Methemoglobinemia

Methemoglobin contains iron in the ferric state (Fe3+) rather than the reduced ferrous form (Fe2+) found in hemoglobin. This structural change causes an alteration in the blood’s ability to bind oxygen. Methemoglobin is a naturally occurring oxidized metabolite of hemoglobin, and physiologic levels (< 1%) are normal. Problems arise as methemoglobin levels increase. Methemoglobin does not bind oxygen, thus effectively leading to a functional anemia.[3, 4, 5, 6]

In addition, methemoglobin causes a leftward shift of the oxygen-hemoglobin dissociation curve, resulting in decreased release of oxygen to the tissues. The presence of anemia and cyanosis despite oxygen treatment results from both of these effects.[6, 7] (See Pathophysiology and Etiology.)

Methemoglobinemia occurs when red blood cells (RBCs) contain methemoglobin at levels higher than 1%. This may be from congenital causes, increased synthesis, or decreased clearance. Increased levels may also result from exposure to toxins that acutely affect oxidation-reduction reactions, resulting in increasing methemoglobin levels.

Clinically, methemoglobinemia has a variable course (see Presentation). Because of the nonspecificity of the clinical findings, mild cases may go undiagnosed. Fatigue, flulike symptoms, and headaches may be the only manifestations in the initial phase. Symptoms are proportional to the methemoglobin level and include skin color changes (cyanosis with blue or grayish pigmentation) and blood color changes (brown or chocolate color). As levels of methemoglobin rise above 15%, neurologic and cardiac symptoms arise as a consequence of hypoxia. Levels higher than 70% are usually fatal.[6]

Tests to rule out hemolysis and to test for organ failure and general end-organ dysfunction should be performed. Urine pregnancy tests should be performed in females of childbearing age. Tests to evaluate a hereditary cause for methemoglobinemia should be ordered when appropriate. (See Workup.)

The most important aspects of the management of methemoglobinemia are recognition of the condition and prompt initiation of treatment, when indicated. For mild asymptomatic cases, treatment is purely for cosmetic or psychological reasons. When methemoglobinemia is severe or symptomatic, specific therapy may be indicated. Initial care includes supplemental oxygen and removal of the offending oxidizing substance. Various agents can reduce the methemoglobin levels to within the reference range, or at least to acceptable levels. (See Treatment.)

RBCs contain hemoglobin, which has a quaternary structure. Each hemoglobin molecule is composed of 4 polypeptide chains. Each of these chains is associated with a heme group, which contains iron in the reduced or ferrous form (Fe2+). In this form, iron can combine with oxygen by sharing an electron, thus forming oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state.

Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin loses an electron and becomes oxidized, the iron atom is converted to the ferric state (Fe3+), resulting in the formation of methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and thus is incapable of oxygen transport.

Under normal conditions, methemoglobin levels remain below 1%; however, under conditions that cause oxidative stress, levels will rise. The low level of methemoglobin is maintained through 2 important mechanisms. The first is the hexose-monophosphate shunt pathway within the erythrocyte. Through this pathway, oxidizing agents are reduced by glutathione.

The second and more important mechanism involves two enzyme systems, diaphorase I and diaphorase II, and requires nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively, to reduce methemoglobin to its original ferrous state.

NADH-dependent methemoglobin reduction (diaphorase I pathway) is the major enzymatic system involved.[8] Cytochrome b5 reductase plays a major role in this process by transferring electrons from NADH to methemoglobin, an action that results in the reduction of methemoglobin to hemoglobin. This enzyme system is responsible for the removal of 95-99% of the methemoglobin that is produced under normal circumstances.

NADPH-dependent methemoglobin reduction (diaphorase II pathway) usually plays only a minor role in the removal of methemoglobin. This enzyme system utilizes glutathione production and glucose-6-phosphate dehydrogenase (G6PD) to reduce methemoglobin to hemoglobin. It assumes a larger and more important role in methemoglobin regulation in patients with cytochrome b5 reductase deficiencies.

The NADPH-dependent methemoglobin reduction pathway can be accelerated by exogenous cofactors such as methylene blue to as much as five times its normal level of activity.[5, 9, 8, 10] In the absence of further accumulation of methemoglobin, these methemoglobin reduction pathways can clear methemoglobin at a rate of approximately 15% per hour.

Acquired methemoglobinemia is considerably more common than congenital forms.

