Early Methylene Blue in the Microhemodynamics of Septic Patients

Evaluation of Early Methylene Blue in the Microhemodynamics of Septic Patients: a Feasibility Randomized Controlled Trial

The aim of the study is to evaluate the viability and feasibility of its protocol in order to conduct a larger clinical trial to assess whether methylene blue can improve patient-centered clinical outcomes such as mortality or length of hospital stay in septic shock patients.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Hypoperfusion
• Intervention / Treatment: Drug: Methylene blue infusion

Detailed Description

One of the primary causes of high mortality in patients with septic shock is microcirculatory dysfunction related to vasodilation caused by excessive oxide nitric production. It has been shown that methylene blue, an old and safe drug that can reduce vasodilation by blocking nitric oxide pathways, is a vasopressor-sparing treatment in sepsis. Nevertheless, there is no evidence that methylene blue improves patient-centered clinical outcomes such as mortality. Understanding how early methylene blue affects the microhemodynamics of septic shock patients may lead to relevant clinical results that can improve their prognosis. So, the objective of the study is to evaluate the viability and feasibility of the study protocol for a larger clinical trial, assessing the effectiveness of early methylene blue in the microhemodynamics of septic shock patients, mainly through the capillary refill time measurement. For this purpose, a pilot study of an open-label, randomized, controlled and single-center clinical trial will be conducted, with two treatment arms: the intervention group (methylene blue plus standard treatment) and the control group (standard treatment). Fifty adult patients with septic shock within the first six hours of diagnosis will be included in this study. They will be randomized to either receive a methylene blue infusion or not. The randomization will be conducted using RedCap with a 1:1 ratio and variable block sizes. The primary outcome will be to assess the feasibility, which is defined as completing the study recruitment within the 12-month timeline and achieving protocol adherence of 90% or higher. Comparisons between groups for serially measured micro and macrohemodynamics parameters will be the secondary outcomes. Additionally, the incidence of adverse events related to methylene blue will be monitored.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Bruna Dal Vesco; Phone Number: +55 (41) 3362-6633; Email: brunadalvesco@gmail.com

Study Locations

• Brazil
  • Paraná
    • Curitiba, Paraná, Brazil, 80010-030
      • Recruiting
      • Irmandade da Santa Casa de Misericórdia de Curitiba
      • Contact: Bruna Dal Vesco; Phone Number: +55 (41) 3362-6633; Email: brunadalvesco@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients with a diagnosis of sepsis and persistent hemodynamic dysfunction despite adequate fluid resuscitation, requiring escalation of noradrenaline dose to maintain mean arterial pressure ≥65 mmHg, with prolonged capillary refill time or septic shock according to Sepsis-3 definition, within less than 6 hours of the diagnosis, will be eligible for the study.

Exclusion Criteria:

