Contraindications and Side Effects of Methylene Blue
Methylene blue is absolutely contraindicated in patients with G6PD deficiency because it is ineffective and causes severe hemolytic anemia, potentially worsening methemoglobinemia rather than treating it. 1, 2
Absolute Contraindications
G6PD Deficiency
- G6PD deficiency is the primary contraindication because methylene blue requires NADPH (generated through the pentose phosphate pathway via G6PD) to be reduced to leukomethylene blue, which is the active form that treats methemoglobinemia 3
- In G6PD-deficient patients, methylene blue not only fails to work but actively precipitates hemolytic anemia with Heinz body formation, which can appear 3 days after administration 4
- The American College of Medical Genetics specifically warns against use in G6PD deficiency due to risk of paradoxical worsening of methemoglobinemia 1
- Alternative treatment: Use ascorbic acid (Vitamin C) instead, with adult dosing ranging from 0.5-10 g IV, though it may take 24 hours or longer to lower methemoglobin levels 5, 6
Concurrent Serotonergic Medications
- Methylene blue acts as a monoamine oxidase inhibitor (MAOI) and precipitates serotonin syndrome when combined with SSRIs or other serotonergic drugs 1, 7
- Serotonin toxicity occurs at doses as low as 1 mg/kg IV, with plasma concentrations reaching levels that inhibit MAO-A even at 0.75 mg/kg 7
- 13 of 14 reported cases of CNS toxicity from methylene blue met Hunter Serotonin Toxicity Criteria 7
- The National Institute of Mental Health advises against use in patients taking serotonergic medications 1
- Clinical approach: Carefully consider cessation of serotonin reuptake inhibitors before using methylene blue, as all therapeutic doses appear to block monoamine oxidase 7
Relative Contraindications and Cautions
Pregnancy
- The American College of Obstetricians and Gynecologists recommends caution due to potential teratogenicity 1
Renal Failure
- The National Kidney Foundation recommends caution in patients with renal impairment 1
Specific Exposures
- Patients exposed to aniline dyes and dapsone present special risks when treated with methylene blue 8
Major Adverse Effects
Hemolytic Anemia
- Dose-related hemolytic effects occur even in patients without G6PD deficiency 8
- Hemolysis can be delayed, appearing days after administration 4
Serotonin Syndrome
- Presents with CNS toxicity when combined with serotonergic agents 7
- Can be severe and life-threatening 1
Clinical Pitfalls to Avoid
- Never assume G6PD status is normal without testing, especially in high-risk populations (Mediterranean, African, Asian descent), though routine functional assay is not recommended before emergency treatment 5
- Screen medication lists for serotonergic drugs (SSRIs, SNRIs, trazodone, MAOIs, tramadol, linezolid) before administering methylene blue 1, 6
- Monitor for delayed hemolysis up to 3 days post-administration, even with initial good response 4
- In patients with known hereditary methemoglobinemia, avoid precipitating factors including nitrates, local anesthetics (benzocaine, prilocaine, lidocaine), dapsone, and sulfonamides 5