Efficacy and Safety of Methylene Blue in the Treatment of Severe Septic Shock

Exploratory Study on the Efficacy and Safety of Methylene Blue in Treating Severe Septic Shock Patients: A Prospective, Randomized, Controlled Trial

The goal of this clinical trial is to investigate whether methylene blue injection can safely and effectively improve the survival rate of patients with severe septic shock, shorten the duration of norepinephrine use, reduce the dosage of vasopressors, promptly correct hemodynamics, and improve tissue perfusion and organ function impairment.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock; Methylene Blue
• Intervention / Treatment: Drug: Methylene Blue Intervention Group; Drug: Normal Saline Control Group

Detailed Description

Researchers will compare methylene blue to a placebo (a look-alike substance that contains no drug) to see if methylene blue works to treat severe septic shock.

Participants will:

Administer a loading dose of 2.5 mg/kg via micro-pump over 15 minutes, followed by a maintenance infusion at a rate of 0.25 mg/kg/hour for 12 hours or until norepinephrine has been continuously discontinued for 4 hours, whichever comes first. If norepinephrine needs to be increased to 0.25 μg/kg/min before the 12-hour period ends, continue using methylene blue until the 12-hour infusion is completed.

Primary Study Endpoint

- 28-day all-cause mortality rate starting from the diagnosis of septic shock.

Secondary Study Endpoints

• Time from the start to the discontinuation of norepinephrine after the diagnosis of septic shock.
• Total dose of norepinephrine used (from enrollment to 72 hours).
• Number of days without norepinephrine within 28 days.
• Duration of mechanical ventilation.
• Rate of CRRT (Continuous Renal Replacement Therapy).
• Length of ICU stay.
• Total hospital stay.

Record the following indicators before methylene blue intervention and at 24 hours, 72 hours, and 5 days after the intervention:

• Highest serum lactate level.
• Lowest mean arterial pressure.
• Alanine aminotransferase (ALT).
• Total bilirubin.
• Creatinine.
• Oxygenation index (P/F ratio).
• Creatine kinase-MB (CK-MB).
• Troponin I (TNI).
• Systemic vascular resistance index (SVRI).

• Study Type: Interventional
• Enrollment (Estimated): 488
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wenqiao Yu, PhD; Phone Number: +86-18868787588; Email: yuwenqiao1980@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • The First Affiliated Hospital, Zhejiang University School of Medicine
      • Contact: Wenqiao Yu, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Meets the Sepsis 3.0 criteria for septic shock: patients with infection who, despite adequate fluid resuscitation, require vasopressor therapy to maintain a mean arterial pressure (MAP) of ≥ 65 mmHg and have a blood lactate concentration > 2 mmol/L.
3. Diagnosed with septic shock and started on norepinephrine within 24 hours.
4. Requires a norepinephrine dose of ≥ 0.1 μg/kg/min to maintain a MAP of ≥ 65 mmHg.

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. Individuals allergic to methylene blue or any components of the methylene blue injection.
3. Individuals with a personal or family history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
4. Patients with an expected survival time of less than 48 hours.
5. Patients who have been on norepinephrine for more than 24 hours.

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 Intervention Group; Methylene blue injection, 2.5 mg/kg loading dose over 15 minutes, followed by a continuous infusion of 0.25 mg/kg/hour for 12 hours or until norepinephrine has been continuously discontinued for 4 hours, whichever comes first.	Drug: Methylene Blue Intervention Group; In addition to standard treatment, patients will receive methylene blue intervention. The method is as follows: a loading dose of 2.5 mg/kg administered via micro-pump over 15 minutes, followed by a continuous infusion at a rate of 0.25 mg/kg/hour for 12 hours or until norepinephrine has been continuously discontinued for 4 hours, whichever comes first. If norepinephrine needs to be increased to 0.1 μg/kg/min before the 12-hour period ends, continue using methylene blue until the 12-hour infusion is completed.
Placebo Comparator: Normal Saline Control Group; Normal saline solution, administered in the same manner and duration as the methylene blue intervention.	Drug: Normal Saline Control Group; In addition to standard treatment, patients will receive a placebo control with normal saline, administered for the same duration as the intervention group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day survival rate of enrolled patients	Our primary endpoint is the 28-day survival rate of enrolled patients: All enrolled patients will be followed from the time of randomization until 28 days post-enrollment, recording the survival status on the 28th day after enrollment. If a patient dies within 28 days post-enrollment, the number of survival days will be recorded. Note: Cases where the family requests discharge to home for end-of-life care and the patient subsequently dies will be counted as death cases.; Cases where the family requests discharge for non-medical reasons such as financial constraints and no further treatment is sought will be counted as dropout cases.	28-day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The duration and dosage of norepinephrine use	The duration of norepinephrine use：The time from the start of norepinephrine (NE) administration after sepsis diagnosis until its discontinuation. The definition of discontinuation: NE must be stopped for ≥2 hours; if NE is stopped for <2 hours, it is not considered discontinued. If NE is re-administered after being stopped for more than 2 hours, it is still considered discontinued. The dosage of norepinephrine use：the total dose of NE used within 72 hours after the patient is enrolled in the study.	28-day
The duration of mechanical ventilation	The number of days without mechanical ventilation within 28 days post-enrollment. Note: Only full days without mechanical ventilation can be counted as one day.	28-day
The duration of ICU stay	ICU length of stay: the number of days in the ICU starting from the time of patient enrollment in the study. Note: Some patients may have multiple ICU admissions; only the ICU stay duration after the current enrollment is recorded.	28-day
The duration of overall hospital stay	The duration of overall hospital stay: the total number of days hospitalized starting from the time of patient enrollment in the study. Note: Days hospitalized prior to enrollment are not included.	28-day
The safety of methylene blue injection	We will record the complications due to the use of methylene blue, such as hemolysis: We will determine the presence of hemolysis by daily monitoring of urine color, red blood cells, hemoglobin count in complete blood count, and bilirubin levels in liver function tests. If the patient's urine turns dark brown (similar to soy sauce), accompanied by a decrease in hemoglobin and red blood cell count and a simultaneous increase in bilirubin, hemolysis will be considered.	28-day

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Zhejiang University
• Collaborators: The First People's Hospital of Huzhou; People's Hospital of Guangxi; The second Nanning People's Hospital; Yuyao People's Hospital; ENZE HOSPITAL OF TAIZHOU ENZE MEDICAL CENTER; NINGBO MEDICAL CENTER LIHUIIHOSPITAI; GUI LIN PEOPLE'S HOSPITAL; Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University; Hangzhou Yuhang District Second People's Hospital; Wuming Hospital of Guangxi Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2024
• Primary Completion (Estimated): June 20, 2026
• Study Completion (Estimated): June 20, 2026

Study Registration Dates

• First Submitted: June 21, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): July 1, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 26, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Septic Shock; Sepsis; Methylene blue
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Methylene Blue
• Other Study ID Numbers: 2024-051

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: You can explain the reason and contact the study initiator via email to request the data. The email address is:yuwenqiao1980@zju.edu.cn
• IPD Sharing Time Frame: After the study results are published
• IPD Sharing Access Criteria: You can explain the reason and contact the study initiator via email to request the data. The email address is:yuwenqiao1980@zju.edu.cn
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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