Does Methylene Blue work for Refractory Shock?

Methylene blue (MB) is a dye that has numerous intracellular actions. When used as a treatment for methemoglobinemia, it is converted by NADPH methemoglobin reductase to leucomethylene blue, which then reduces the iron in heme, restoring its oxygen carrying capacity (1). It inhibits guanylate cyclase, an enzyme that produces cyclic guanosine monophosphate (cGMP), which decreases intracellular calcium concentrations, activates potassium channels, and activates a protein kinase that activates myosin light chain phosphatase, all of which lead to relaxation of smooth muscle. MB also scavenges and inhibits nitric oxide, and these actions within the same pathway lead to increased cGMP levels (2,3). The production of nitric oxide is a common endpoint for multiple etiologies that cause vasodilation. Thus, MB works to inhibit vascular smooth muscle relaxation, particularly in patients with excessive nitric oxide production.

Methylene blue has been in use for postoperative vasoplegia for decades. Evora reviewed the literature for this indication of methylene blue in 2015, concluding that while MB was safe and should be used in select cases of vasoplegia, additional studies were needed to find the optimal timing of dosing (4). This vasoplegic syndrome is unlikely to be encountered in the Emergency Department as it is most often seen in patients that have just undergone cardiothoracic surgery.

A review by Lo, et al in 2014 looked at the available data until 2012 and concluded that methylene blue may be a useful adjunct to vasopressors in shock due to sepsis (n=159), overdose (n=1), or anaphylaxis (n=9) (5). Limitations of this review include the use of numerous case reports with only two RCTs, and significant heterogeneity with regard to patient population, study design, MB dosage, vasopressor use, timing of administration, and clinically oriented outcomes. However, there was a universal improvement in BP or MAP of patients who received MB. These effects on MAP were also confirmed by a systematic review of 5 RCTs that included the two evaluated by Lo and 3 others involving postoperative patients (6). In the studies that examined it, vasopressor requirements were significantly decreased with MB administration. The two RCTs (7,8) did not show a significant mortality difference between treatment groups, but these studies may not have been sufficiently powered to detect such a difference. Pasin et. al also noted there was no significant effect on mortality with MB.

Since these reviews, Abd-Alhameed, et al in 2014 conducted a small RCT (n=40) in which the treatment group received methylene blue via bolus followed by a 4-hour infusion and the control group received normal saline. All patients met severe sepsis or septic shock criteria, and required pressor support. There was a significant difference in the MAP between groups from 2 – 24 hours after infusion (9). Cardiac output and SVR were also significantly higher in the MB group in the same time interval. The MB group also required significantly less pressors, shorter ICU length-of-stay, and significantly lower mortality. This study was unique in that methylene blue was not studied as a rescue medication for refractory shock but rather was initiated once the patient required at least 0.2 ug/kg/min of norepinephrine.

There are case reports of methylene blue being used to successfully treat patients who presented with anaphylaxis from various agents, such as protamine, aprotinin, penicillin, and radiocontrast. All of these patients had received standard therapy with epinephrine and steroids. In some cases, additional pressors were given without improvement in hypotension or urticaria until MB was started (5). It is worth noting that the reactions to radiocontrast were likely anaphylactoid reactions as true IgE-mediated anaphylaxis to radiocontrast is unlikely. Jang, et. al reported a case of shock due to amlodipine overdose that was refractory to 3L NS, calcium gluconate, glucagon, dopamine, norepinephrine, and high dose insulin drip. Improvement in BP was noted 1 hour into MB infusion, allowing weaning of insulin and vasopressors (3).

MB has long been used as a treatment for methemoglobinemia, but it can paradoxically cause methemoglobinemia when used in excess (1,10). Juffermans, et al. performed a small study (n=15) to evaluate for the effects of MB at different dosages and found that higher doses (7+ mg/kg) may compromise splanchnic perfusion (11). In patients with G6PD deficiency, MB can induce hemolytic anemia (1). It is also known to cause a temporary blue-greenish discoloration of skin and secretions and should be used cautiously in patients with severe renal impairment (12).

A number of case reports have identified a range of symptoms including vomiting, aphasia, confusion, and agitation that develop in post-op parathyroidectomy patients who had received MB for parathyroid staining. The association between methylene blue and psychotropic medications, especially those that affect serotonin levels, was discovered as the number of these cases grew (13). The FDA has since put out a safety communication on the potential interaction between MB and serotonergic medications. These patients developed a syndrome similar to serotonin syndrome that generally resolved within 48-96 hours. Not all patients on SSRIs who received MB developed this syndrome, however, suggesting that there may be another factor at play (14). A similar presentation with outright serotonin syndrome was also seen in patients receiving MB for vasoplegia status post cardiac surgery (15).

Weiner, et. al performed a single-center, retrospective review of postop patients that received MB with propensity score matching, which concluded that MB is independently associated with poor outcomes (16). However, this study had multiple methodological problems limiting its validity and the reported increased mortality was not replicated in propensity matching.