The Timing of Discharge From the Intensive Care Unit and Subsequent Mortality: A Prospective, Multicenter Study

COMMENT An important function of the cardiovascular system is to provide adequate systemic blood flow and perfusion pressure to achieve and maintain organ homeostasis. This goal requires that vasoconstrictor and vasodilator influences be meticulously balanced. However, in “distributive shock,” a vasodilatory state predominates and can cause inadequate end-organ perfusion. Despite satisfactory or even high cardiac output, the lack of vascular tone results in unacceptable, dangerously low endorgan perfusion. Methylene blue is commonly used by clinicians as a dye in assorted medical procedures or, less frequently, to treat nitrateinduced methemoglobinemia. Importantly, the vasoconstrictive effect of MB is manifested only in circumstances of nitric oxide (NO) up-regulation. Hence, increases in blood pressure are not seen when MB is given as a dye during uncomplicated procedures involving nonvasoplegic patients. Nitric oxide binds to and activates the enzyme-soluble guanylate cyclase, forming cyclic guanosine monophosphate (cGMP), which, in turn, eventually produces vascular smooth muscle relaxation. Nitric oxide is continuously produced at low concentrations by the calcium-dependent enzyme NO synthase. Methylene blue directly inhibits NO synthase. It also inhibits the enzyme-soluble guanylate cyclase and prevents accumulation of cGMP. By competitively blocking the target enzyme of NO, MB reduces the responsiveness of vessels to cGMP-dependent vasodilators and restores vascular tone. Increases in intracellular cGMP relax both vascular smooth muscle and myocardial myocytes. This may explain why experimental animal studies have shown that, in addition to reduction in vasopressor requirements, inotropic support is reduced after administration of MB, probably owing to attenuation of ischemia/reperfusion injury. Although MB certainly improves blood pressure, enhanced oxygen delivery or reduced mortality secondary to MB has not yet been confirmed. Given these incomplete data, the authors believe that MB should be used to treat vasoplegia unresponsive to traditional vasopressors, rather than as a first-line agent, until more information becomes available. Clearly, large, randomized controlled trials are urgently required to establish the role of MB in treating vasoplegia.