What are the major clinical trials of methylene blue (MB) in refractory septic shock?

Major Clinical Trials of Methylene Blue in Septic Shock

The most recent and highest-quality evidence comes from a 2023 single-center RCT by Farhadi et al., which demonstrated that early methylene blue administration (within 24 hours) significantly reduced time to vasopressor discontinuation and ICU length of stay in septic shock patients, without serious adverse effects. 1

Key Randomized Controlled Trials

1. Farhadi et al. (2023) - Early Adjunctive Methylene Blue Trial

• Study Design: Single-center RCT with 91 patients (45 MB, 46 placebo) 1
• Intervention: MB initiated within 24 hours of septic shock onset 1
• Primary Outcome: Significantly shorter time to vasopressor discontinuation (69 hours vs 94 hours, p < 0.001) 1
• Secondary Outcomes:
  • One additional vasopressor-free day at 28 days (p = 0.008) 1
  • ICU length of stay reduced by 1.5 days (p = 0.039) 1
  • Hospital length of stay reduced by 2.7 days (p = 0.027) 1
  • No difference in mortality or mechanical ventilation days 1
• Safety: No serious adverse effects related to MB administration 1

2. Pilot RCT by Fernandes et al. (2024) - Acute-Phase Septic Shock

• Study Design: 1:1 RCT with 42 patients (19 MB, 23 control) 2
• Intervention: Loading dose 3 mg/kg followed by continuous infusion 0.5 mg/kg/h for 48 hours 2
• Timing: MB started when vasopressin was indicated as second vasopressor 2
• Key Findings:
  • Immediate reduction in norepinephrine dosage 2
  • Earlier reduction in vasopressin dosage 2
  • Higher IL-10 levels (anti-inflammatory cytokine) compared to control 2
• Safety: No adverse events reported with continuous 48-hour infusion 2

Meta-Analyses Synthesizing Trial Evidence

Systematic Review by Hosseini et al. (2024)

• Included Studies: 6 RCTs with 302 patients total 3
• Mortality: MB may reduce short-term mortality (RR 0.66,95% CI 0.47-0.94, low certainty) 3
• Vasopressor Duration: Reduced by 31.1 hours (95% CI -16.5 to -45.6, low certainty) 3
• Hospital Length of Stay: Reduced by 2.1 days (95% CI -1.4 to -2.8, low certainty) 3
• Hemodynamics: Increased mean arterial pressure at 6 hours by 10.2 mm Hg (95% CI 6.1-14.2, low certainty) 3
• Safety: No evidence of increased adverse events 3

Meta-Analysis by Oliveira et al. (2024)

• Included Studies: 3 RCTs with 141 patients (70 MB, 71 control) 4
• ICU Length of Stay: Reduced by 1.58 days (MD -1.58,95% CI -2.97 to -0.20, p = 0.03) 4
• Mechanical Ventilation: Reduced by 0.72 days (MD -0.72,95% CI -1.26 to -0.17, p = 0.010) 4
• Time to Vasopressor Discontinuation: Reduced by 31.49 hours (MD -31.49,95% CI -46.02 to -16.96, p < 0.0001) 4
• Methemoglobinemia: No association found with abnormal methemoglobin levels 4

Ongoing Trials

Multicenter RCT Protocol (2024)

• Design: Multicenter, randomized, placebo-controlled trial planning to enroll 100 patients with refractory septic shock 5
• Intervention: 2 mg/kg bolus followed by 0.5 mg/kg/h continuous infusion for 48 hours 5
• Primary Outcome: Total vasopressor dose required in first 48 hours 5
• Status: Protocol published, results pending 5

Guideline Context and Clinical Positioning

Current guideline support for MB is limited to vasoplegic shock post-cardiac surgery, not septic shock. The 2018 Intensive Care Medicine guidelines note that early methylene blue administration may improve survival in vasoplegic shock post-cardiac surgery, but do not recommend it for septic shock 6. This represents a significant gap between emerging trial evidence and formal guideline recommendations.

Critical Safety Considerations from Guidelines

Absolute Contraindications

• G6PD deficiency: Can cause hemolytic anemia and paradoxically worsen methemoglobinemia 7, 8
• All patients should ideally be tested for G6PD deficiency before administration 7, 8

Drug Interactions

• Serotonergic medications: Risk of serotonin syndrome due to MB's monoamine oxidase inhibitor properties 7, 8
• Use with caution in patients on SSRIs or other serotonergic drugs 7, 8

Other Precautions

• Caution in pregnancy due to potential teratogenicity 7, 8
• Caution in renal failure 7
• Maximum cumulative dose should not exceed 7 mg/kg 7, 8

Dosing Protocols from Trials and Guidelines

Initial bolus: 1-2 mg/kg IV over 3-5 minutes 7 Repeat dosing: May repeat 1 mg/kg if no improvement in 30-60 minutes 7 Continuous infusion: 0.10-0.25 mg/kg/hour for prolonged refractory shock 7

The trial by Fernandes used higher dosing (3 mg/kg loading, 0.5 mg/kg/h maintenance) without adverse effects 2, while Farhadi's trial used early initiation within 24 hours 1.

Clinical Interpretation

The evidence suggests MB is most effective when initiated early (within 24 hours) rather than as rescue therapy in refractory shock. The 2023 Farhadi trial's early intervention approach showed superior outcomes compared to historical studies using MB as late rescue therapy 1. This timing distinction is critical and represents an evolution in MB use strategy.

All trials consistently demonstrate vasopressor-sparing effects without increased adverse events, though the certainty of evidence remains low to moderate due to small sample sizes 4, 3. The lack of mortality benefit in individual trials may reflect inadequate power, while the meta-analysis suggests a potential mortality reduction 3.