Low Dose Versus High Dose Methylene Blue in Septic Patients

NCT ID: NCT06005558

Last Updated: 2024-07-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-01
• Study Completion Date: 2024-05-15

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

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Normal saline

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

Group Type: ACTIVE_COMPARATOR

Methylene Blue low dose

Intervention Type: DRUG

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.

Methylene Blue high dose

Intervention Type: DRUG

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.

methylene blue low dose

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.

Group Type: ACTIVE_COMPARATOR

Normal saline

Intervention Type: DRUG

100 ml 0.9% Nacl over 20 minutes, followed by continuous infusion of normal saline for 72 hours.

Methylene Blue high dose

Intervention Type: DRUG

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.

methylene blue high dose

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.

Group Type: ACTIVE_COMPARATOR

Normal saline

Intervention Type: DRUG

100 ml 0.9% Nacl over 20 minutes, followed by continuous infusion of normal saline for 72 hours.

Methylene Blue low dose

Intervention Type: DRUG

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.

Interventions

Normal saline

100 ml 0.9% Nacl over 20 minutes, followed by continuous infusion of normal saline for 72 hours.

Intervention Type: DRUG

Methylene Blue low dose

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.

Intervention Type: DRUG

Methylene Blue high dose

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.

Intervention Type: DRUG

Other Intervention Names

Control; Low dose; High 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute, Egypt

OTHER

Sponsor Role: lead

Responsible Party

Ehab Hanafy Shaker

Associate Professor of Anesthesia, ICU and Pain management

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ehab H Shaker, MD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Cancer Institute

Cairo, , Egypt

Countries

Egypt

References

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.

Reference Type: RESULT

PMID: 36505110 (View on PubMed)

Shaker EH, Soliman AM, Bedewy AAE, Elrawas MM. Comparative study between high and low dose methylene blue infusion in septic cancer patients: a randomized, blinded, controlled study. BMC Anesthesiol. 2025 Jan 8;25(1):15. doi: 10.1186/s12871-024-02792-3.

Reference Type: DERIVED

PMID: 39780053 (View on PubMed)

Other Identifiers

Methylene blue

Identifier Type: -

Identifier Source: org_study_id