Congenital (hereditary) methemoglobinemia

At least two forms of congenital cytochrome b5 reductase deficiency exist. Both are inherited in an autosomal recessive pattern. In type I b5R deficiency, the more common form, cytochrome b5 reductase is absent only in RBCs. Homozygotes appear cyanotic but usually are otherwise asymptomatic. Methemoglobin levels typically range from 10% to 35%. Life expectancy is not adversely influenced, and pregnancies are not complicated. Heterozygotes may develop acute, symptomatic methemoglobinemia after exposure to certain drugs or toxins.

The type II b5R form is substantially less common, accounting for only 10-15% of cases of congenital cytochrome b5 reductase deficiency. In this condition, cytochrome b5 reductase is deficient in all cells, not just RBCs. It is associated with several other medical problems, including mental retardation, microcephaly, and other neurologic complications. Life expectancy is severely compromised, and patients usually die at a very young age. The exact mechanism of the neurologic complications is not known.

Methemoglobinemia may also involve the presence of abnormal hemoglobins (hemoglobin M [Hb M]). In most of these hemoglobins, tyrosine replaces the histidine residue, which binds heme to globin. This replacement displaces the heme moiety and permits oxidation of the iron to the ferric state. Consequently, Hb M is more resistant to reduction by the methemoglobin reduction enzymes (see above). This results in a functionally impaired hemoglobin with a decreased affinity for oxygen.

The inheritance pattern for Hb M variants is autosomal dominant, whereas that for methemoglobinemia due to cytochrome b5 reductase deficiency is autosomal recessive. Patients with Hb M appear cyanotic but are otherwise generally asymptomatic. There are three phenotypic varieties of Hb M, corresponding to the globulin gene affected (alpha, beta, or gamma) as follows[8, 11, 12] :

• Alpha-chain variants cause neonatal cyanosis that is persistent
• Beta-chain variants do not cause cyanosis until several months after birth, when the level of fetal hemoglobin has decreased
• Gamma-chain variants cause transient neonatal cyanosis that resolves once the level of fetal hemoglobin decreases

Another hemoglobin variant, hemoglobin E (Hb E), is associated with methemoglobinemia as well. In a study from the National Thalassemia Center in Sri Lanka, 45 patients who had a diagnosis of Hb E beta-thalassemia were found to have significantly higher median methemoglobin levels that normal control subjects and patients with other hemoglobinopathies (2.7% vs 0.3%.) Furthermore, methemoglobin levels were significantly elevated in patients who had undergone a previous splenectomy.[13]

Acquired methemoglobinemia

Acquired methemoglobinemia is much more common than the congenital form and involves excessive production of methemoglobin. Often, it is associated with the use of or exposure to oxidant drugs, chemicals, or toxins, including dapsone,[14] local anesthetic agents,[15] and nitroglycerin. This increased production overwhelms the normal physiologic regulatory and excretory mechanisms. These oxidant agents can cause an increase in methemoglobin levels either by ingestion or by absorption through the skin. A study involving two tertiary care teaching hospitals indicated that methemoglobinemia was present in a significant proportion of all hospitalized patients, and the frequency may be much more than anticipated or expected.[16]

The presence of methemoglobin may also be a marker and predictor of sepsis, resulting from release of excessive amounts of nitrous oxide (NO).[17]

Clinical manifestations

Organs with high oxygen demands (eg, the central nervous system [CNS] and the cardiovascular system) usually are the first systems to manifest toxicity. Oxygenated blood is bright red, deoxygenated blood is dark red, and blood containing methemoglobin is dark reddish brown (see the image below). This dark hue is responsible for clinical cyanosis.

Note chocolate brown color of methemoglobinemia. In tubes 1 and 2, methemoglobin fraction is 70%; in tube 3, 20%; and in tube 4, normal.

Clinical evidence of cyanosis depends on the level of methemoglobin. Skin discoloration can occur in patients who are not anemic when as little as 1.5 g/dL (about 10%) of hemoglobin is in the form of methemoglobin. By comparison, a deoxyhemoglobin level of 5 g/dL is required to produce clinical cyanosis. When methemoglobin levels are relatively low, cyanosis may be observed without cardiopulmonary symptoms.

In methemoglobinemia, cyanosis is usually the first presenting symptom. In other conditions associated with cyanosis resulting from hypoxemia, it is a much later finding.

In patients with severe anemia, a higher percentage of methemoglobin is required for cyanosis to be obvious. These patients are more likely to exhibit signs of hypoxemia and have less cyanosis than is seen in patients who do not have anemia.

