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Methylene Blue
Indications
Methylene blue has FDA approval for the treatment of methemoglobinemia, a condition when Fe2+ of hemoglobin gets oxidized to Fe3+, reducing the oxygen-carrying capacity of hemoglobin, and typically presents with cyanosis of the lips and extremities, characteristic "chocolate-colored urine," and hypoxia.[1] Methemoglobinemia results from exposure to certain drugs such as dapsone, a drug indicated for the treatment of Mycoplasma leprae and Pneumocystis jirovecii prophylaxis, benzocaine (a local anesthetic), high altitude water sources, and nitrites such as nitroglycerin or amyl nitrite used for treating coronary artery disease.[1]
The remaining indications are non-FDA approved. The first indication is for vasoplegic syndrome, a type of distributive shock that occurs during coronary procedures (specifically coronary artery bypass grafting) as a means to increase systemic vascular resistance when the use of epinephrine is refractory.[2] Another indication for methylene blue is during a lumpectomy/mastectomy with sentinel lymph node biopsy, as it is applied as a dye to map out which lymph nodes, if any, have any signs of malignancy.[3] It can also reduce post-injection pain when used 45 seconds before the administration of propofol.[4] Indications for methylene blue also include the treatment of Plasmodium falciparum in areas that have shown resistance to chloroquine and pyrimethamine-sulfadoxine.[2] Methylene blue is also used to treat ifosfamide-induced encephalopathy due to the drug's ability to prevent the formation of neurotoxic metabolites that cause the encephalopathy.[5][6] Another indication for the use of methylene blue is to identify the parathyroid glands during parathyroidectomy procedures.[7]
Mechanism of Action
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Mechanism of Action
The main mechanism of action of methylene blue is reducing the oxidized form of hemoglobin Fe3+ when in a state of methemoglobinemia to Fe2+. In turn, this will increase the oxygen-binding capacity of hemoglobin and thus increase oxygen delivery to tissues. This property is also exhibited by vitamin C, which is an alternative treatment option for methemoglobinemia. Methylene blue also inhibits the enzymes endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and guanylate cyclase, decreasing the amount of cGMP needed for nitrous oxide to be released, therefore causing vasoconstriction of blood vessels via inhibition of vascular smooth muscle relaxation.[2] Regarding malaria treatment, methylene blue has been shown to improve the chloroquine response to malaria by decreasing its resistance and inhibiting Plasmodium falciparum glutathione reductase, an enzyme that prevents the formation of byproducts formed by the Plasmodium species that triggers the body's immune response.[2][8]
Administration
Administration of methylene blue for both children and adults experiencing methemoglobinemia is done intravenously at a dose of 1 mg/kg of a 1% solution over 5 to 30 minutes. When using methylene blue for lymph node mapping, the most common two doses are 2 mL and 5 mL of a 1% solution t given intraparenchymal.[3] When used to prevent post-injection pain, when used 45 seconds before propofol administration, the dose is 50 mg given as a 2 mL bolus.[4] Treating ifosfamide-induced encephalopathy with methylene blue is given intravenously at a dose of 50 mg every 4 hours until asymptomatic.[9] Methylene blue is also infused for 20 minutes at a dose of 2 mg/kg for a patient experiencing vasoplegic syndrome and may be given pre-operatively and post-operatively to reduce mortality.[10][11] To identify the parathyroid glands, methylene blue is administered 1 hour before the parathyroidectomy intravenously at a dose of 5 mg/mL.[7] Treating Plasmodium falciparum requires three days of treatment at a dose of 300 to 1000 mg per day in adults and 20–300 mg per day in children of methylene blue, given as a supplement.[12]
Adverse Effects
One of the most common adverse effects of methylene blue is the bluish-green discoloration of urine. Another common adverse effect is limb pain following IV administration. methylene blue may contribute to serotonin syndrome if combined with other serotonergic drugs such as SSRIs, SNRIs, MAOIs, and TCAs due to the MAOI activity that methylene blue has.[13] Serotonin syndrome increases sympathetic and neuromuscular activity; therefore, symptoms include diaphoresis, clonus, and tremors. In adults, methylene blue can cause central nervous system-related symptoms such as dizziness, confusion, and headaches.[14] Administration of methylene blue in neonates has led to hyperbilirubinemia, respiratory depression, pulmonary edema, phototoxicity, and hemolytic anemia.[15][16]
Contraindications
Methylene blue is contraindicated in patients who have demonstrated hypersensitivities or anaphylaxis after past administration and for those with glucose-6-phosphate dehydrogenase deficiency due to susceptibility to experiencing hemolytic anemia. Those experiencing hemolytic anemia in this situation will have jaundice and characteristic Heinz bodies on a peripheral blood smear.[17] Methylene blue is also contraindicated in pregnant women. The FDA has assigned a pregnancy class X rating for methylene blue due to intestinal atresia and fetal death following an intra-amniotic injection, specifically in the second trimester.[18]
Monitoring
Methylene blue is a safe drug at a therapeutic dose of less than 2 mg/kg; however, when levels are greater than 7 mg/kg, many of the adverse effects it exhibits will occur.[2] Serotonin syndrome has been found to occur when combining serotonergic agents with methylene blue at a dose of 5 mg/kg.[19] Methylene blue use also requires caution in patients with renal failure due to its ability to reduce renal blood flow.[2] Also, as noted in adverse effects, patients taking any drug with serotonergic activity, such as SSRIs, should avoid the administration of methylene blue due to the risk of serotonin syndrome.
