Pathophysiology of Methemoglobinemia
Methemoglobinemia is characterized by elevated blood levels of hemoglobin (Hb) containing oxidized ferric (+3) iron (Fe) rather than ferrous (+2) Fe . Hb with ferric Fe cannot reversibly bind oxygen (O2) and has increased affinity for the O2 bound to the other functional ferrous heme groups, further preventing delivery of O2 to tissue [5, 6]. Because methemoglobin cannot effectively deliver O2 to peripheral tissue and organs, the oxyhemoglobin dissociation curve is shifted left and hypoxia results . The pathogenesis of methemoglobinemia is either congenital or acquired and consists of four main types: severe, acute acquired, chronic mild, and chronic. Severe is life threatening and requires immediate emergency therapy. Acute acquired requires the cessation of the inducing agent and immediate emergency therapy. Chronic mild may present as asymptomatic with cyanosis (or no cyanosis), and there is no specific therapy required. Finally, chronic methemoglobinemia requires medications to reduce cyanosis such as methylene blue, citric acid, or oxygen. These will be discussed in more detail below. See Fig. 1, used with permission from .
Risk Factors for Methemoglobinemia
Various pre-existing medical conditions can also predispose a person to developing methemoglobinemia during and outside of the perioperative setting. Under normal physiologic conditions in healthy individuals, approximately 1% of total hemoglobin exists as oxidized methemoglobin . In congenital methemoglobinemia, the enzyme responsible for the reduction of ferric methemoglobin to ferrous oxyhemoglobin, cytochrome b5 reductase, is deficient which results in decreased reduction of methemoglobin back to oxyhemoglobin. This deficiency can be present in all cells, as seen in type II congenital methemoglobinemia or absent only in red blood cells (RBCs) as seen in type I congenital methemoglobinemia .
Hemoglobin M disease is an autosomal dominant genetic disorder resulting from mutation in either the alpha, beta, or gamma chains of the hemoglobin molecule. These mutations result in hemoglobin that resists reduction from the oxidized ferric state back to the ferrous state. This causes a permanent increase in levels of methemoglobin ranging between 15% and 30%.
Heterozygotes of the autosomal recessive deficiency in cytochrome b5 reductase are at an increased risk of developing clinically significant methemoglobinemia in the perioperative setting when compared to homozygotes. This may result from the lack of compensation present in the heterozygotes, which is otherwise present in the homozygotes from the chronicity of phenotype . Even in light of the varying degrees of compensation seen in patients with congenital methemoglobinemia, conditions causing imbalances in the supply/demand ratio of O2 can lead to decompensation and development of severe symptoms of hypoxia .
Pre-existing conditions including cardiovascular disease and/or anemia place all patients at an increase susceptibility to develop acute symptoms of hypoxia in the setting of exposure to various oxidizing agents in the environment and perioperative setting . Thus, it is recommended for patients intolerant to reduction in oxygen carrying capacity, including those with coronary artery disease, peripheral vascular disease, cerebrovascular disease, sepsis, respiratory disease, acidosis and/or anemia, that they be treated regardless of symptoms when methemoglobin levels reach 10%. Furthermore, it is recommended that all patients with methemoglobin levels of 30% or more be treated with an appropriate therapy regardless of symptoms .
Infants and premature infants have only half the erythrocyte cytochrome b5 reductase activity seen in adults. As such, they are more susceptible to the development of methemoglobinemia . The elderly are also at an increased risk of developing methemoglobinemia . Patients with G6PD deficiency are at an increased risk of developing methemoglobinemia because the deficit in the G6PD enzyme causes red blood cells to prematurely break down. G6PD is the most prevalent enzyme deficiency, occurring almost exclusively in male individuals, with an estimated 400 million people affected worldwide . Overall, however, the majority of cases of methemoglobinemia are due to exposure to medications and others toxic agents [4, 11]. Common agents implicated in causing methemoglobinemia are listed in Table 1 .
Diagnosis of Methemoglobinemia
Methemoglobinemia can be assessed in the intraoperative setting through several methods. See Fig. 2, reused with permission . One of the first and most readily available clues that methemoglobinemia is present is cyanosis, or a blueish hue to the mucous membranes of the hands and feet and is easily detected by the naked eye. Furthermore, sulfhemoglobinemia, a rare but potentially comorbid condition to methemoglobinemia, may also occur and present as cyanosis. Sulfhemoglobinemia is caused by excess sulfhemoglobin in the blood, which is the product of the irreversible binding of sulfur by the hemoglobin in red blood cells which makes them unable to transport oxygen. It can result from ingestion of dapsone, phenacetin, and sulfonamides; therefore, the health care provider must consider this as a differential diagnosis . The most clinically effective method of methemoglobin detection is through use of a CO-oximeter, which directly measures the light wavelength absorption of methemoglobin in the blood. In standard pulse oximetry, light absorption is measured at wavelengths of 660 nm and 940 nm, allowing calculation of the oxyhemoglobin to deoxyhemoglobin ratio. The pulse oximeter then translates this ratio into an estimated percentage of blood oxygen saturation, with an oxyhemoglobin to deoxyhemoglobin ratio of 1 corresponding to an oxygen saturation of approximately 85% . This is of clinical importance since methemoglobin absorbs light equally at wavelengths of 660 nm and 940 nm . Thus, as methemoglobin levels in the blood increase, oxygen saturation would be expected to hover around 85% due to the equal absorbance occurring at the 660 nm and 940 nm wavelengths.