• Pregnant or breastfeeding patients;
• Patients with any withdrawal or withholding life-sustaining intervention;
• Cardiac surgery patients in the immediate postoperative period;
• Refractory septic shock, with a high propability of death within 24 hours;
• Personal or familiar history of glucose-6-phosphate dehydrogenase (G6PD) deficiency;
• Allergy to methylene blue, phenothiazines, or food dyes;
• Recent administration of linezolid (less than 14 days ago);
• Recent intake of serotonergic psychiatric medications (less than 2 weeks ago - with the exception of fluoxetine, which must be less than 5 weeks ago),
• Recent intake (less than 2 weeks ago) of monoamine oxidase inhibitors (MAOIs), such as rasagiline and selegiline.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylene blue group; The intervention group will receive methylene blue plus standard treatment for septic shock, according to the international guidelines.	Drug: Methylene blue infusion; Methylene blue at a dose of 100mg (diluted in 100ml of 5% dextrose solution) in continuous infusion for 06 hours per day, for 03 days, plus standard treatment according to international guidelines for the management of sepsis and septic shock. The 03 consecutive MB infusions, each lasting 06 hours, will be performed every 24 hours, starting from randomization: the first infusion at T0, the second at T24, and the third at T48, considering T0 the moment after the patient randomization into the study. The interruption of the protocol will be recommended if vasopressors are completely discontinued during the three days of methylene blue infusion. The attending physician may discontinue methylene blue treatment if judges necessary. Similarly, interruption may occur if the family or patient request.; Other Names: Methylene blue; Phenothiazines
No Intervention: Control group; The control group will receive the standard treatment according to international guidelines for the management of sepsis and septic shock.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the feasibility of the study protocol.	The primary outcome of the study is to evaluate feasibility, defined as completing the study protocol according to the planned timeline and with 90% or more protocol adherence. Protocol adherence will be defined as the use of the allocated therapy in the intervention group for 6 hours for 3 days (or interruption of methylene blue if the patient does not require a vasoactive drug anymore). Justified interruptions will not be considered violations.	28 days after randomization.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Capillary refill time	Serial capillary refill time from randomization up to 72 hours later.	72 hours after randomization.
Serum lactate level	Serial measurements of serum lactate level during the 72 hours after randomization.	72 hours after randomization.
Arteriovenous carbon dioxide difference (gapCO2)	Serial measurements of arteriovenous carbon dioxide difference (gapCO2) during 72h after randomization.	72h after randomization.
Central venous oxygen saturation (SvO2)	Serial measurements of central venous oxygen saturation (SvO2) during 72h after randomization.	72h after randomization.
Serial measurements of heart rate	Serial measurements of heart rate from randomization up to 72 hours later.	72 hours after randomization.
Serial measurements of mean arterial pressure	Serial measurements of mean arterial pressure from randomization up to 72 hours later.	72 hours after randomization.
Serial measurements of pulse pressure	Serial measurements of pulse pressure from randomization up to 72 hours later.	72 hours after randomization.
Serial measurements of systolic arterial pressure	Serial measurements of systolic arterial pressure from randomization up to 72 hours later.	72 hours after randomization.
Serial measurements of dyastolic arterial pressure	Serial measurements of dyastolic arterial pressure from randomization up to 72 hours later.	72 hours after randomization.
Methylene blue-related adverse events	Incidence of adverse events during the three days of administration of methylene blue and up to 28 days after.	28 days after randomization.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variations in the Sequential Organ Failure Assessment-2 Score (SOFA-2)	Daily SOFA-2 score pontuatin from enrollment to 72 hours later. The SOFA score ranges from 0 to 24, being 24 the worst pontuation, indicating multiple organ dysfunction.	From enrollment to 72 hours later.
Time to vasopressor discontinuation	Time to complete vasopressor discontinuation from the enrollment up to 28 days.	28 days after randomization.
Vasopressor dose (norepinephrine and vasopressin)	Vasopressor dose (norepinephrine and vasopressin) before and after the start of MB infusion, measuring before and after the methylene blue on the first, second, and third days of infusion.	72 hours after randomization.
Time to weaning from mechanical ventilation	Total number of days to wean from mechanical ventilation during the 28 days after randomization.	28 days after randomization.
Need for renal replacement therapy (RRT)	Total number of days of renal replacement therapy (RRT) during 28 days after randomization.	28 days after randomization.
Intensive care unit length of stay	Total number of days until intensive care unit discharge.	28 days after randomization.
28-day mortality	All-cause mortality at day 28 after randomization.	28 days after randomization.

Collaborators and Investigators

• Sponsor: Centro de Estudos e Pesquisa em Emergencias Medicas e Terapia Intensiva
• Collaborators: Irmandade da Santa Casa de Misericordia de Curitiba
• Investigators: Study Chair: Álvaro Réa-Neto, CEPETI - Centro de Estudos e Pesquisa em Emergências Médicas e Terapia Intensiva

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2026
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: December 2, 2025
• First Posted (Actual): December 4, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Septic Shock; Microcirculation; Methylene Blue; Capillary Refill Time
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Shock, Septic; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring; Methylene Blue; Phenothiazines
• Other Study ID Numbers: U1111-1331-7627; Approval number 7.955.174 (Other Identifier: Pontifícia Universidade Católica do Paraná - Research and Ethics Committee); CAAE 93099325.5.0000.0020 (Other Identifier: Pontifícia Universidade Católica do Paraná - Research and Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No