Toxicity
The research concludes that there has been no antidote for treating methylene blue toxicity to be found to exist. If anaphylaxis does occur, the administration of methylene blue should stop immediately and promptly, followed by supportive care, although severe anaphylactic shock with methylene blue is quite rare. Methylene blue may become potentially fatal when used in combination with medications that include or increase serotonin; this is because of its monoamine oxidase-inhibiting properties. It may precipitate serotonin toxicity at doses greater than 5 mg/kg.
Enhancing Healthcare Team Outcomes
Clinicians primarily use methylene blue for methemoglobinemia and lymph node mapping during breast surgery; however, there are other serious life-threatening situations where it can be applied that are considered off-label uses. Understanding and mastering the indications for the use of methylene blue is essential in many potentially life-threatening situations, such as vasoplegic syndrome and ifosfamide-induced encephalopathy, and if not acted upon appropriately and promptly, these disorders could spell disaster for the patient. The entire interprofessional healthcare team, including clinicians, mid-level practitioners, nurses, and pharmacists, must maintain open communication and information sharing to optimize the use of methylene blue for maximum patient benefit. [Level 5]
References
do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: from diagnosis to treatment. Revista brasileira de anestesiologia. 2008 Nov-Dec:58(6):651-64 [PubMed PMID: 19082413]
Ginimuge PR, Jyothi SD. Methylene blue: revisited. Journal of anaesthesiology, clinical pharmacology. 2010 Oct:26(4):517-20 [PubMed PMID: 21547182]
Li J, Chen X, Qi M, Li Y. Sentinel lymph node biopsy mapped with methylene blue dye alone in patients with breast cancer: A systematic review and meta-analysis. PloS one. 2018:13(9):e0204364. doi: 10.1371/journal.pone.0204364. Epub 2018 Sep 20 [PubMed PMID: 30235340]
Level 2 (mid-level) evidenceSalman AE, Salman MA, Saricaoglu F, Akinci SB, Aypar Ü. Pain on injection of propofol: a comparison of methylene blue and lidocaine. Journal of clinical anesthesia. 2011 Jun:23(4):270-4. doi: 10.1016/j.jclinane.2010.09.008. Epub [PubMed PMID: 21663809]
Level 1 (high-level) evidencePelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. British journal of cancer. 2000 Jan:82(2):291-4 [PubMed PMID: 10646879]
Level 3 (low-level) evidenceAjithkumar T, Parkinson C, Shamshad F, Murray P. Ifosfamide encephalopathy. Clinical oncology (Royal College of Radiologists (Great Britain)). 2007 Mar:19(2):108-14 [PubMed PMID: 17355105]
Dudley NE. Methylene blue for rapid identification of the parathyroids. British medical journal. 1971 Sep 18:3(5776):680-1 [PubMed PMID: 5569552]
Olivier M, Van Den Ham K, Shio MT, Kassa FA, Fougeray S. Malarial pigment hemozoin and the innate inflammatory response. Frontiers in immunology. 2014:5():25. doi: 10.3389/fimmu.2014.00025. Epub 2014 Feb 5 [PubMed PMID: 24550911]
Küpfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet (London, England). 1994 Mar 26:343(8900):763-4 [PubMed PMID: 7510815]
Shanmugam G. Vasoplegic syndrome--the role of methylene blue. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2005 Nov:28(5):705-10 [PubMed PMID: 16143539]
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. The Annals of thoracic surgery. 2004 Feb:77(2):496-9 [PubMed PMID: 14759425]
Level 1 (high-level) evidenceMeissner PE, Mandi G, Coulibaly B, Witte S, Tapsoba T, Mansmann U, Rengelshausen J, Schiek W, Jahn A, Walter-Sack I, Mikus G, Burhenne J, Riedel KD, Schirmer RH, Kouyaté B, Müller O. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malaria journal. 2006 Oct 8:5():84 [PubMed PMID: 17026773]
Gillman PK. CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. Journal of psychopharmacology (Oxford, England). 2011 Mar:25(3):429-36. doi: 10.1177/0269881109359098. Epub 2010 Feb 8 [PubMed PMID: 20142303]
Level 3 (low-level) evidenceMartindale SJ, Stedeford JC. Neurological sequelae following methylene blue injection for parathyroidectomy. Anaesthesia. 2003 Oct:58(10):1041-2 [PubMed PMID: 12969068]
Level 3 (low-level) evidenceCragan JD. Teratogen update: methylene blue. Teratology. 1999 Jul:60(1):42-8 [PubMed PMID: 10413340]
Crooks J. Haemolytic jaundice in a neonate after intra-amniotic injection of methylene blue. Archives of disease in childhood. 1982 Nov:57(11):872-3 [PubMed PMID: 6890790]
Level 3 (low-level) evidenceClifton J 2nd, Leikin JB. Methylene blue. American journal of therapeutics. 2003 Jul-Aug:10(4):289-91 [PubMed PMID: 12845393]
Kidd SA, Lancaster PA, Anderson JC, Boogert A, Fisher CC, Robertson R, Wass DM. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenatal diagnosis. 1996 Jan:16(1):39-47 [PubMed PMID: 8821851]
Level 2 (mid-level) evidenceGillman PK. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia. 2006 Oct:61(10):1013-4 [PubMed PMID: 16978328]
Level 3 (low-level) evidence