Methylene blue - an emerging vasopressor

Table 1 A summary of trials from 2023 to 2025

Ref.	Study design/population	Methylene blue regimen	Comparator	Major findings/clinical outcomes	Safety/adverse events	Key interpretation
Ibarra-Estrada et al[19], 2023	Randomised controlled trial (n = 91); adult septic shock (sepsis-3)	100 mg IV bolus infusion over 6 hour daily × 3 days (approximately 3.6 mg/kg total)	Placebo (saline)	Decreasing time to vasopressor discontinuation (69 hours vs 94 hours, P < 0.001); increasing vasopressor-free days; intensive care units and hospital LOS decrease; no mortality difference	No significant toxicity; no methemoglobinemia	Early adjunctive MB within 24 hours shortened vasopressor duration without added risk
Fernando et al[22], 2024	Systematic review + meta-analysis (> 1000 patients)	Pooled 1-4 mg/kg bolus ± 0.25-1 mg/kg/hour infusion	Standard therapy	Decreasing vasopressor duration (approximately 20 hours); trend 28-day mortality decrease (RR: 0.82); mean arterial pressure increase	No increase in adverse events	MB benefit most pronounced when used early as adjunct
Ballarin et al[21], 2024	Systematic review + meta-analysis (15 studies/1200 patients)	1-4 mg/kg bolus ± continuous infusion	Placebo/standard care	Decreasing norepinephrine dose (-16%); increasing urine output and CrCl; no mortality harm	No toxicity reported	Confirms hemodynamic benefit and renal protection
Arias-Ortiz and Vincent[25], 2024	Narrative review/mechanistic update	Summative PK-PD review; discussed dose-response	-	Defined biphasic response; supports 2-4 mg/kg as effective and safe	Warns against > 7 mg/kg due to splanchnic vasoconstriction	Clarifies pharmacologic rationale and dose limits
Shaker et al[20], 2025	Double-blind randomised controlled trial (n = 90) - cancer patients with septic shock	Low dose: 1 mg/kg bolus + 0.25 mg/kg/hour × 72 hour. High dose: 4 mg/kg bolus + 0.25 mg/kg/hour × 72 hours	Placebo (saline)	Both MB arms decrease vasopressor duration and increasing vasopressor-free days vs placebo (P < 0.05); trend mortality decrease (P = 0.083)	No methemoglobinemia or hemodynamic instability	Confirms efficacy up to 4 mg/kg; possible dose ceiling effect

IV: Intravenous; LOS: Length of stay; MB: Methylene blue; RR: Relative risk; PK-PD: Pharmacokinetics-pharmacodynamics.

Table 2 Adverse effects[28-31]

Adverse effect	Comments/mechanism
Hemolysis (glucose-6-phosphate dehydrogenase deficiency)	Contraindicated; oxidative stress triggers hemolysis
Methemoglobinemia	< 2% incidence; dose-related
Serotonin syndrome	Occurs with MAOI/SSRI co-administration
Green-blue discoloration	Urine/secretions/skin; due to metabolites; affects pulse oximetry
Pulse oximetry artifacts	Spurious low SpO2; due to light absorption
Fall in P/F ratio	Possibly from pulmonary vasoconstriction → V/Q mismatch. Rare-high doses 31
Splanchnic vasoconstriction	At doses > 7 mg/kg (possibly > 4 mg/kg)
Extravasation injury	Can cause necrosis; central line preferred
ECG changes, diaphoresis, dyspnea	Reported at higher doses
Pregnancy risk	Avoid use; insufficient safety data

MAOI/SSRI: Monoamine oxidase inhibitor/selective serotonin reuptake inhibitor; P/F: PaO₂/FiO₂ ratio; V/Q: Ventilation/perfusion; ECG: Electrocardiogram.