Low Dose Versus High Dose Methylene Blue in Septic Patients

National Cancer Institute, Egypt

Status and phase: Completed; Phase 3; Phase 2

Conditions: Septic Shock

Treatments: Drug: Methylene Blue low dose; Drug: Methylene Blue high dose; Drug: Normal saline

Study type: Interventional

Funder types: Other

Identifiers

NCT06005558

Methylene blue

Details and patient eligibility

About

The main aim of this study is to examine the various effects of continuous methylene blue infusion in septic cancer patients and to compare it with the traditional infusion of noradrenaline in such patients .

Full description

Exaggerated host response to infection, may result in sepsis, which is life-threatening organ dysfunction . Though considered the number one cause of in-hospital deaths , it can be treatable with early prompt interventions.

The 2021 SSC Guidelines use the Third International Consensus definitions, also known as Sepsis-3. Where sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection." Organ dysfunction is evidenced by an increased score of 2 or more in the Quick Sequential [Sepsis-related] Organ Failure Assessment (QSOFA), and septic shock is considered as "a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone." To diagnose septic shock, an euvolemic patient must require vasopressor support to achieve a mean arterial pressure of at least 65 mm Hg and have a lactate level above 2 mmol/L.

The triad of intravenous fluid, vasopressors and antibiotics in the first hour is the mainstay of septic shock management. Aim of management is to maintain patient hemodynamically stable until antibiotics kick in and fight infection. In case of non-responders, low dose corticosteroids are prescribed. Other drugs need to be studied to also help in cases of non-responders and to improve outcome in general. Methylene blue (MB) is a nitric oxide inhibitor that can counteract the vasodilatation in early septic shock.

Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) which activates cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKGs) that cause vasodilatation. Methylene blue selectively blocks sGC and inhibits iNOS. Therefore, it selectively acts on the microcirculation.

Onset of action of intravenous MB is 30-60 min. Peak concentration at 30 min. It is excreted through bile and fecal routes plus through the kidneys. Due to the short Plasma half-life of 5-6 hours, some studies used continuous infusion of 0.25-2 mg/kg/h, for up to 3 days following the initial bolus dose

Enrollment: 90 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients aged ≥ 18 years and ≤ 65 with septic shock as defined by Sepsis-3 criteria (confirmed infection, requiring vasopressor to maintain a mean arterial blood pressure (MAP) ≥ 65 mmHg, and serum lactate > 2 mmol/L after adequate fluid resuscitation), and requiring mechanical ventilation.

Exclusion criteria

• myocardial infarction or cerebrovascular accident within the last 3 months.
• severe lung , liver or kidney disease (creatinine >3.5 mg/dL).
• pregnancy.
• glucose 6-phosphate-dehydrogenase deficiency.
• known allergy to MB or food dyes and the use of nitrates within the last 3 days.
• more than 24 hrs since initiation of norepinephrine.
• other causes of shock than sepsis .
• recent intake (4-weeks) of selective serotonin re-uptake inhibitors or MAOi.
• refusal of the patient guardian to participate.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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90 participants in 3 patient groups

Normal saline

Active Comparator group

Description:

30 patients will receive placebo of 100ml 0.9% Nacl over 20 minutes followed by continuous infusion of Nacl for 72 hours.

Treatment:

Drug: Methylene Blue high dose

Drug: Methylene Blue low dose

methylene blue low dose

Active Comparator group

Description:

30 patients will receive a bolus of MB 1mg/kg in 100ml 0.9% Nacl over 20 minutes followed by continuous infusion of 0.25mg/kg/hour for 72 hours.

Treatment:

Drug: Normal saline

Drug: Methylene Blue high dose

methylene blue high dose

Active Comparator group

Description:

30 patients will receive a bolus of MB 4mg/kg in 100ml 0.9% Nacl over 20 minutes followed by continuous infusion of 0.25mg/kg/hour for 72 hours.

Treatment:

Drug: Normal saline

Drug: Methylene Blue low dose