Which medications can cause a patient to develop cyanosis (turn blue) due to methemoglobinemia?

Medications That Can Turn Patients Blue (Methemoglobinemia)

The most common medications that cause patients to turn blue through methemoglobinemia are local anesthetics (particularly benzocaine, prilocaine, and lidocaine), dapsone, and nitrate derivatives, with benzocaine being especially dangerous and no longer recommended for use. 1

High-Risk Medications by Category

Local Anesthetics (Most Common Culprits)

• Benzocaine: A single spray can induce methemoglobinemia and should no longer be used due to severe risk 1, 2, 3
• Prilocaine: Can cause symptomatic methemoglobinemia in children >6 months at doses exceeding 2.5 mg/kg, and in adults at doses >5.0 mg/kg (reduced to 3.2 mg/kg with renal insufficiency) 1, 4, 2
• Lidocaine, tetracaine, articaine, cocaine mixed with aniline: All reported causes 1

Antimicrobials

• Dapsone: Particularly at doses >200 mg/day; can cause delayed methemoglobinemia up to 5 days post-ingestion 1, 5, 6
• Sulfonamides, trimethoprim: Commonly implicated 1
• Antimalarials: Chloroquine, primaquine 1

Nitrate Derivatives

• Nitroglycerin, nitroprusside, amyl nitrite, nitric oxide: All can oxidize hemoglobin 1

Other Medications

• Phenazopyridine (urinary analgesic) 1
• Metoclopramide (antiemetic) 1
• Rasburicase, cyclophosphamide, flutamide (chemotherapy agents) 1

Clinical Recognition Algorithm

Key Diagnostic Features

1. Cyanosis without respiratory distress: The hallmark finding that distinguishes methemoglobinemia from cardiac/pulmonary causes 7, 8
2. "Saturation gap": Pulse oximetry shows ≤90% while arterial PaO2 is ≥70 mmHg (discrepancy present in 91.8% of cases) 6, 2
3. Cyanosis unresponsive to 100% oxygen: Unlike hypoxemia, supplemental oxygen does not improve the blue discoloration 7, 8
4. Chocolate-colored blood: Though other colors may be observed 2, 3

Confirmation Testing

• Co-oximetry is mandatory: Standard pulse oximetry is unreliable and will give falsely low readings 1, 9, 8
• Methemoglobin levels >10% cause visible cyanosis; levels of 20-30% are typical in congenital forms 7, 8

Treatment Protocol

First-Line Treatment

Methylene blue 1-2 mg/kg IV over 3-5 minutes is the definitive treatment for symptomatic methemoglobinemia or levels >20-30%. 1, 9

• Expected response: Methemoglobin levels normalize within 30-60 minutes after initial dose 1, 9
• Repeat dosing: If no improvement after 30 minutes, additional methylene blue may be given, not exceeding cumulative dose of 5.5 mg/kg 9
• Supportive care: High-flow oxygen should be administered to maximize oxygen carriage by remaining normal hemoglobin 10

Critical Contraindications to Methylene Blue

1. G6PD deficiency: Methylene blue is ineffective and can worsen hemolysis in these patients (affects ~2% of US population) 1, 9
2. Pregnancy: Methylene blue is teratogenic; treatment decisions require weighing hypoxia risk against fetal toxicity 9
3. Hemoglobin M or unstable hemoglobins: Methylene blue is ineffective and should be avoided 1, 9

Rescue Therapies for Refractory Cases

When methylene blue fails or is contraindicated:

• Exchange transfusion: Survival rate approximately 81.6% in refractory cases 1, 9
• Hyperbaric oxygen therapy: Used as rescue modality but effect may be delayed several hours 1
• Ascorbic acid: Can be adjunctive therapy but effect is slow, requiring multiple doses over hours; not effective for acute resuscitation 1, 9

High-Risk Populations

Infants and Neonates

• Increased susceptibility due to diminished enzyme systems and fetal hemoglobin being more easily oxidized 11
• Avoid prilocaine in children <6 months old 2
• Beware of over-the-counter products: Even topical benzocaine cream (e.g., for diaper rash) can cause severe methemoglobinemia 11

Patients on Multiple Oxidizing Drugs

• Dose reduction required: Prilocaine dose should be reduced to 1.3 mg/kg when other oxidizing drugs are used concurrently 2

Renal Insufficiency

• Prilocaine dose reduction: Maximum 3.2 mg/kg in renal impairment 2

Critical Pitfalls to Avoid

1. Do not rely on pulse oximetry alone: It cannot distinguish between hypoxemia and methemoglobinemia and gives falsely low readings 8, 2
2. Watch for rebound methemoglobinemia: Particularly with benzocaine on mucous membranes, levels as high as 59.9% may occur up to 18 hours after methylene blue administration 2
3. Do not assume low levels are safe: Clinical symptoms including coma can occur at relatively low methemoglobin values (29-32%) 2
4. Recognize delayed presentation: With dapsone and some aromatic compounds, symptoms may develop over hours to days after exposure 6, 10
5. Consider poison control consultation: Recommended for methemoglobin >20%, refractory cases, or uncertainty about methylene blue dosing/contraindications 9

Prevention Strategies

Patients with known hereditary methemoglobinemia or heterozygous CYB5R3 variants should avoid all precipitating medications and receive a medical alert system. 1

• Avoid well water or food from areas with nitrate-contaminated groundwater, particularly for infants and pregnant women 1
• Promptly treat infections and other conditions that may increase methemoglobin levels 1
• Screen first-degree relatives of patients with hereditary methemoglobinemia 1