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

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

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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. 


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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                                    The Pharm So Hard Podcast: An Emergency Medicine and Hospital Pharmacy PodcastBy Jimmy Pruitt & Oscar Santalo