Congenital (hereditary) methemoglobinemia

Hereditary methemoglobinemias may be divided into two categories, as follows[2] :

• Methemoglobinemia due to an altered form of hemoglobin (ie, Hb M)
• Methemoglobinemia due to an enzyme deficiency (NADH reductase deficiency) that decreases the rate of reduction of iron in the hemoglobin molecule

Several variants of hemoglobin M have been described, including Hb Ms, Hb MIwate, Hb MBoston, Hb MHyde Park, and Hb MSaskatoon. These are usually autosomal dominant in nature. Alpha-chain substitutions cause cyanosis at birth, whereas the effects of beta-chain substitutions become clinically apparent in infants at 4-6 months of age.

There are four types of hereditary methemoglobinemias that are secondary to deficiency of NADH cytochrome b5 reductase, which is encoded by the CYB5R3 gene. All of them are autosomal recessive disorders. Heterozygotes have 50% enzyme activity and no cyanosis; homozygotes who have elevated methemoglobin levels above 1.5% have clinical cyanosis. The four types are as follows:

• Type I – This is the most common variant, and the enzyme deficiency is limited to the erythrocytes causing cyanosis; cyanosis usually, but not always, develops during infancy. ^[18]
• Type II – Widespread deficiency of the enzyme occurs in various tissues, including erythrocytes, liver, fibroblasts, and brain; it is associated with severe CNS symptoms, including encephalopathy, microcephaly, hypertonia, athetosis, opisthotonos, strabismus, mental retardation, and growth retardation; cyanosis is evident at an early age.
• Type III – Although the entire hematopoietic system (platelets, RBCs, and white blood cells [WBCs]) is involved, the only clinical consequence is cyanosis.
• Type IV – As in type I, involvement is limited to the erythrocytes. This type results in chronic cyanosis

Deficiency of NADPH-flavin reductase can also cause methemoglobinemia.

Acquired methemoglobinemia

Acquired methemoglobinemia is more common. It is usually due to the ingestion of drugs or toxic substances. Exposure to such substances in amounts that exceed the enzymatic reduction capacity of RBCs precipitates symptoms.[16]   Acquired methemoglobinemia is more frequent in premature infants and infants younger than 4 months, and the following factors may have a role in the higher incidence in this age group:

• Fetal hemoglobin may oxidize more easily than adult hemoglobin
• The level of NADH reductase is low at birth and increases with age; it reaches adult levels by age 4 months
• Higher gastric pH in infants may facilitate bacterial proliferation, resulting in increased conversion of dietary nitrates to nitrites
• An association between methemoglobinemia and acute gastroenteritis in infants has been noted in several studies. This may be due to acidosis from loss of stool bicarbonate, which impairs the already immature function of the methemoglobin reductase system in these young patients

Benzocaine, phenazopyridine, dapsone, and nitrates/nitrites are the most common substances associated with methemoglobinemia.[19] Organic and inorganic nitrites can be absorbed through the skin, and many prescription cardiac medications contain these compounds. Treatment of preterm infants with inhaled nitric oxide may lead to methemoglobinemia; susceptibility to methemoglobinemia in these infants may be increased by carriage of a single-nucleotide polymorphism in the CYB5R3 gene.[20]

Dietary intake may occur in infants or adults who ingest well water that has been contaminated with nitrites caused by water runoff from fertilized fields.[21] Sodium nitrite is used as a food preservative, and prepackaged foods may contain significant levels of nitrites.[22, 23] Intentional ingestion of sodium nitrite has been increasingly reported as a method of suicide.[24, 25]

Consumption of vegetables (eg, spinach, beets, carrots) that were contaminated with bacteria and inadequately cooked has been associated with methemoglobinemia.[26] Infants and patients on gastric acid−reduction therapy are particularly vulnerable to methemoglobinemia because gastric acid production may not be sufficient to maintain low levels of nitrate-reducing bacteria in the intestine.

Fava bean ingestion in patients with G6PD deficiency is another potential dietary cause of methemoglobinemia.[27] Favism has been reported in breastfed infants with G6PD deficiency whose mother consumed fava beans.[28]

Medarov et al reported methemoglobinemia associated with dialysis sessions using a portable dialysis unit in five critically ill hospitalized patients. The episodes were traced to inadequate clearance of the disinfectant chloramine from the tap water used for the dialysis.[29]

Chlorates are another group of oxidizing agents that can cause methemoglobinemia. These substances are found in matches, explosives, and fungicides.

