Methylene Blue in Early Septic Shock (SHOCKEM-Blue)

Early Use of Methylene Blue in Patients With Septic Shock: a Pilot Randomized Controlled Trial

Septic shock is a subset of sepsis characterized by a decrease in vascular tone, which contributes to impaired regional blood flow distribution, and leads to organic failure. Besides intravenous fluids and adequate antimicrobial therapy, patients with septic shock require vasopressor support, which can lead to many adverse effects, therefore, non-vasopressor agents that can improve hemodynamic status are needed. In this randomized controlled-study, the investigators will address the efficacy and safety of infusion with methylene blue in patients with septic shock.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: 0.9% sodium chloride; Drug: Methylene Blue

Detailed Description

Unlike sepsis, septic shock mortality is not declining for the last decade, and is still around 40%. After restoring intravascular volume, many patients need vasopressor agents to maintain arterial blood pressure, which leads to improvement of perfusion at some vascular beds, however some organs may suffer from maldistribution of blood flow. These changes of regional blood flow may compromise oxygen delivery and perpetuate the inflammation and tissue damage associated with the state of shock.

One of the main mechanisms of vasodilation after inflammatory insults, is the activation of the inducible isoform of Nitric Oxide Synthase (iNOS), and the subsequent increase in the levels of nitric oxide, which even reduces the response to vasoconstrictor agents. Methylene blue (MB) is a selective inhibitor of iNOS, which has been used successfully in patients with post-cardiopulmonary bypass associated vasoplegia, however, the evidence of the use of MB in septic shock patients is limited to case reports, observational and small studies. In this randomized controlled trial, the investigators will compare the efficacy and safety outcomes of repeated doses of MB in patients with septic shock.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Mexico
  • Guadalajara, Mexico, 44280
    • Hospital Civil Fray Antonio Alcalde

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Septic shock diagnosis, according to the Sepsis-3 consensus.
• Prior adequate fluid resuscitation according to dynamic predictors of volume responsiveness.
• More than 6 h and less than 24 h of norepinephrine requirement to maintain a mean arterial pressure ≥65 mmHg.

Exclusion Criteria:

• Age < 18 years.
• Pregnancy.
• Not expected to survive 48 hours.
• Presence or high suspicion of concurrent hemorrhagic, obstructive or hypovolemic shock.
• Personal or familiar history of glucose-6-phosphate dehydrogenase deficiency.
• Allergic to methylene blue, phenothiazines, or food dyes.
• Recent intake (4-weeks) of selective serotonin re-uptake inhibitors.
• Refusal of the patient or decision maker to enroll in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard care; Placebo	Drug: 0.9% sodium chloride; Intravenous infusion of 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.
Experimental: Methylene blue	Drug: Methylene Blue; Intravenous infusion of 100 mg methylene blue in 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasopressor requirement	Total time to shock resolution (hours)	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to lactate normalization	Time in hours until lactate is <2 mmol/L	7 days
Length of stay in intensive care unit	Time in days until ICU discharge	28 days
Intensive care unit mortality	Mortality in intensive care unit	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pulmonary function after treatment	Change in P/F index after three doses of methylene blue	7 days

Collaborators and Investigators

• Sponsor: Hospital Civil de Guadalajara
• Investigators: Principal Investigator: Miguel Ibarra-Estrada, MD, Investigator

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2017
• Primary Completion (Actual): December 10, 2020
• Study Completion (Actual): January 25, 2021

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Septic shock; Methylene blue; Norepinephrine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Methylene Blue
• Other Study ID Numbers: HCG/CEI-0252/17

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
• product manufactured in and exported from the U.S.: No