports of the successful use of MB in refractory shock in the literature. This manuscript describes the historical aspects of the identification of NO as the endothelial derived relaxation factor and its role in the pathogenesis of vasoplegia in septic shock. An analysis of the existing evidence for the use of MB as an inhibitor of NO in vasodilatory shock is provided. The adverse effects associated with the use of MB and an approach to optimal dosing in septic shock are also addressed.

Keywords: Methylene blue; Nitric oxide; Septic shock; Vasoplegia.

Publication types

  • Review

MeSH terms

  • Humans
  • Methylene Blue / administration & dosage
  • Methylene Blue / adverse effects
  • Methylene Blue / therapeutic use*
  • Nitric Oxide / antagonists & inhibitors*
  • Shock, Septic / complications
  • Shock, Septic / drug therapy*
  • Shock, Septic / metabolism
  • Vasodilation / drug effects
  • Vasoplegia / drug therapy*
  • Vasoplegia / etiology
  • Vasoplegia / metabolism


  • Nitric Oxide
  • Methylene Blue