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Methylene blue (MB) has been used with some success as a treatment for the vasoplegia of vasopressor-refractory septic shock. The putative mechanism of action of MB is the inhibition of endothelial nitric oxide within the microvasculature and improved responsiveness to endogenous catecholamines (norepinephrine (NE)). However, to date, no study has demonstrated the microcirculatory effect of methylene blue in septic shock. The objective of this randomized, controlled, animal study was to show, in an experimentally-induced, septic shock model in rats, the effects of MB and NE on global hemodynamics and the microcirculation. Mean arterial pressure (MAP) was drastically reduced following bacterial endotoxin (lipopolysaccharide, LPS) administration in animals not receiving vasopressors. Only the combination of NE + MB restored MAP to control levels by the end of the three hour experiment. Intravital microscopy of the microcirculation was performed in the terminal ileum in order to examine functional capillary density in intestinal muscle layers and the mucosa, as well as leukocyte activation in venules (rolling, adhesion to the endothelium). Untreated LPS animals showed a significant increase in leukocyte adhesion and a decrease in capillary perfusion in the intestinal microcirculation. In groups receiving NE or NE+MB, we observed a significant decrease in leukocyte adhesion and improved functional capillary density, indicating that microvasculature function was improved. This study suggests that methylene blue may be able to improve hemodynamics while preserving microvascular function in septic shock.

Objective: To report a case of methylene blue extravasation and subsequent tissue necrosis in a patient with refractory septic shock., Case Summary: A 47-year-old female presented with febrile neutropenia secondary to chemotherapy. The patient quickly decompensated to refractory septic shock in the critical care unit despite implementation of early goal-directed therapy as well as intravenous norepinephrine and vasopressin to stabilize her hemodynamic status. She received a 16-hour infusion of 1% methylene blue 0.25 mg•kg(-1)•h(-1), titrated up to 0.5 mg•kg(-1)•h(-1), via a peripheral intravenous catheter. Ten hours after the start of the methylene blue infusion, she experienced a local extravasation injury, which led to distal digital necrosis. While her hemodynamic status improved dramatically, allowing discharge from the intensive care unit and eventually to home, the extravasation site became necrotic and required debridement and skin graft., Discussion: Methylene blue is a vasoactive chemical that has been shown to provide hemodynamic stability in the treatment of refractory septic shock. Methylene blue administration is not considered standard of practice in the treatment of refractory septic shock and many aspects of its dosing, route, duration, and adverse effects are poorly described. As such, there is little guidance for its administration. We postulate that, in our patient, in the presence of systemic vasopressin and norepinephrine, methylene blue caused extensive vasoconstriction at the site of extravasation, resulting in tissue ischemia and necrosis. Tissue necrosis secondary to peripheral intravenous extravasation has not been previously described and is not listed as an adverse outcome on the drug monograph. The Naranjo probability scale indicates that the tissue necrosis was probably caused by the methylene blue extravasation., Conclusions: To mitigate future risk to limb and skin, we recommend that methylene blue infusions be delivered via central venous catheter. Extra care should be given to patients with risk factors for extravasation, such as sedation, presence of systemic disease, proximal intravenous puncture sites, and improperly placed catheters.

Purpose: Methylene blue (MB) has been advocated for the treatment of refractory hemodynamic instability in patients with septic shock. However, the use of MB infusions in septic shock is not considered standard treatment, and the available literature describes infusions of short duration, typically less than six hours., Clinical Features: We report a case of septic shock in a 67-yr-old male who required maximal vasopressor support with norepinephrine, epinephrine, and vasopressin. Despite standard protocols for the treatment of septic shock, the patient's hemodynamic status was refractory 80 hr post admission. However, initiation of a MB infusion resulted in the rapid restoration of hemodynamic stability and a subsequent decrease in vasopressor requirements. Multiple attempts to discontinue the MB infusion resulted in immediate and repeated increases in vasopressor requirements, necessitating a continuous infusion with a slow taper of MB for 120 hr. Ultimately, the patient survived the illness and was discharged home. We observed no adverse events that could be attributed to the use of MB., Conclusion: In our patient, the use of MB resulted in hemodynamic stability unattained with standard vasopressor support. Further research is warranted on the use of MB in patients with septic shock.