Early Methylene Blue for Mortality Reduction in High-Dose VasoPREssor-Dependent Septic Shock (EMPRESS): protocol for a multicenter randomized controlled trial.

BACKGROUND

Septic shock remains one of the most lethal emergency and critical care conditions, with underlying pathophysiology closely linked to uncontrolled vasodilation mediated by nitric oxide activation of the soluble guanylate cyclase pathway (NO-sGC-cGMP pathway). Methylene blue (MB), through its inhibition of this pathway, has demonstrated hemodynamic benefits and may serve as a targeted adjunctive therapy particularly in patients with septic shock requiring high-dose vasopressors, a severely vasoplegic subpopulation characterized by markedly elevated mortality. However, large-scale randomized controlled trials (RCTs) evaluating MB treatment for mortality benefit in high-dose vasopressor-dependent septic shock patients are currently lacking.

METHODS

This is an investigator-initiated, multicenter, open-label, blinded endpoint RCT that will recruit adult septic shock patients requiring norepinephrine equivalent doses > 0.3 μg/kg/min within 24 h of vasopressor initiation across multiple centers in China. A total of 566 patients will be randomized 1:1 to receive MB treatment (2 mg/kg loading dose followed by 0.25 mg/kg/h maintenance infusion for up to 48 h or 4 h after vasopressor discontinuation) or equal volume 5% dextrose control. Randomization will be stratified by baseline SOFA-1 score and study center. The primary endpoint is 28-day all-cause mortality. Secondary outcomes include ICU-free days, vasopressor-free days, ventilator-free days, in-hospital mortality, and SOFA score improvement.

DISCUSSION: This multicenter RCT will generate evidence on whether early MB administration reduces mortality in patients with high-dose vasopressor-dependent septic shock, potentially informing clinical practice regarding MB's role as an adjunctive therapy in severe septic shock management.

TRIAL REGISTRATION: ChiCTR2500112352.