How do I diagnose methaemoglobinaemia?

How to Check for Methemoglobinemia

The gold standard diagnostic test is co-oximetry measurement of methemoglobin levels on arterial or venous blood gas analysis, which must be performed to definitively diagnose methemoglobinemia. 1, 2

Clinical Recognition: When to Suspect Methemoglobinemia

Suspect methemoglobinemia in the following scenarios:

• Cyanosis unresponsive to supplemental oxygen with a characteristic lavender-blue or slate-gray appearance, particularly prominent on lips, nose, cheeks, and buccal mucosa 1, 2, 3
• Chocolate-brown colored arterial blood that remains dark despite exposure to air 2
• Discordance between pulse oximetry (SpO2) and arterial blood gas oxygen saturation (SaO2), where pulse oximetry reads falsely low (often plateaus around 85%) while calculated oxygen saturation on ABG appears normal 1, 2
• Patient appears less unwell than expected from the severity of cyanosis 4
• Unexplained or discordant pulse oximetry results compared to clinical assessment 1

Diagnostic Testing Algorithm

Immediate Testing

Co-oximetry is mandatory and must be performed first:

• Order arterial or venous blood gas with co-oximetry to directly measure methemoglobin levels 1, 2
• Cyanosis becomes visible when methemoglobin levels exceed 10% (or 1.5% in some sources) 1, 2
• Normal methemoglobin levels are <1-2% 2

Expected arterial blood gas findings:

• Normal partial pressure of oxygen (pO2) 4
• Normal partial pressure of carbon dioxide (pCO2) 4
• Normal calculated hemoglobin oxygen saturation 4
• Elevated methemoglobin concentration 4
• Possible metabolic acidosis in severe cases 4

Critical Pitfall to Avoid

Never rely on pulse oximetry to rule out methemoglobinemia - it is falsely reassuring and unreliable in the presence of elevated methemoglobin levels. 2, 4

Distinguishing Acquired from Hereditary Methemoglobinemia

While treatment should not be delayed to establish this distinction 1, 2, the following tests help differentiate:

For Hereditary Methemoglobinemia

Molecular testing with DNA analysis is the gold standard for diagnosing hereditary methemoglobinemia (90.9% expert consensus): 1, 2

• Cytochrome b5 reductase enzymatic activity measurement using ferricyanide as substrate with NADH oxidation at 340 nm 1
• Targeted next-generation sequencing (NGS) panels including CYB5R3 gene (for enzyme deficiency) and globin genes (for hemoglobin M variants) 1, 2, 3

Clinical Features Suggesting Hereditary Forms

• Family history suggesting autosomal recessive (Type I or II) or autosomal dominant (Hemoglobin M variants) inheritance 1
• Cyanosis present from birth and persistent without variation unless treated 1
• Methemoglobin levels typically 20-30% in hereditary cases 1, 3
• Type II methemoglobinemia: severe neurodevelopmental disorder with microcephaly, axial hypotonia, dystonia, and seizures emerging by 9 months of age 1

For Acquired Methemoglobinemia

Document thorough drug and toxin exposure history, particularly: 5

• Local anesthetics: benzocaine, prilocaine, lidocaine 5, 6
• Antibiotics: dapsone, sulfonamides 5, 7
• Nitrites and nitrates (well water contamination, alkyl nitrites/"poppers") 3, 8
• Aromatic compounds (amino- and nitro-derivatives of benzene) 4

Differential Diagnosis Testing

When methemoglobinemia is confirmed, additional testing may be needed:

• G6PD deficiency testing in all symptomatic patients without known history of methemoglobinemia (methylene blue is contraindicated in G6PD deficiency) 1, 4
• Hemolysis evaluation: peripheral blood smear for Heinz bodies, isopropanol or heat stability testing for unstable hemoglobins 1
• Test first-degree relatives of patients with hereditary methemoglobinemia 1

Severity Assessment Based on Methemoglobin Levels

• 10-30%: Cyanosis, dark brown blood; patients generally asymptomatic or with headaches, tachycardia, mild dyspnea 1, 2
• 30-50%: Clinically significant tissue hypoxia 2
• >50%: Severe complications including dysrhythmias, seizures, altered mental status, coma 2
• >70%: Potentially lethal 2

Special Populations at Higher Risk

Infants require heightened clinical suspicion due to 50-60% of adult cytochrome b5 reductase activity and higher fetal hemoglobin levels that oxidize more readily. 3