ToxCard: Methylene Blue

Authors: Quinton Nannet, MD, (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center), Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Case:

A 34-year-old male presents to the emergency department (ED) via emergency medical services (EMS) for near syncope and altered mental status. The patient was picked up at a popular night club where his friends note he had been sniffing amyl nitrate “poppers.” EMS calls out that he is somnolent with non-bloody emesis on his shirt. The EMS crew notes the patient is hypoxic to the 80s and looks blue.

Initial ED vitals were HR 110; BP 65/48; RR 24 breaths/min; O₂ sat 85% on 15L non-rebreather; Temp 37.8 °C. Physical exam reveals a patient who can speak with clear lung sounds, 2+ pulses, and a GCS of 15 but with marked cyanosis and dusky skin.

When drawing labs, the patient’s blood is appreciably dark. Chest x-ray and EKG are unremarkable. His venous blood gas demonstrates a pH of 7.41, pCO₂ 38, pO₂ 105, and methemoglobin of 35%.

Questions:

1. What is the cause and mechanism of methemoglobinemia?
2. How does methylene blue treat methemoglobinemia?
3. How can methylene blue be used as a vasopressor in the ED?
4. What are some current alternative uses of methylene blue?

Background: Methemoglobinemia¹

• Methemoglobinemia occurs when the iron molecule in hemoglobin (Hgb) becomes oxidized from the ferrous (Fe²⁺) to ferric (Fe³⁺) state preventing it from being able to bind oxygen
• This resultant oxidation shifts the oxygen dissociation curve to the left, impairing oxygen distribution reducing the amount of functional hemoglobin
• Subsequently, patients with methemoglobinemia present with cyanosis, somnolence, dyspnea, and tachycardia
• As methemoglobin levels rise, the oxidative stress can also lead to hemolysis; particularly when reducing agents such as glutathione cannot be repleted, such as in glucose-6-phosphate-dehydrogenase (G6PD) deficiency
• The key diagnostic features include:
  • Refractory pulse oximetry suggesting hypoxemia as the sPO₂ will often remain < 85% despite 100% FiO₂
  • Cyanosis occurs despite an O₂ saturation of ~ 80%, whereas cyanosis normally would occur < 75%
  • Brown blood, as it cannot absorb oxygen and return to a normal red hue
• Causes of methemoglobinemia include anything that causes increased oxidative stress:

Figure 1. Methemoglobin-inducing agents. Image adapted from The Internet Book of Critical Care ²

Methylene Blue to Treat Methemoglobinemia

• Mechanism of Action:
  • Methylene blue acts as a carrier for electrons to aid in reduction of ferric iron (Fe³⁺) back to ferrous iron (Fe²⁺)

Figure 2. Methylene blue redox cycling. Image courtesy of The Internet Book of Critical Care (IBCC)²

