ACMT Toxicology Visual Pearl: Out of the Blue

4 – Oral analgesic gel

Oral analgesic gel contains benzocaine, which is an oxidizing agent and a common cause of methemoglobinemia. The pictured cyanosis and classic “chocolate” blood are seen with this condition.

Background

Methemoglobinemia is a disorder of hemoglobin in which the iron atom has been oxidized from the normal Fe²⁺ to Fe³⁺. The Fe³⁺ iron is unable to bind to oxygen, effectively resulting in anemia and impaired oxygen delivery.  Methemoglobinemia can be congenital due to enzyme deficiency, or acquired from exposure to a potent oxidizing agent. A variety of xenobiotics can act as oxidizing agents, inducing methemoglobinemia. Common agents include local anesthetics, dapsone, quinones, sulfonamides, phenazopyridine, and nitrites [1, 2].

What are the symptoms of Methemoglobinemia?

All symptoms are the result of impaired oxygen delivery to tissues and resulting end-organ dysfunction.

Signs and symptoms can include [3]:

• Cyanosis
• Chocolate brown color of arterial blood
• Low O₂ saturation (usually about 85%) on pulse oximetry that does not improve with supplemental oxygen.
• Dyspnea
• Headache
• Syncope
• Coma
• Seizures

How can you diagnose methemoglobinemia?

• Regular pulse oximeters work by measuring absorption of different wavelengths of light, and since methemoglobin absorbs light differently, pulse-oximetry readings will be falsely low, usually about 85%-88%. [4]
• The most common confirmatory test for methemoglobinemia is co-oximetry (multiple-wavelength oximetry) and results are usually reported as a percentage of methemoglobin.
• Some blood gas analyzers are also able to detect methemoglobin from arterial or venous samples.
• The oxidative stress that causes methemoglobinemia can also cause hemolysis, therefore patients being evaluated for methemoglobinemia should also be evaluated for hemolytic anemia.

How do you treat methemoglobinemia?

• The primary treatment of acquired methemoglobinemia is identifying the offending agent and avoiding further exposure.
• Mild acquired methemoglobinemia is self-limited and does not require further treatment.
• Methylene blue is the antidote of choice for patients with signs and symptoms of end-organ injury from methemoglobinemia. It can reduce the Fe³⁺ in methemoglobin back to Fe²⁺.
• Exchange transfusion can be used in patients with severe methemoglobinemia.
• Vitamin C (ascorbic acid) can reduce Fe³⁺, but because it takes 24-48 hours to take effect, it is of limited use in patients with severe methemoglobinemia.

What are the indications and dosage for methylene blue?

• Indications
  • Blood methemoglobin level > 30%
  • Lower methemoglobin levels with symptoms of poor oxygen delivery including [5]:
    • Altered mental status
    • Ischemic chest pain
    • Shortness of breath
    • Signs of hypoperfusion
• Dosing
  • 1 to 2 mg/kg of body weight infused intravenously over 5 minutes, followed by a 15-30 mL flush of normal saline or LR to minimize pain [6-8]
  • May be repeated if cyanosis persists.
  • If cyanosis persists after 2 doses, consider the possibility of G6PD deficiency. Treatment for methemoglobinemia in G6PD deficiency may consist of ascorbic acid, exchange transfusion, and hyperbaric oxygen [7, 9].

Adverse Effects of Methylene Blue

• Pain at infusion site
• Blue discoloration of urine and serum
• Interferes with pulse oximetry, resulting in falsely low readings after administration.
• Interference with laboratory studies that use light absorption.
• Can cause serotonin toxicity in combination with serotonergic medications.
• Use with caution in patients with G6PD deficiency, as methylene blue is itself an oxidizing agent and can cause hemolytic anemia in high doses.

Bedside Pearls

• Methemoglobinemia results from oxidation, or loss of an electron, of the iron atom in hemoglobin.
• Methemoglobinemia can be induced by medications such as
  • Local anesthetics
  • Dapsone
  • Quinones
  • Sulfonamides
  • Phenazopyridine
  • Ntrites
• Symptoms include cyanosis, pulse oximetry reading in mid-80’s that does not improve with supplemental oxygen, shortness of breath, and altered mental status.
• Methylene blue is the first-line treatment for severe methemoglobinemia.