Chapter 128: Methemoglobinemia

High-Yield Facts

• Suspect methemoglobinemia in patients with cyanosis unresponsive to 100% oxygen.

• The antidote for methemoglobinemia is methylene blue.

• In patients with methemoglobinemia, conventional pulse oximetry produces factitiously low oxygen saturations.

• Co-oximetry is the method of choice for methemoglobin measurement.

• Young infants with diarrhea and sepsis can develop methemoglobinemia.

Introduction

Methemoglobinemia occurs when the ferrous (Fe⁺²) iron of hemoglobin is oxidized to its ferric (Fe⁺³) counterpart. The amount in the blood is expressed as a percentage of the total hemoglobin. Because of its decreased affinity for oxygen, hypoxia and a shift of the oxygen dissociation curve to the left results.^1,2 Methemoglobinemia may be hereditary or acquired; the former is usually milder, occurs early in life, and may be relatively asymptomatic. The acquired form is often more severe and secondary to a diverse group of chemicals and drugs. The classic presentation of methemoglobinemia is cyanosis that does not correct with the administration of 100% oxygen.^1,2

Pathophysiology

The iron of hemoglobin is ferrous (Fe⁺²) which is capable of carrying oxygen. However, background oxidative stress converts it to its ferric (Fe⁺³) counterpart resulting in the formation of small amounts of methemoglobin. It is incapable of carrying oxygen, but the body has protective mechanisms to reverse the process.^1–3

The major process is the cytochrome b5 methemoglobin reductase system. This two-enzyme process accounts for 99% of the methemoglobin reduction. This is the NADH methemoglobin reductase in older literature.^1–3 Another enzyme that can reduce methemoglobin is reduced nicotinamide adenine dinucleotidephosphate (NADPH)-methemoglobin reductase. This system has negligible activity in normal conditions. However, it has an affinity for dyes such as methylene blue and likely plays a role in metabolizing oxidant xenobiotics.² Ascorbic acid and glutathione may also play a role in reducing small amounts of methemoglobin.²

Normally, only 1% of hemoglobin is methemoglobin at any time.^2,4,5 However, if significant oxidative stress is present, these protective systems may be overcome resulting in significant methemoglobinemia.

Etiology of Methemoglobinemia

Methemoglobinemia may be either hereditary or acquired. The former is uncommon, presents very early, often in the first hours or days of life, and may be misdiagnosed as congenital cyanotic heart disease. Acquired methemoglobin is more common and is more likely to be severe and life threatening.

Hereditary methemoglobinemia is a consequence of cytochrome b5 reductase deficiency, or the presence of one of a number of abnormal hemoglobin variants termed Hemoglobin M. Deficiency of the reduced nicotinamide adenine dinucleotidephosphate (NADPH)-methemoglobin reductase also occurs, but these patients do not manifest methemoglobinemia as this pathway normally plays a very minor role in methemoglobin reduction.^1,2

Patients with cytochrome b5 reductase deficiency may be either ...