The differential diagnosis for the cyanotic infant should focus on pulmonary or cyanotic heart disease, but when the cyanosis does not respond to oxygen and the PaO₂ in the arterial blood gas is normal, methemoglobinemia should be considered as a potential diagnosis. Blood with significant amounts of methemoglobin (MHb) appears chocolate brown as opposed to dark red/violet, and the color does not lighten when exposed to oxygen (i.e., when placed on filter paper). The paradoxical elevation of PaO₂ despite a low saturation is a reflection of the normal oxygen diffusion into the blood with abnormal hemoglobin.

Pulse oximetry by measuring the absorbance at two light wavelengths only determines the saturation of functional hemoglobin: hemoglobin that is capable of carrying oxygen. Consequently, the pulse oximeter provides misleading results when significant amounts of carboxyhemoglobin or MHb are present in the blood. Co-oximeters, by using 4 to 6 wavelengths of light, are able to determine the ratio of oxygenated hemoglobin to all other hemoglobin types, including methemoglobin. MHb significantly absorbs light at both light wavelengths used in pulse oximeters, which is then interpreted by the photodetector as an increase in both oxyhemoglobin and reduced hemoglobin. Subsequent calculations lead to a reading in the mid-80s even as MHb rises to very high levels. Therefore, although levels of oxyhemoglobin are low, the reported saturation is falsely elevated. Co-oximetry, by contrast, is an accurate measure of MHb levels, because it measures this level directly.

Methemoglobinemia is a condition in which oxidized hemoglobin molecules cannot effectively bind oxygen and release it to the tissues. When ingested oxidants in food, drugs, or chemicals cause oxidation of ferrous iron (Fe²⁺) in hemoglobin to the ferric state (Fe³⁺), MHb is formed. Any increase in the percent of MHb will be manifest as a reduced oxygen-carrying capacity of red blood cells and can cause impaired aerobic respiration, metabolic acidosis, and death. Several physiologic reduction reactions, such as the cytochrome-b5-MHb reductase system, exist in the body to limit MHb to
>2% of normal circulating hemoglobin. In anemic patients with a given MHb level, the pathologic effects will be more severe, as the true effect of the condition relates to the remaining concentration of functioning hemoglobin rather than the percent of MHb (Table 166.1).