Topical and injected local anesthetics (eg, benzocaine,[16, 30] lidocaine,[31] prilocaine, phenazopyridine,[32, 33] cerium nitrate, and silver sulfadiazine[34] ) have also caused methemoglobinemia. Predisposing factors for the development of this toxicity include the presence of a mucosal injury with resultant increased absorption or a previously undiagnosed methemoglobin reductase enzyme deficiency. This toxicity can also be idiosyncratic.

Acquired methemoglobinemia caused by use of cocaine laced with benzocaine has been reported.[35]  

A 10-year retrospective case-control study by Chowdhary and colleagues of 94,694 procedures in which topical anesthetics were used identified 33 cases of methemoglobinemia, for an incidence of 0.035%. However, risk was increased in hospitalized patients and those who received benzocaine-based anesthetics. The procedures included bronchoscopy, nasogastric tube placement, esophagogastroduodenoscopy, transesophageal echocardiography, and endoscopic retrograde cholangiopancreatography.[36]

Dapsone, a drug used to prevent and treat Pneumocystis jirovecii pneumonia (PCP) and to treat leprosy and other skin diseases (including a topical preparation used for acne[37] ), has also been associated with methemoglobinemia. This drug should be used with great caution in patients with known G6PD deficiency, methemoglobin reductase deficiency, or hemoglobin M.[16, 38]

Rasburicase treatment for tumor lysis syndrome in patients with low catalase activity (inherited or acquired) may result in methemoglobinemia secondary to the formation of hydrogen peroxide.[39, 40, 41] Some authors have suggested measuring catalase activity before initiating rasburicase therapy in this setting.

RBCs in patients with liver cirrhosis undergo severe oxidative stress, especially in the setting of bleeding complications.[42] The level of methemoglobin is significantly higher in the RBCs of these patients than in those of nonbleeding patients.

Idiopathic methemoglobinemia can occur in association with systemic acidosis. This typically occurs in infants younger than 6 months and is usually caused by dehydration and diarrhea. Idiopathic methemoglobinemia is exacerbated by the lower levels of methemoglobin reductase enzyme found in infants (50% of adult levels).

A case study suggested methemoglobinemia as a potential adverse effect of the combination of pembrolizumab and axitinib for treatment of metastatic renal cell carcinoma (most likely that complication was related to axitinib).[43]  

Other substances that can cause methemoglobinemia include the following:

• Copper sulfate
• Organic compounds – Sodium chlorite, ^[44] ammonium carbonate (smelling salts), ^[45] and 2,4-dinitrophenol (weight loss agent) ^[46]
• Recreational drugs – Phenylamine (psychoactive stimulant), ^[47] cocaine, ^[48] and volatile nitrates ^[49]
• Antimalarials – Primaquine, ^[50] chloroquine, ^[51] and sitamaquine ^[52]
• Analgesics and antipyretics – Acetaminophen, ^[53] acetanilide, phenacetin, and celecoxib
• Zopiclone ^[54]
• Herbicides and insecticides – Paraquat (dipyridylium), indoxacarb, ^[55] and aluminum phosphide ^[56]
• Methylene blue (high dose or in G6PD-deficient patients ^[57] )
• Indigo carmine
• Resorcinol
• Metoclopramide ^[58]
• Antibiotics – Sulfonamides, nitrofurans, and para-aminosalicylic acid
• Industrial/household agents – Aniline dyes, nitrobenzene, naphthalene (moth balls), aminophenol, and nitroethane (nail polish remover)

COVID-19

Many case reports have documented methemoglobinemia in patients with COVID-19. Most of these patients had taken hydroxychloroquine and were critically ill.[59]  It is unclear whether the severe infection leads to methemoglobinemia or the oxidative stress contributes to the severity of COVID-19 infection. A few cases of methemoglobinemia have been reported in patients with COVID-19 with underlying G6PD deficiency, although no precipitating drugs were identified.[60, 61, 62]

United States statistics

Hereditary methemoglobinemia is rare. The most common cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency (type I b5R). This enzymatic deficiency is endemic in certain Native American tribes (Navajo and Athabaskan Alaskans).

