EMPRESS Study

Early Methylene Blue for Mortality Reduction in High-Dose VasoPREssor-Dependent Septic Shock — Protocol for a Multicenter Randomized Controlled Trial

Registration: ChiCTR2500112352 Scand J Trauma Resusc Emerg Med 2026;34:44 Open access · CC BY 4.0

About the Study

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.

EMPRESS (Early Methylene Blue for Mortality Reduction in High-Dose VasoPREssor-Dependent Septic Shock) is an investigator-initiated, multicenter, open-label, blinded-endpoint randomized controlled trial evaluating whether early administration of methylene blue reduces mortality in patients with high-dose vasopressor-dependent septic shock.

Design	Investigator-initiated, multicenter, open-label, blinded-endpoint RCT
Population	Adult patients with septic shock requiring norepinephrine-equivalent doses > 0.3 μg/kg/min within 24 h of vasopressor initiation
Sample size	566 patients, randomized 1:1
Intervention	Methylene blue 2 mg/kg loading dose, followed by 0.25 mg/kg/h maintenance infusion (up to 48 h or 4 h after vasopressor discontinuation)
Control	Equal volume 5% dextrose
Randomization	Stratified by baseline SOFA-1 score and study center
Primary outcome	28-day all-cause mortality
Secondary outcomes	ICU-free days, vasopressor-free days, ventilator-free days, in-hospital mortality, and SOFA score improvement
Study centers	> 50 tertiary hospital centers across China (emergency, respiratory, medical, surgical, and other ICUs)
Coordinator / Sponsor	Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital (University of Electronic Science and Technology of China)
Ethics approval	Central ethics committee approval (No. 2025-583)

Figure 1. EMPRESS study design schematic.

Members

The study is overseen by the network’s Steering Committee, Coordinating Committee, and Data Safety Monitoring Board; committee rosters are available on the Members page.

Progress

Study milestones and progress updates, revised as the trial proceeds.

2026-11-0682 patients enrolled; approximately half of the study sites initiatedOngoing
2026-07-18DSMB Charter releasedReleased
2026-04-07Patient enrollment officially initiatedOngoing
2026-01-24Study protocol published (PMID: 41580807)Published
2025-11-20Protocol submitted to Scand J Trauma Resusc Emerg MedDone
2025-11-12Registered with the Chinese Clinical Trial Registry (ChiCTR2500112352)Done
2025-08-20Central ethics committee approval (No. 2025-583)Done

Additional Materials

The statistical analysis plan and interim reports will be updated in the Related Documents section above as the study progresses. For collaboration or enrollment inquiries, please use the Contact page.