🫀Methylene blue in septic shock: rescue drug or an adjunct we are using too late? Methylene blue has traditionally appeared at the end of the vasopressor algorithm, when severe vasoplegia has become refractory. This review by Fernando and colleagues raises a more interesting possibility: perhaps its physiology makes more sense before shock becomes refractory. In septic vasoplegia, excessive nitric oxide activates soluble guanylate cyclase, increases cGMP in vascular smooth muscle and contributes to loss of vascular tone. Methylene blue interferes with this pathway by inhibiting NOS and soluble guanylate cyclase. In other words, it targets a mechanism distinct from the adrenergic, vasopressin and angiotensin pathways. This makes it conceptually attractive as another catecholamine-sparing strategy. Yet clinical practice is almost the opposite. In a large US cohort, only 0.5% of septic shock patients received methylene blue, and approximately half of patients who eventually died received it on the day of death, suggesting predominantly salvage use. The randomized evidence, although small, points toward earlier administration. The largest RCT found early methylene blue reduced vasopressor duration from 94 to 69 hours, alongside shorter ICU and hospital stays. A meta-analysis of six RCTs involving 302 patients suggested lower short-term mortality, shorter vasopressor duration and an approximately 10 mmHg greater MAP at 6 hours, but certainty remains low because the trials are small and heterogeneous. BUT...this is not enough evidence for routine use. Safety also matters. Methylene blue can interact with serotonergic drugs, may increase pulmonary vascular resistance, interferes with pulse oximetry, and can cause hemolysis in G6PD deficiency. High doses raise additional toxicity concerns. Methylene blue may eventually have a place in that strategy, but we need larger trials before moving it from promising physiology to routine bedside practice. The ongoing BLUSH trial and other RCTs should help answer that question. Reference 📚 Fernando SM, et al. 2026. What every intensivist should know about…methylene blue in septic shock. Journal of Critical Care. 92:155353. doi.org/10.1016/j.jcrc.2025.… #SepticShock #Hemodynamics #MethyleneBlue #Vasopressors #CriticalCare #Sepsis