Most cases of methemoglobinemia are acquired and result from exposure to certain drugs or toxins. One of the more common causes of acquired methemoglobinemia is exposure to topical benzocaine during medical procedures. An estimated 0.115% of patients undergoing transesophageal echocardiography (TEE) develop methemoglobinemia.[15, 63, 64]

A large retrospective cohort study found a high incidence of methemoglobinemia (up to 19.8%) in 167 pediatric patients receiving dapsone for PCP prophylaxis.[65] The median methemoglobin level was 9% (range, 3.5-22.4%). The risk of developing methemoglobinemia was increased in those patients receiving a higher dose of dapsone (≥20% above the target dosage of 2 mg/kg/day).

International statistics

Methemoglobinemia occurs rarely throughout the world. Cytochrome b5 reductase deficiency (type I b5R) is also endemic in the Yakutsk people of Siberia.

Age-related demographics

Children, especially those younger than 4 months, are particularly susceptible to methemoglobinemia. The primary erythrocyte protective mechanism against oxidative stress is the NADH system. In infants, this system has not fully matured, and the NADH methemoglobin reductase activity and concentrations are low. Children between the ages of 6 and 10 years may have higher baseline levels of methemoglobinemia than adults do.[66]

Race-related demographics

The congenital form of methemoglobinemia due to cytochrome b5 reductase deficiency (type Ib5R) is endemic in certain ethnic groups. These groups include the Navajo, Athabaskan Alaskans, and the Yakutsk people in Siberia. Because G6PD deficiency is a risk factor for acquired methemoglobinemia, populations in which such deficiency is endemic, including populations of Mediterranean and African descent, are at higher risk for acquired methemoglobinemia.

The prognosis of mild cases of methemoglobinemia is very favorable. In severe cases, the prognosis is determined by the degree of anoxic end-organ damage. Complications of methemoglobinemia may include myocardial infarction, seizure, coma, and death. As methemoglobin levels increase, patients demonstrate evidence of cellular hypoxia. Death occurs when methemoglobin fractions approach 70%. Complications, including death, can occur at lower levels in patients with significant comorbidities.

The clinical course of hereditary forms of methemoglobinemia is generally benign. Patients are usually asymptomatic, except for the presence of chronic cyanosis. However, individuals with type II b5 cytochrome reductase deficiency have a markedly shortened life expectancy, primarily because of multiple neurologic complications.

Acquired methemoglobinemia is usually mild but may be severe and rarely fatal, depending on the cause. Mild-to-moderate transient methemoglobinemia may be present but may escape clinical detection; a high index of suspicion must be maintained.[67]

Patients with acquired methemoglobinemia due to toxin exposure can be severely ill when diagnosed. In some cases, acquired toxic methemoglobinemia can be life-threatening, particularly when the exposure is intentional or the condition is not recognized. However, acquired toxic methemoglobinemia usually responds to treatment when it is recognized and properly treated.

Patients with inherited methemoglobinemia should be counseled regarding the avoidance of toxins, chemicals, and certain drugs (eg, dapsone). Genetic counseling is important. Treatment of type II cases does not prevent or reverse CNS progression.

Patients with both congenital and acquired methemoglobinemia should receive instructions regarding avoidance of precipitating factors.

Patients who develop methemoglobinemia from the oxidant stress of pharmaceutical agents should be warned about other potent oxidant compounds. Patients who develop methemoglobinemia secondary to environmental exposure require a meticulous workup to prevent reexposure to the offending agent. All workplace or household members should be evaluated.

Patients receiving therapy for chronic methemoglobinemia should receive adequate information regarding the risks and benefits expected with treatment.

For patient education information, see Anemia.

The characteristic history in the congenital (hereditary) form of methemoglobinemia is the presence of diffuse, persistent, slate-gray cyanosis, often present from birth without evidence of cardiopulmonary disease. Patients with hereditary methemoglobinemia are asymptomatic despite the presence of cyanosis. The failure of 100% oxygen to correct cyanosis is very suggestive of methemoglobinemia.

Acute methemoglobinemia can be life-threatening and usually is acquired as a consequence of exposure to toxins or drugs. Therefore, obtaining a detailed history of exposure to methemoglobinemia-inducing substances is important. Such history may not always be forthcoming, but it should always be sought actively since long-term or repeated exposure may occur. Consultation with a toxicologist may be necessary, especially with exposure to a new medication, because the list of medications known to cause methemoglobinemia changes constantly.

