EMPRESS Trial Tests Methylene Blue to Cut Death Rates in Severe Septic Shock

Septic shock is among the most lethal conditions managed in ICUs worldwide, with mortality driven largely by uncontrolled vasodilation mediated by nitric oxide (NO) activation of soluble guanylate cyclase (sGC) and subsequent cyclic GMP (cGMP) accumulation in vascular smooth muscle. Patients requiring high-dose vasopressors represent a particularly severe subgroup—characterized by underlying vasoplegia—where conventional catecholamine therapy delivers diminishing returns and significant toxicity including arrhythmias, peripheral ischemia, and increased myocardial oxygen demand.

Methylene blue (MB) directly inhibits sGC by binding to its heme-iron center, blocking the NO–sGC–cGMP pathway and restoring vascular tone. Since its first use in human septic shock in 1992, smaller studies and retrospective analyses have consistently shown hemodynamic improvements and reduced catecholamine requirements. A recent single-center RCT demonstrated faster vasopressor weaning, improved fluid balance, and shorter mechanical ventilation duration, though it was underpowered for mortality. Retrospective data also suggest a combined bolus-plus-maintenance regimen is associated with better survival than either strategy alone. Despite these signals, no adequately powered RCT has evaluated MB's effect on mortality specifically in the high-dose vasopressor-dependent septic shock population.

EMPRESS is an investigator-initiated, multicenter, prospective, parallel-group, open-label, blinded-endpoint RCT coordinated by Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital. The trial targets enrollment of 566 adult patients across more than 50 centers in mainland China. Eligible patients must meet Sepsis-3 criteria, require norepinephrine equivalent doses exceeding 0.3 μg/kg/min for at least 30 minutes, and be enrolled within 24 hours of vasopressor initiation. A comprehensive norepinephrine equivalence formula accounts for vasopressin, terlipressin, epinephrine, dopamine, phenylephrine, angiotensin II, and metaraminol. Key exclusion criteria include severe hypoxemic respiratory failure (PaO₂/FiO₂ <100 mmHg), severe pulmonary hypertension, G6PD deficiency, recent serotonergic agent use, and anticipated survival less than 48 hours.

Patients are randomized 1:1 using a centralized web-based system stratified by baseline SOFA score (>10 vs. ≤10) and study center, with permuted block randomization. The MB arm receives a 2 mg/kg loading dose over 20 minutes followed by 0.25 mg/kg/h continuous infusion for up to 48 hours or 4 hours after vasopressor discontinuation. The control arm receives an equal volume of 5% dextrose at identical rates. The primary endpoint is 28-day all-cause mortality. Secondary endpoints include ICU-free days, vasopressor-free days, ventilator-free days, in-hospital mortality, and change in SOFA score. Background care follows 2021 Surviving Sepsis Campaign and 2024–2025 international guideline recommendations, with standardized training provided across centers.

IMPRESS addresses a critical evidence gap. If early MB administration proves effective, it could establish a rationale-driven adjunctive therapy for one of the most treatment-resistant ICU phenotypes, potentially reshaping guidelines for vasopressor-refractory septic shock management globally.