• Indications:
  • Symptomatic methemoglobinemia
    • Neurologic: dizziness, headache, syncope, lethargy, coma, seizures
    • Cardiovascular: dyspnea, exercise intolerance, fatigue, dysrhythmia, acidosis
  • Methemoglobin level >30%
    • Of note, cyanosis as a lone symptom is not an indication for treatment, as skin discoloration can be seen at methemoglobin levels of 3-20%
  • Relative Contraindications:
    • G6PD deficiency
      • G6PD reduces NADP to NADPH
      • NADPH in turn repletes oxidized glutathione stores in cells to limit free radical damage
        • The G6PD pathway is the only source of glutathione in red blood cells making G6PD deficient patients more susceptible to oxidative stress which can lead to hemolysis
      • NADPH is also needed to convert methylene blue to leukomethylene blue, which is the form that reduces methemoglobin (Fe³⁺) to hemoglobin (Fe²⁺), as illustrated in the image above. Thus, if NADPH stores are depleted due to ongoing oxidative stress, methylene blue is theoretically less beneficial
      • Additionally, since methylene blue is an oxidizing agent, high doses of methylene blue could precipitate hemolysis through further oxidative stress
      • Given the variability in G6PD activity, even in patients with “deficiency”, it is reasonable to consider treating with a small dose of methylene blue in patients with severe methemoglobinemia
      • Alternative treatment options in patients with G6PD deficiency include exchange transfusions and hyperbaric oxygen³
        • Ascorbic acid, frequently touted as a treatment for methemoglobin, can cause hemolysis in G6PD deficient patients and should not be used
      • Methylene blue and serotonergic medications
        • Methylene blue acts as a MAO-A inhibitor, meaning it blocks the degradation of amines (serotonin, norepinephrine, and dopamine)⁴
        • When given in high doses at one time or over an extended duration methylene blue can precipitate serotonin syndrome
          • This typically occurs in patients taking other medications with serotonin reuptake inhibition or those who have not had a long enough washout period after discontinuing a serotonin reuptake inhibitor⁵
          • In most case reports noting this effect, patients received > 7 mg/kg. However, if a patient is on multiple medications blocking serotonin reuptake or increasing serotonin in the synapse, this could happen at lower doses.
        • Again, this is a relative contraindication, as the risks of shock may outweigh the risks of serotonin syndrome
      • Dosing³:
        • 1-2 mg/kg IV over 5 minutes with a max initial dose of 100 mg for pediatric and adult patients
        • For neonates, smaller doses of 0.3 mg/kg to 1 mg/kg are effective
        • Most patients should improve clinically within minutes, and methemoglobin levels should reduce to < 10% within an hour
        • If symptoms still persistent after 60 minutes, an additional 1 mg/kg can be given
        • Failure to respond to two doses of 1 mg/kg should raise questions of G6PD deficiency or an alternative diagnosis
        • Repeat dosing may be required if there is continued exposure to the cause of the patient’s methemoglobinemia, i.e., the drug continues to be absorbed or has a slow elimination time like dapsone
      • Side effects:
        • Transiently and falsely lowered pulse oximetry readings during administration
        • Blue-green urine discoloration
        • Infusion site discomfort
        • The most common side effects noted in Goldfrank’s by healthy individuals receiving doses > 2 mg/kg were: extremity and back pain, chromaturia, dizziness, diaphoresis, nausea, skin discol­oration, and headache³
        • Doses > 7 mg/kg are typically thought as an upper limit and can potentiate further methemoglobinemia

Methylene Blue to Treat Vasoplegic Shock

• Mechanism of Action: Methylene blue causes vasoconstriction by inhibiting nitric oxide synthase and the conversion of guanine triphosphate to cGMP
• Indications: Distributive shock states
  • Vasoplegia following cardiac surgery^{6, 7}
  • Sepsis⁸
• Dosing:
  • Varies depending on sources and hospital practices:
    • Bolus: 1-2 mg/kg IV
    • If improvement noted, consider infusion from 0.5 – 2 mg/kg/hour

Alternative Uses for Methylene Blue:

• Methylene Blue for Anaphylaxis^{9, 10}

Figure 3. Methylene blue inhibits guanylate cycle and prevents vasodilatation. Image created by Dr. Nannet, adapted from Circulation Research¹¹

• • The pathophysiology of anaphylaxis is multifactorial, but it is known that the release of nitric oxide plays a large component
  • The inhibition of guanylate cyclase by methylene blue reduces the vasodilatory effects of nitric oxide and can be considered in treating the hypotension associated with anaphylaxis

• Methylene Blue for vasoplegic shock from metformin toxicity^12,13

Figure 4. Electron transport chain in the mitochondria. Image courtesy of Fvasconcellos 22:35, 9 September 2007 (UTC), Public domain, via Wikimedia Commons

• • One of proposed mechanisms of metformin toxicity is via inhibition of the mitochondrial respiratory chain complex I in the electron transport chain preventing aerobic metabolism and promoting anaerobic metabolism and lactic acidosis, (http://www.emdocs.net/toxcard-metformin-toxicity/)
  • Methylene blue is theorized to act as a NADH electron acceptor, bypassing the electron transport chain when inhibited by metformin