The advantage of CO-oximetry in evaluating methemoglobinemia is that it measures light absorbance at two additional wavelengths, 600 nm and 631 nm, compared to standard pulse oximetry . Multiple wavelength CO-oximetry, thus, provides physicians with a non-invasive method for intraoperatively assessing methemoglobin, which also absorbs light at a 631 nm wavelength. The specificity of CO-oximetry for detecting methemoglobin can be further improved by addition of the Evelyn-Malloy assay, also known as the acid diazo coupling method, which is the most widely used industrial reaction in the production of dyes, helps to eliminate methylene blue and sulfhemoglobin as possible false positives . The assay provides cyanide binding of methemoglobin and subsequent alteration of the 631 nm absorption peak.
Hypoxia and cyanosis in the setting of discrepancy between the SpO2 and the SaO2 that is refractory to oxygen therapy should elevate methemoglobinemia on the differential list. In addition to this “saturation gap,” signs and symptoms classically associated with methemoglobinemia include cyanosis refractory to oxygen therapy, decreased SpO2 often with a nadir of 85%, chocolate-colored  or black/brown blood [6, 8, 9], physiologically appropriate PaO2 on ABG, acidosis and tachycardia . These are described in Table 2 .
Management of Methemoglobinemia
Current treatments for methemoglobinemia vary depending on the contributing factors whether genetic and/or drug exposure. For hereditary methemoglobinemia oxidant drugs should be avoided, but ascorbic acid may be of benefit if used daily .
For methemoglobinemia caused primarily by drug exposure, methylene blue infusion is used typically when methemoglobin levels are 30% for asymptomatic and 20% for symptomatic patients. If the patient has underlying anemia, cardiac, or pulmonary comorbidities, lower thresholds of methemoglobin levels should be considered for administration of methylene blue. Interestingly, patients with hemoglobin M disease do not respond to ascorbic acid or methylene blue treatment, because individuals with this disease do not have symptoms. However, exchange transfusion may be used.
Because methylene blue depends on the availability of reduced NADPH, dextrose should be given in addition to methylene blue as it is used to form NADPH through the hexose monophosphate shunt . Nicotinamide adenine dinucleotide (NADH) is also reduced from NAD+ by catabolism of dextrose in glycolysis and therefore addition of dextrose helps replenish NADH. Alternative methods such as riboflavin are effective via flavin reductase in human erythrocytes and the reduction of methemoglobin. Ascorbic acid is a water-soluble reducing agent and a donor antioxidant. Cimetidine inhibits conversion of dapsone to its oxidizing metabolite, dapsone hydroxylamine, by the cytochrome P450 system, thereby preventing further development of dapsone-induced methemoglobinemia . Ketoconazole has shown a similar mechanism of action in treatment of dapsone-related methemoglobinemia . There is conflicting data regarding the efficacy of N-acetyl cysteine and its ability as a reducing agent in methemoglobinemia. In vitro studies have demonstrated positive results, while a randomized control crossover study concluded that intravenous administration of N-acetyl cysteine failed to enhance methemoglobin reduction [1, 3, 12].
Treatment for symptomatic methemoglobinemia involves promoting the reduction of methemoglobin back to oxyhemoglobin through the use of methylene blue, ascorbic acid, riboflavin, and hyperbaric oxygen therapy. As a last resort in emergency situations where the previous therapies are insufficient, unavailable, or contraindicated, red blood cell transfusion therapy can be attempted in cases of critically elevated methemoglobin levels exceeding 70% .
The detailed treatment for methemoglobinemia is intravenous administration of 1% methylene blue, in a dose of 1–2 mg/kg over a 5-min interval, with repeat doses every 30 min to an hour if necessary. The total amount of methylene blue given should not exceed 7 mg/kg and any dose 15 mg/kg or greater will result in direct lysis of red blood cell. Rebound methemoglobinemia may occur up to 18 h after methylene blue administration, due to prolonged absorption of lipophilic agents (benzocaine) from adipose tissue. Serial measurements of methemoglobin levels should be performed following treatment with methylene blue . Of note, methylene blue increases the reducing capacity of the NADPH-MHb reductase system by acting as a cofactor in the electron transfer from NADPH to the oxidized methemoglobin . Therefore, an adjuvant therapy to consider is ascorbic acid, which works by non-enzymatically reducing methemoglobin, although to a much lesser extent than methylene blue [11, 20]. The substitution of ascorbic acid for methylene blue is necessary in circumstances where methylene blue is not available or is contraindicated. With regard to hemoglobin M disorder, methemoglobinemia does not respond to either ascorbic acid or methylene blue . Methylene blue is also contraindicated in patients with G6PD deficiency. In these patients, the use of methylene blue can worsen methemoglobinemia and promote red blood cell lysis. This is because the reduction of methemoglobin by methylene blue is dependent on NADPH generated by G6PD . Methylene blue can also act by reversibly inhibiting monoamine oxidase A (MOA), leading to a rise in serotonin levels. Therefore, methylene blue is also contraindicated in individuals on selective serotonin reuptake inhibitor therapy. Of note, there have been reported cases of methylene blue-induced acute encephalopathy and serotonin syndrome . Therefore, the health care provider should be sure to take a detailed patient history, including any and all medications and/or supplements before making the decision to administer methylene blue.
There is no consistent recommendation regarding dosage of ascorbic acid for treatment of methemoglobinemia provided in the literature. The dosages and duration of treatment vary widely across these cases ranging from 1 g ascorbic acid as a one-time dose [reportedly lowering the patient’s methemoglobin level from 26.2% to 2.1% within 6 h of dosing]  to high-dose 10 g ascorbic acid every 6 h . Dosing recommendations from four case reports of successful resolution of methemoglobinemia using only vitamin C have been outlined in a 2016 review by Sahu et al. . See Fig. 3, used with permission from .