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Guanylate Cyclase / Nitric Oxide Pathway Inhibitor Pregnancy: Avoid in first trimester — associated with intestinal atresia in case reports (intra-amniotic injection); IV route at low doses for life-threatening indication acceptable after first trimester

Methylene Blue

Brand names: Provayblue, Methylthioninium chloride

Adult dose

Dose: Vasoplegic shock: 1–2 mg/kg IV over 15–20 minutes; Methaemoglobinaemia: 1–2 mg/kg IV over 5 minutes, repeat at 1 mg/kg after 1 hour if MetHb >30% or inadequate response
Route: Intravenous
Frequency: Single or repeated doses
Max: 7 mg/kg total (higher doses cause paradoxical methaemoglobinaemia)
Vasoplegic/distributive shock refractory to conventional vasopressors; methaemoglobinaemia from oxidising agents (dapsone, nitrites, prilocaine); only effective if NADPH-methylene blue reductase is functional (NOT in G6PD deficiency)

Paediatric dose

Dose: 1–2 mg/kg IV over 5 minutes mg/kg
Route: Intravenous
Frequency: Single dose; repeat at 1 mg/kg after 1 hour if needed
Max: 7 mg/kg total
Paediatric methaemoglobinaemia — G6PD exclusion important before giving

Dose adjustments

Renal

No dose adjustment required

Hepatic

No dose adjustment required

Paediatric weight-based calculator

Paediatric methaemoglobinaemia — G6PD exclusion important before giving

Clinical pearls

  • Vasoplegic shock mechanism: methylene blue inhibits guanylate cyclase (downstream of nitric oxide) — reduces cyclic GMP, reversing pathological vasodilation; effective in distributive shock states where excessive nitric oxide is the culprit (septic shock, post-cardiac bypass, anaphylaxis)
  • MHRA 2012 serotonin syndrome warning: methylene blue inhibits MAO-A — in patients on SSRIs/SNRIs/fentanyl/tramadol/linezolid, methylene blue can precipitate fatal serotonin syndrome; in elective settings, discontinue serotonergic drugs ≥2 weeks before; in emergencies, benefit of treating life-threatening methaemoglobinaemia may outweigh risk
  • G6PD deficiency paradox: methylene blue requires NADPH (generated by G6PD) for its activity as a methaemoglobin reductase cofactor — in G6PD-deficient patients, methylene blue CANNOT reduce methaemoglobin and may worsen it; alternatives include ascorbic acid 1000 mg IV or exchange transfusion
  • Methaemoglobinaemia treatment: MetHb >20% with symptoms OR MetHb >30% regardless of symptoms — treat with methylene blue 1-2 mg/kg; response usually within 30-60 minutes; failure to respond suggests G6PD deficiency or insufficient dose
  • Post-cardiac bypass vasoplegic syndrome: methylene blue added to vasopressor protocol in refractory post-bypass vasoplegic shock — reduces noradrenaline requirements and ICU stay in several case series; RCT evidence limited but clinical practice well-established

Contraindications

  • G6PD deficiency (paradoxical worsening of methaemoglobinaemia — alternative: ascorbic acid, exchange transfusion)
  • Severe renal impairment
  • 5-HT (serotonin) syndrome risk — MAO-B inhibitor interactions (methylene blue inhibits MAO)

Side effects

  • Blue-green discolouration of urine and skin (expected)
  • Nausea
  • Hypertension (vasopressor effect — desired in vasoplegic shock)
  • Serotonin syndrome (via MAO inhibition — dangerous with SSRIs/SNRIs)
  • Pain at injection site

Interactions

  • SSRIs/SNRIs — MHRA warning: methylene blue inhibits MAO-A → potentially fatal serotonin syndrome with serotonergic drugs; delay SSRIs for 2 weeks after methylene blue if non-emergency
  • Serotonergic drugs — avoid combination

Monitoring

  • MetHb level (pulse co-oximetry or blood gas co-oximetry — before and 1 hour post-treatment)
  • Blood pressure (vasopressor response in vasoplegic shock)
  • SpO2 (methylene blue absorbs at 660 nm — falsely low SpO2 readings transiently)
  • Serotonin syndrome signs (agitation, hyperthermia, clonus) if on serotonergic drugs

Reference: BNFc; BNF 90; MHRA Drug Safety Update 2012 (serotonin syndrome); TOXBASE NPIS (methaemoglobinaemia); Methylene Blue in Vasoplegic Shock — Systematic Review (Belletti et al. 2018); MHRA SPC Provayblue. Verify against your local formulary and the latest BNF before prescribing.

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Curated clinical cross-links plus same-class fallbacks.

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