Clinical Pearls

• Methemoglobinemia is the result of hemoglobin oxidation which prevents oxygen binding resulting in refractory hypoxemia, cyanosis, and brown or “chocolate” blood
• The treatment for methemoglobinemia is methylene blue which acts as an electron shuttle to reduce oxidized hemoglobin
• Methylene blue is relatively contraindicated in patients with G6PD deficiency due to the risk of hemolysis
• Methylene blue is dosed at 1-2 mg/kg IV over 5 minutes for methemoglobinemia, or you can give a bolus of 1-2 mg/kg and infusion of 0.5-2 mg/kg/hour for refractory vasoplegic shock

References

1. Agarwal A.M., & Prchal J.T. (2015). Methemoglobinemia and other dyshemoglobinemias. Kaushansky K, & Lichtman M.A., & Prchal J.T., & Levi M.M., & Press O.W., & Burns L.J., & Caligiuri M(Eds.), Williams Hematology, 9e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1581&sectionid=101238113
2. Farkas, J. (2021, November 30). Methemoglobinemia. EMCrit Project. Retrieved March 27, 2022, from https://emcrit.org/ibcc/methemoglobinemia/
3. Hoffman RS, Nelson LS, Goldfrank LR, Howland MA, Lewin NA, Smith SW. Goldfrank’s Toxicologic Emergencies, Eleventh Edition. McGraw-Hill Education; 2019.
4. Ramsay, R. R., Dunford, C., & Gillman, P. K. (2007). Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. British journal of pharmacology, 152(6), 946–951. https://doi.org/10.1038/sj.bjp.0707430
5. Ng BK, Cameron AJ. The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010 May-Jun;51(3):194-200. doi: 10.1176/appi.psy.51.3.194. PMID: 20484716.
6. Levin R, Degrange M, Bruno G, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery.Ann Thorac Surg. 2004;77(2):496-499. https://www.ncbi.nlm.nih.gov/pubmed/14759425.
7. Mehaffey JH, Johnston LE, Hawkins RB, Charles EJ, Yarboro L, Kern JA, Ailawadi G, Kron IL, Ghanta RK. Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival. Ann Thorac Surg. 2017 Jul;104(1):36-41. doi: 10.1016/j.athoracsur.2017.02.057. Epub 2017 May 24. PMID: 28551045; PMCID: PMC5523819.
8. Kwok ES, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med. 2006 Nov-Dec;21(6):359-63. doi: 10.1177/0885066606290671. PMID: 17095500.
9. Evora PR, Simon MR. Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue. Ann Allergy Asthma Immunol. 2007 Oct;99(4):306-13. doi: 10.1016/S1081-1206(10)60545-5. PMID: 17941276.
10. Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PR. Methylene blue for clinical anaphylaxis treatment: a case report. Sao Paulo Med J. 2007 Jan 4;125(1):60-2. doi: 10.1590/s1516-31802007000100012. PMID: 17505688.
11. Friebe A, Koesling D. Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res. 2003 Jul 25;93(2):96-105. doi: 10.1161/01.RES.0000082524.34487.31. PMID: 12881475.
12. Warrick BJ, Tataru AP, Smolinske S. A systematic analysis of methylene blue for drug-induced shock. Clin Toxicol (Phila). 2016 Aug;54(7):547-55. doi: 10.1080/15563650.2016.1180390. Epub 2016 May 19. PMID: 27196698.
13. Graham RE, Cartner M, Winearls J. A severe case of vasoplegic shock following metformin overdose successfully treated with methylene blue as a last line therapy. BMJ Case Rep. 2015 Jul 6;2015:bcr2015210229. doi: 10.1136/bcr-2015-210229. PMID: 26150642; PMCID: PMC4493209.