Methylene Blue

CLASS

• heterocyclic aromatic molecule

MECHANISM OF ACTION

• two opposite actions on Hb

(1) low concentrations: methylene blue -> NADPH-dependent reduction to leucomethylene blue (due to action of methaemoglobin reductase) -> reduces methaemoglobin -> Hb
(2) high concentrations: methylene blue -> converts ferrous iron of reduced Hb to ferric ion -> forms methaemoglobin

• inhibits guanylate cyclase (which is stimulated by NO and other mediators), thus decreasing C-GMP and vascular smooth muscle relaxation
• MAO inhibition

PHARMACEUTICS

• 1%
• blue!
• stored at room temperature

DOSE

Methaemoglobinaemia

• 1-2mg/kg IV over 5 minutes followed by saline flush; repeat at 30-60 min if MetHb levels not falling
• repeat dose every 6-8h when MetHb continues for days, e.g. dapsone toxicity

Vasoplegia

• 1.5-2 mg/kg IV over 30-60min

INDICATIONS

• methaemoglobinemia
  — symptomatic
  — asymptomatic with >20% MetHb, or >10% if risk factors such as anaemia or ischemic heart disease
• vasoplegic shock post cardiopulmonary bypass
• other possible roles in critical illness: hepatopulmonary syndrome, septic shock
• other uses have included use as an antimalarial agent, anti-cancer treatment, treatment of ifosfamide neurotoxicity, as a dye/stain (e.g. test for aspiration), priapism

CONTRA-INDICATIONS

• G6PD deficiency (lack of NADPH prevents methylene blue from working and may lead to haemolysis)
• renal impairment
• methaemoglobin reductase deficiency
• nitrite-induced methaemoglobinaemia due to cyanide poisoning
• hypersensitivity

ADVERSE EVENTS

• inability to monitor oxygen saturation by SpO2 or continuous central venous saturation monitoring
• non-specific symptoms: dizziness, headache, confusion, chest pain, shortness of breath, nausea and vomitng
• local pain and irritation
• blue staining of mucous membrane may mimic cyanosis
• paradoxical methaemoglobinaemia due to direct oxidative effect on Hb (typically at very high doses > 7 mg/kg)
• acute haemolytic anemia in G6PD deficiency (typically doses >15mg/kg)
• anaphylaxis
• MAO inhibiton may contribute to serotonin toxicity or hypertensive crisis

PHARMACOKINETICS

• Absorption – given IV
• Distribution – ?
• Metabolism – rapidly converted to leucomethylene blue by methemoglobin reductase
• Elimination – leucomethylene is mostly excreted in the urine as a salt complex

EVIDENCE

Levin, R.L., et al (2004) “Methylene Blue Reduces Mortality and Morbidity in Vasoplegic Patients After Cardiac Surgery” Ann Thorac Surg 77:496-9 PMID: 14759425.

• NO is a mediator involved in post cardiac surgery vasoplegia (SIRS)
• RCT
• methylene blue (2mg/kg) vs placebo
• vasoplegia defined as: hypotension, MAP <50mmHg, low filling pressures, CVP <5, normal or elevated cardiac index of > 2.5L/min/m2, low peripheral resistance dramatic resolution of vasoplegia!
• vasoplegic postoperative syndrome was seen in 8.8% of all patients (636 total)
  -> better outcomes in every area of study!
  -> morbidity and mortality reductions (0% versus 21.4% or 6 of 28 patients; p value = 0.01)

References and Links

LITFL

• CCC — Methaemoglobinaemia
• Tox Conundrum – Why so Blue?
• Tox Library – Methylene blue

Journal articles

• Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):517-20. PubMed PMID: 21547182; PubMed Central PMCID: PMC3087269.
• Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004 Feb;77(2):496-9. PMID: 14759425.