Episode 110. The use of Methylene Blue for Refractory Hypotension with Rosa Malloy-Post, MD

The Pharm So Hard Podcast: An Emergency Medicine and Hospital Pharmacy Podcast

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Guest For the podcast

Rosa Malloy-Post

Hometown: Brooklyn, NY

College: Fort Lewis College Durango, CO

Medical school: University of Colorado

What you love about living in/moving to Charlotte: The food and the trees. Coming from Denver it’s nice to have some greenery. The variety and concentration of good food is impressive, I haven’t had a bad meal yet.

What you see yourself doing in 10 years: Who knows? I’m opened to exploring fellowship opportunities in toxicology or palliative care. I enjoy teaching so I see an academic career in my future. I’ll most likely be somewhere in the mountain west.

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Methylene blue

History and Background

• First synthesized in 1876 by Heinrich Caro at BASF as a blue textile dye, originally named “methyl blue”
• In 1891, Paul Ehrlich discovered it could stain certain microorganisms and used it to differentiate bacterial species
• Used as antiseptic/antibacterial in late 1800s, including treating tropical diseases like malaria
• Approved by FDA in 1959 as a treatment for methemoglobinemia, a condition where hemoglobin is oxidized to the ferric (Fe3+) form, making it unable to carry oxygen. Doses of 1-2 mg/kg IV can reduce methoglobin levels by acting as an electron donor.
• Studied as potential treatment for hypotension starting in 1980s. Case reports showed benefit in refractory septic shock. Proposed as nitric oxide scavenger and vasopressor.
• Multiple human studies in 1990s looked at methylene blue for sepsis. Showed transient improvements in blood pressure but no mortality benefit.

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
  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

• Key Clinical Studies
  • Levin et al. 2004 RCT in post-CABG vasoplegic shock
    • 28 patients, MB 2 mg/kg vs placebo
    • Marked improvement in hemodynamics
    • Mortality benefit – 0% vs 21% in placebo group (p=0.01)
  • Kirov et al. 2001 RCT in established septic shock
    • 20 patients, MB vs placebo
    • Increased MAP, decreased vasopressor needs
  • Porizka et al. 2020 retrospective study
    • Looked at MAP increase ≥10% to define “responders”
    • Improved survival in responders
  • Franz et al. 2021 case series
    • 11 patients with post-cardiotomy shock
    • 82% rate of MB response based on 20% MAP increase
    • Survival benefit in responders (92% vs 50%)
      

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