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
CCC Pharmacology Series
Respiratory: Bosentan, Delivery of B2 Agonists in Intubated Patients, Nitric Oxide, Oxygen, Prostacyclin, Sildenafil
Cardiovascular: Adenosine, Adrenaline (Epinephrine), Amiodarone, Classification of Vasoactive drugs, Clevidipine, Digoxin, Dobutamine, Dopamine, Levosimendan, Levosimendan vs Dobutamine, Milrinone, Noradrenaline, Phenylephrine, Sodium Nitroprusside (SNiP), Sotalol, Vasopressin
Neurological: Dexmedetomidine, Ketamine, Levetiracetam, Lignocaine, Lithium, Midazolam, Physostigmine, Propofol, Sodium Valproate, Sugammadex, Thiopentone
Endocrine: Desmopressin, Glucagon Therapy, Medications and Thyroid Function
Gastrointestinal: Octreotide, Omeprazole, Ranitidine, Sucralfate, Terlipressin
Genitourinary: Furosemide, Mannitol, Spironolactone
Haematological: Activated Protein C, Alteplase, Aprotinin, Aspirin, Clopidogrel, Dipyridamole, DOACs, Factor VIIa, Heparin, LMW Heparin, Protamine, Prothrombinex, Tenecteplase, Tirofiban, Tranexamic Acid (TXA), Warfarin
Antimicrobial: Antimicrobial Dosing and Kill Characteristics, Benzylpenicillin, Ceftriaxone, Ciprofloxacin, Co-trimoxazole / Bactrim, Fluconazole, Gentamicin, Imipenem, Linezolid, Meropenem, Piperacillin-Tazobactam, Rifampicin, Vancomycin
Analgesic: Alfentanil, Celecoxib, COX II Inhibitors, Ketamine, Lignocaine, Morphine, NSAIDs, Opioids, Paracetamol (Acetaminophen), Paracetamol in Critical Illness, Tramadol
Miscellaneous: Activated Charcoal, Adverse Drug Reactions, Alkali Therapies, Drug Absorption in Critical Illness, Drug Infusion Doses, Epidural Complications, Epidural vs Opioids in Rib Fractures, Magnesium, Methylene Blue, Pharmacology and Critical Illness, PK and Obesity, PK and ECMO, Sodium Bicarbonate Use, Statins in Critical Illness, Therapeutic Drug Monitoring, Weights in Pharmacology
Toxicology: Digibind, Flumazenil, Glucagon Therapy, Intralipid, N-Acetylcysteine, Naloxone, Propofol Infusion Syndrome
CCC Toxicology Series
General
Approach to acute poisoning, ECGs in Tox, Evidenced-based Tox, Toxicology literature summaries, Does anti-venom work?
Toxins / Overdose
Amphetamines, Barbituates, Benzylpiperazine, Beta Blockers, Calcium Channel Blocker, Carbamazepine, Carbon Monoxide, Ciguatera, Citrate, Clenbuterol, Cocaine, Corrosive ingestion, Cyanide, Digoxin, Ethanol, Ethylene Glycol, Iron, Isoniazid, Lithium, Local anaesthetic, Methanol, Monoamine oxidase inhibitor (MAOI), Mushrooms (non-hallucinogenic), Opioids, Organophosphate, Paracetamol, Paraquat, Plants, Polonium, Salicylate, Scombroid, Sodium channel blockers, Sodium valproate, Theophylline, Toxic alcohols, Tricyclic antidepressants (TCA)
Envenomation
Marine, Snakebite, Spider, Tick paralysis
Syndromes
Alcohol withdrawal, Anticholinergic syndrome, Cholinergic syndrome, Drug withdrawals in ICU, Hyperthermia associated toxidromes, Malignant hyperthermia (MH), Neuroleptic malignant syndrome (NMS), Opioid withdrawal, Propofol Infusion Syndrome (PrIS) Sedative toxidrome, Serotonin syndrome, Sympatholytic toxidrome, Sympathomimetic toxidrome
Decontamination
Activated Charcoal, Gastric lavage, GI Decontamination
Enhanced Elimination
Enhanced elimination, Hyperbaric therapy for CO
Antidotes
Antidote summary, Digibind, Glucagon, Flumazenil, HIET – High dose euglycaemic therapy, Intralipid, Methylene Blue, N-Acetylcysteine (NAC), Naloxone
Miscellaneous
Cocaine chest pain, Digoxin and stone heart theory, Hyperbaric oxygen, Hypoxaemia in tox, Liver failure in tox, Liver transplant for paracetamol, Methaemoglobinaemia, Urine drug screen
LITFL
- 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.
Critical Care
Compendium
Chris is an Intensivist and ECMO specialist at The Alfred ICU, where he is Deputy Director (Education). He is a Clinical Adjunct Associate Professor at Monash University, the Lead for the Clinician Educator Incubator programme, and a CICM First Part Examiner.
He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives. He was one of the founders of the FOAM movement (Free Open-Access Medical education) has been recognised for his contributions to education with awards from ANZICS, ANZAHPE, and ACEM.
His one great achievement is being the father of three amazing children.
On Bluesky, he is @precordialthump.bsky.social and on the site that Elon has screwed up, he is @precordialthump.
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