Methemoglobinemia

Introduction

• Methemoglobinemia is a state in which the ferrous (Fe²⁺) irons of heme within Hb are oxidized to the ferric (Fe³⁺) state. These ferric hemes are then unable to bind O₂. As a result, the oxygen-dissociation curve is shifted toward the left, making it more difficult to release O₂.^1-4
• In the normal state, when hemoglobin binds oxygen, it transfers an electron from the iron to oxygen and the oxygen resembles a superoxide. Subsequent deoxygenation returns the electron to the iron. If the electron is not returned, MetHb is formed. Normally, erythrocytes maintain MetHb levels at less than 1% via the MetHb reductase enzyme system.¹
• MetHb has the same absorption coefficient at both red and infrared wavelengths. The resulting 1:1 absorption ratio corresponds to a SpO₂ reading of 85% on pulse oximetry. Thus, methemoglobinemia causes a falsely low saturation reading when the arterial oxygen saturation (SaO₂) is greater than 85%, and a falsely high reading if the SaO₂ is less than 85%.²

Causes

There are two types of methemoglobinemia: congenital and acquired.^1,2,4

• Congenital methemoglobinemia is relatively rare and can occur due to:
  • Inherited defect or deficiency in nicotinamide adenine dinucleotide (NADH)-dependent MetHb reductase which enzymatically reduces MetHb back to functional Hb
  • Infants generally have lower levels of MetHb reductase in their erythrocytes and manifest greater susceptibility to oxidizing agents.¹
  • Globin chain mutations favoring the formation of MetHb
• Acquired: Secondary to drugs that oxidize Hb to MetHb at a rate that exceeds the capacity of MetHb reductase system. Drugs that can cause methemoglobinemia include:
  • Prilocaine is metabolized by the liver to o-toluidine which oxidizes hemoglobin. Can cause dose-dependent (10mg/kg or >600mg) methemoglobinemia.^2,3
  • Benzocaine, a common ingredient in topical local anesthetic sprays, can also cause dangerous levels of methemoglobinemia in a dose-independent fashion.^2,3
  • Nitrates
  • Sulfonamides
  • Dapsone: common cause for methemoglobinemia
  • Phenytoin
  • Metoclopramide
  • Aniline dye
  • Antimalarials like chloroquine or primaquine

Signs and Symptoms

• Clinical evidence of cyanosis despite normal PaO₂ and pulse oximetry in the 80s is suggestive of methemoglobinemia.
• The blood of a patient with methemoglobinemia is chocolate brown in color as opposed to cherry red color from carboxyhemoglobin or green color from sulfhemoglobin.⁴
• In a patient with methemoglobinemia, the degree of cyanosis depends on the total amount of MetHb (total Hb x percent MetHb = total MetHb) and not just the percent of MetHb.⁴
• Total MetHb > 1.5 g/dL causes cyanosis.⁴
• For example, a patient with a Hb of 10 g/dL and 10% MetHb will have a total MetHb of 1 g/dL and will not be cyanotic. On the other hand, a patient with a Hb of 18 g/dL with the same 10% MetHb will have a total MetHb of 1.8 g/dL and will be cyanotic.
• Patients with abnormal MetHb levels are usually asymptomatic until the MetHb levels exceed 20% of total Hb.⁴
• MetHb levels between 20 and 50% cause mild to moderate symptoms of hypoxemia, while levels between 50 and 70% cause severe symptoms (Table 1).⁴

Diagnosis

• The diagnosis is confirmed by direct measurement of MetHb by a multiple wavelength co-oximeter. Pulse oximetry is not reliable and will typically read in the mid-80s despite a normal to high PaO₂ reading on arterial blood gas.

Treatment

• Treatment should be initiated in symptomatic patients or when the MetHb level is greater than 30%.⁴
• The definitive treatment of methemoglobinemia is the administration of methylene blue 1-2 mg/kg intravenous over 5 minutes. The dose can be repeated in an hour after the initial dose.¹
• Methylene blue acts as an electron donor reducing oxidized Hb.
• Doses above 7-8 mg/kg and rapid administration of methylene blue can paradoxically case oxidation of Hb to MetHb.¹
• Rebound methemoglobinemia can occur within 18 hours, as lipid-soluble agents (e.g., benzocaine) are slowly released. Therefore, serial measurements of MetHb should be performed.
• The action of methylene blue as an electron donor requires the activity of the enzyme glucose-6 pyruvate dehydrogenase (G-6PD). The administration of methylene blue in patients with G6PD deficiency can cause hemolysis. Therefore, methemoglobinemia in these patients should be treated with vitamin C (2 mg/kg IV). An exchange transfusion may be required.¹
• Methylene blue can also precipitate serotonin syndrome in patients taking selective serotonins reuptake inhibitors (SSRIs) and should be avoided in these patients.⁴
• Other treatments for refractory methemoglobinemia includes hyperbaric oxygen therapy and red blood cell transfusion.^1,4

Anesthetic Considerations

Anesthetic management of a patient with methemoglobinemia includes the following:¹

• Hypoxia should be avoided and acidosis should be corrected.
• Arterial line placement should be considered for continuous hemodynamic monitoring, serial arterial blood gases, and measurement of MetHb levels.
• EKG should be monitored for ischemia.
• Drugs likely to cause methemoglobinemia should be avoided (see above).