1. Clinical Assessment and Initial Clues

Early recognition relies on specific signs—cyanosis that does not improve with oxygen, chocolate-brown blood, and a saturation gap. Prompt bedside assessment accelerates definitive testing.

Key Clinical Findings

• Refractory Central Cyanosis: Appears when MetHb levels exceed 10–15%, causing a bluish discoloration of the lips, nail beds, and mucous membranes. A hallmark feature is the lack of improvement with high-flow supplemental oxygen.
• Chocolate-Brown (“Muddy”) Blood: A venous or arterial blood sample that retains a distinct dark brown color upon exposure to air is a pathognomonic sign of significant methemoglobinemia.
• Saturation Gap (“Cyanosis-Saturation Gap”): This is a critical diagnostic clue. It is defined as a difference of more than 5% between the arterial oxygen saturation measured by pulse oximetry (SpO₂) and the saturation calculated from an arterial blood gas (SaO₂). In methemoglobinemia, the SpO₂ often plateaus around 85%, regardless of the actual PaO₂.

Symptom Correlation with MetHb Percentage

• <20%: Often asymptomatic apart from isolated cyanosis and potentially a mild headache.
• 20–50%: Systemic symptoms appear, including dyspnea, tachycardia, fatigue, and dizziness.
• >50%: Life-threatening signs emerge, such as severe metabolic acidosis, cardiac arrhythmias, seizures, and coma.
• >70%: Levels are frequently fatal if left untreated.

2. Laboratory Diagnostics

Standard pulse oximetry is unreliable for diagnosis. Co-oximetry remains the gold standard for quantifying dyshemoglobins, while enzymatic and genetic tests are used to distinguish acquired from hereditary forms.

A. Pulse Oximetry Limitations

Standard two-wavelength pulse oximeters are designed to detect oxyhemoglobin and deoxyhemoglobin. They cannot differentiate methemoglobin, carboxyhemoglobin, or sulfhemoglobin. Because methemoglobin absorbs light at both 660 nm and 940 nm, the device incorrectly interprets the signal, leading to a reading that trends toward 85%.

B. Co-oximetry (Multi-wavelength Spectrophotometry)

This is the definitive diagnostic test. By measuring light absorbance at multiple specific wavelengths, a co-oximeter can accurately quantify the fractions of different hemoglobin species:

• Oxyhemoglobin (O₂Hb)
• Deoxyhemoglobin (HHb)
• Carboxyhemoglobin (COHb)
• Methemoglobin (MetHb)
• Sulfhemoglobin (SulfHb)

Note: Accurate results depend on regular calibration, daily quality control, and awareness of potential sample interference from hemolysis or severe lipemia.

C. Enzymatic and Genetic Testing

These tests are indicated when a congenital cause is suspected (e.g., in infants, or patients with recurrent episodes without clear oxidant exposure).

• Enzymatic Assays: Measurement of erythrocyte cytochrome b₅ reductase (CYB5R) activity is the primary test. An activity level <30% of normal confirms a congenital deficiency (Type I or II).
• Genetic Testing: Sequencing of the CYB5R3 gene can identify the specific mutation causing diaphorase deficiency. Analysis for Hemoglobin M variants is used for suspected autosomal dominant forms.

3. Severity Classification

Patients are stratified by their MetHb percentage to guide the intensity of management, from observation to antidotal therapy and critical care escalation.

Classification by MetHb Level

• Mild (<20% MetHb):
  • Signs: Asymptomatic cyanosis.
  • Management: Remove the offending oxidant agent, provide supportive oxygen, and monitor clinically.
• Moderate (20–50% MetHb):
  • Signs: Headache, tachycardia, mild dyspnea, lethargy.
  • Management: Methylene blue is indicated for symptomatic patients. Ascorbic acid may be considered in patients with G6PD deficiency or in refractory cases.
• Severe (>50% MetHb):
  • Signs: Severe tissue hypoxia, arrhythmias, seizures, coma, metabolic acidosis.
  • Management: Requires ICU admission, high-flow oxygen, and prompt antidotal therapy. Exchange transfusion or hyperbaric oxygen should be considered if methylene blue is contraindicated or ineffective.

Adjusted Thresholds for Vulnerable Groups

Patients with limited physiological reserve, such as neonates, the elderly, and those with pre-existing anemia or cardiopulmonary disease, cannot tolerate even moderate levels of methemoglobinemia. In these populations, antidotal treatment should be strongly considered at lower thresholds, typically when MetHb levels are 10–15%.

4. Differential Diagnosis

It is crucial to differentiate methemoglobinemia from other causes of cyanosis and dyshemoglobinemia using a combination of clinical and laboratory clues.

5. Decision Algorithms for Management

Treatment decisions are guided primarily by the MetHb percentage, the presence of symptoms, and key patient factors like G6PD status.

A. Methylene Blue (First-Line Agent)

• Mechanism: Acts as an electron carrier, allowing NADPH-methemoglobin reductase to rapidly reduce ferric iron (Fe³⁺) in methemoglobin back to its functional ferrous state (Fe²⁺).
• Indications: MetHb >30% in any patient, or >20% in a symptomatic patient. Lower thresholds (10-15%) apply to vulnerable groups.
• Dose: 1–2 mg/kg administered as a slow IV infusion over 5 minutes. The dose may be repeated once after 30–60 minutes if the MetHb level remains >20% or symptoms persist.
• Pitfalls: Ineffective and potentially harmful in G6PD deficiency, as it can induce hemolysis. Use with caution in patients on serotonergic agents due to a risk of serotonin syndrome.

B. Alternative and Adjunctive Therapies

• Ascorbic Acid (Vitamin C): A slower, non-enzymatic reducing agent. Used primarily in patients with G6PD deficiency, methylene blue shortages, or very mild cases. Dose is typically 300–1000 mg IV every 6 hours.
• Exchange Transfusion: A rescue therapy for severe cases refractory to methylene blue, or when MB is absolutely contraindicated. It physically removes affected red blood cells.
• Hyperbaric Oxygen: Increases the amount of dissolved oxygen in the plasma, which can help sustain tissues in life-threatening cases, especially with concomitant carbon monoxide poisoning.

6. Controversies and Evidence Gaps

Despite clear guidelines for severe cases, several areas of methemoglobinemia management lack robust data, particularly concerning special populations and emerging technologies.