Methylene Blue in Early Septic Shock

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: 0.9% sodium chloride
* Drug: Methylene Blue


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Standard care<br>Placebo | Drug: 0.9% sodium chloride<br>* Intravenous infusion of 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.<br>|
| Experimental: Methylene blue<br>Methylene blue | Drug: Methylene Blue<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Methylene blue, Norepinephrine