Clinical trial NCT06005558: Low Dose Versus High Dose Methylene Blue in Septic Patients
Official title: Comparative Study Between High and Low Dose Methylene Blue Infusion in Septic Cancer Patients. A Randomized Blinded Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Septic Shock
Lead sponsor: National Cancer Institute, Egypt
Sponsor class: OTHER
First posted: 2023-08-22
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 .

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Discontinuation of vasopressor
timeFrame: 7 days
Secondary outcomes:
measure: Mortality
timeFrame: 28 days
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: National Cancer Institute
Study officials:
affiliation: National Cancer Institute (NCI)
name: Ehab H Shaker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chalise SN, Sahib TA, Boyer GA, Pathak V. Methylene Blue in Refractory Shock. Cureus. 2022 Nov 6;14(11):e31158. doi: 10.7759/cureus.31158. eCollection 2022 Nov.