Guideline sources The following summarized guidelines for the evaluation and management of methemoglobinemia (MetHb-emia) are prepared by our editorial team based on guidelines from the European Hematology Association (EHA 2021). 1 Guidelines 1. Screening and diagnosis Screening of family relatives: test first-degree relatives of patients with hereditary metHgbemia. E 2. Diagnostic investigations Clinical assessment: https://web.pathway.md/diseases/reciPiCsxkWjnMps1 1/4 6/30/23, 1:02 AM Methemoglobinemia Pathway Clinical assessment: Assess clinical findings and elicit family history to distinguish acquired from inherited forms of metHgbemia. E Recognize the neurologic and cardiac symptoms and their progression with increasing metHgb. E Methemoglobin levels: Measure venous blood metHgb levels in all symptomatic patients. E Recognize that: key symptoms of metHgbemia are related to the metHgb levels metHgb levels in inherited conditions range between 10-30% accounting for the occurrence of cyanosis and dark brown blood as the main signs patients are generally asymptomatic or may present with headaches, tachycardia, and mild dyspnea at these levels (10-30%) of metHgb. E Testing for NADH-cytochrome b5 reductase deficiency: Obtain cytochrome b5 reductase activity measurement as the gold standard test to discriminate hereditary CYB5R3 deficiency from acquired metHgbemia. E Consider obtaining molecular testing as the gold standard test for the diagnosis of hereditary metHgbemia. E Testing for G6PD deficiency: test for G6PD deficiency in symptomatic patients without a known history of metHgbemia. E 3. Respiratory support Oxygen supplementation: administer oxygen supplementation if needed in minimally symptomatic or asymptomatic patients. Obtain routine monitoring of oxygen saturation with pulse oximetry in case oxygen is initiated, at least in neonates. E Hyperbaric oxygen therapy: perform hyperbaric oxygen therapy in patients not responding to first-line therapy. E 4. Medical management General principles: manage metHgbemia in pediatric patients based on the symptoms, level of metHgb, cause of metHgbemia, and patient's age. E Show 2 more Methylene blue: initiate methylene blue at a starting dose of 1-2 mg/kg of 1% methylene blue as first-line therapy in symptomatic patients with metHgbemia. Repeat up to a dose of 5.5 mg/kg if there is no response after 30 minutes. E Ascorbic acid: consider adding ascorbic acid to methylene blue therapy as an adjunctive therapy. E https://web.pathway.md/diseases/reciPiCsxkWjnMps1 2/4 6/30/23, 1:02 AM Methemoglobinemia Pathway 5. Therapeutic procedures Exchange transfusion: perform exchange transfusion in patients not responding to first-line therapy. E Therapeutic phlebotomy: do not perform phlebotomy in patients with polycythemia as higher erythrocyte mass allows provision of normal tissue oxygenation. D 6. Perioperative care Perioperative care: identify potential precipitating and exacerbating factors before surgery. E Show 6 more 7. Specific circumstances Pregnant patients: ensure a multidisciplinary decision for methylene blue treatment during pregnancy and discussed with the patient weighing the risk of hypoxia on the fetus and the teratogenic and other effects of methylene blue. E 8. Patient education General counseling: advise avoiding precipitating factors in patients with known hereditary or acquired metHgbemia and in patients with a CYB5R3 heterozygous variant. E Show 2 more 9. Follow-up and surveillance Indications for referral: refer patients with mild symptoms to specialized laboratories or directly to emergency units in case of more severe symptoms to establish metHgb levels and initiate treatment. E Clinical findings Symptoms Past medical history Chest pain G6PD deficiency Confusion Neurological exam Dizziness Fatigue Altered mental status Headache Lab findings Seizure Shortness of breath https://web.pathway.md/diseases/reciPiCsxkWjnMps1 3/4 6/30/23, 1:02 AM Methemoglobinemia Pathway cytochRome b5 reductase activity Vital signs Hypoxemia ECG findings Tachycardia Tachypnea Ischemic changes O2 saturation Integument exam Cyanosis Hematological findings "chocolate-brown" colored blood MetHgbemia References 1. Achille Iolascon, Paola Bianchi, Immacolata Andolfo et al. Recommendations for diagnosis and treatment of methemoglobinemia. Am J Hematol. 2021 Dec 1;96 12 1666 1678. Open https://web.pathway.md/diseases/reciPiCsxkWjnMps1 4/4