Methylene blue

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Related FACEM curriculum (2022) learning objectives:

• ME 3.8.1.6(e) Principles of management of toxicological presentations including: Indications for antidotes
• ME 3.8.2.4 Identify the appropriate antidote or antivenom.

Toxicological Indications

• Symptomatic drug-induced methaemoglobinaemia (e.g., chest pain, dyspnoea, confusion with signs of hypoxaemia).
• Consider in asymptomatic patients with MetHb levels >20%.
• Adjunct in anaphylactic and toxic shock states with persistent hypotension despite vasopressors.

Contraindications

• G6PD deficiency: Inadequate NADPH, rendering methylene blue ineffective and causing haemolysis.
• Renal impairment: Dose reduction required.
• Methaemoglobinaemia reductase deficiency.
• Nitrite-induced methaemoglobinaemia post-cyanide treatment.
• Hypersensitivity.

Mechanism of Action

• Increases the natural reduction rate of MetHb to haemoglobin by converting methylene blue to leucomethylene blue via methaemoglobin reductase and NADPH.
• In shock states, methylene blue inhibits nitric oxide synthase and guanylate cyclase, scavenging endothelial nitric oxide, producing vasoconstriction and positive inotropic effects.

Administration

• Initial dose: 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) IV slowly over 5 minutes, followed by a saline flush.
• Measure MetHb levels hourly until consistent decrease observed.
• Repeat dose: 1–2 mg/kg after 30–60 minutes if inadequate response.
• For dapsone poisoning or other cases with prolonged methaemoglobin formation, repeat doses every 6–8 hours for several days.
• In toxic shock states, a single dose of 1–2 mg/kg may be used adjunctively.

Therapeutic Endpoints

• Resolution of hypoxaemia symptoms.
• Improved haemodynamic parameters.
• Confirm improvement via repeat MetHb levels.

Adverse Drug Reactions and Management

• Common: Local pain, irritation, and possible necrosis from extravasation. Non-specific effects include headache, dizziness, nausea, vomiting, chest discomfort, shortness of breath.
• Blue discolouration of mucous membranes and urine (may mimic cyanosis).
• Paradoxical methaemoglobinaemia may occur at doses >7 mg/kg due to direct oxidative effects on haemoglobin.
• G6PD deficiency or high doses (>15 mg/kg) may lead to acute haemolytic anaemia.

Specific Considerations

• Pregnancy & Lactation: No restrictions.
• Paediatrics: Initial dose of 1 mg/kg.

Handy Tips

• Asymptomatic patients with MetHb >20% but without symptoms may not need treatment.
• Pulse oximetry is unreliable because both MetHb and methylene blue interfere with readings.
• The clinical sign of blue discolouration is an unreliable indicator of response to therapy due to methylene blue's own blue staining effect.
• If MetHb levels don't decrease after 2 doses, consider:
  • Continued exposure to oxidising agents.
  • Sulfhaemoglobinaemia (e.g., sulfonamides).
  • G6PD deficiency, methaemoglobin reductase deficiency, abnormal haemoglobin, or excessive methylene blue.
• If methylene blue fails, consider exchange transfusion or hyperbaric oxygen therapy.

Controversies

• Debate exists on the threshold of MetHb concentration that mandates methylene blue therapy. Many clinicians monitor asymptomatic patients even with MetHb >20%.
• The role and dosing of methylene blue in refractory toxic shock states are still under investigation.