Symptoms are proportional to the fraction of methemoglobin. A normal methemoglobin fraction is about 1% (range, 0-3%). At methemoglobin levels of 3-20%, a slight discoloration (eg, pale, gray, blue) of the skin may be present.

Signs and symptoms at levels of 20-50% include the following:

• Headache
• Dyspnea
• Lightheadedness, even syncope
• Weakness
• Confusion
• Palpitations, chest pain

Methemoglobin levels of 50-70% can cause the following:

• Cardiovascular - Arrhythmias
• CNS - Delirium, seizures, coma
• Metabolic - Profound acidosis

At methemoglobin fractions exceeding 70%, death usually results.

Infants and children can develop methemoglobinemia in association with metabolic acidosis that is caused by prolonged dehydration and diarrhea. Sources of accidental toxin exposure that must be considered in infants and children include ingestion of water from wells contaminated with excess nitrates and exposure to local anesthetics in teething gels.[21] These factors can sometimes be elicited in a thorough history.

Any known family history of methemoglobinemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency is important to clarify. Even patients who are heterozygous for methemoglobin reductase enzyme deficiencies are susceptible to low doses of oxidant drugs with resultant methemoglobinemia.

The presence of gastrointestinal (GI) symptoms (eg, nausea, vomiting, or diarrhea) may suggest the possibility of ingestion of a toxic substance.

The clinical effects of methemoglobinemia are exacerbated in the presence of anemia.

The physical examination of patients with suspected methemoglobinemia should include examination of the skin and mucous membranes. Vital signs should be documented, and mental status should be assessed. Careful attention should be paid to the cardiac, respiratory, and circulatory examinations to assess for evidence of an underlying disease (either congenital or acquired).

Physical findings may include the following:

• Discoloration of the skin, mucous membranes, and blood (the most striking physical finding)
• Cyanosis - This occurs with the presence of greater than 1.5 g/dL of methemoglobin (compared with 5 g/dL of deoxygenated hemoglobin)
• Pallor of the skin or conjunctiva suggests anemia (and possible hemolysis), which can mask cyanosis if significant.
• Seizures
• Coma
• Cardiac dysrhythmias (eg, bradyarrhythmia or ventricular dysrhythmia)
• Acidosis
• Signs associated with cardiac and/or neurologic ischemia

Skeletal abnormalities and mental retardation are associated with certain types of methemoglobin reductase enzyme deficiencies.

Patients with hereditary methemoglobinemia are commonly described as being more blue than sick. They appear cyanotic with a diffuse slate-gray appearance. Cyanosis is easily observed on the nose, cheeks, fingers, toes, and in the mucous membranes, including the fundi, and may go unrecognized for a long time in patients with more heavily pigmented skin or in patients with moderate-to-severe anemia. Clubbing is absent.

Patients with hemoglobin M disease with the alpha chain variant can present at birth with cyanosis, whereas patients with the beta chain variants present in the latter half of infancy.

Chaurasia and colleagues reported corneal epitheliopathy in four patients with congenital methemoglobinemia. They observed dark-colored conjunctival vessels and recurrent corneal epitheliopathy in three girls and one boy from two affected families. The corneal lesions resolved within 2 to 3 weeks with supportive therapy and vitamin C supplements.[68]

Investigations to rule out hemolysis (complete blood count [CBC], reticulocyte count, peripheral smear review, lactate dehydrogenase [LDH], bilirubin, haptoglobin and Heinz body preparation) and end-organ dysfunction or failure (liver function tests, electrolytes, renal function tests) should be included in the workup. Urine pregnancy tests should be performed in females of childbearing age.

Investigations to evaluate a hereditary cause for methemoglobinemia should be ordered when appropriate. Hemoglobin electrophoresis and DNA sequencing of the globin chain gene can be used to identify hemoglobin M.

Specific enzyme assays (nicotinamide adenine dinucleotide [NADH]–dependent reductase, cytochrome b5 reductase) may be determined, often in multiple cell lines (ie, platelets, granulocytes, and fibroblasts), to diagnose inherited cases. A quick and easy bedside test for determining whether dark blood is due to methemoglobinemia is to bubble 100% oxygen in a tube that contains the dark blood. If the blood remains dark, that is likely because of the presence of methemoglobin.

Another simple test (and one that is less likely to splash potentially infectious blood) is to place 1-2 drops of blood on white filter paper, then evaluate for color change upon exposure to oxygen. (This test can be accelerated by gently blowing supplemental oxygen onto the filter paper.) Deoxygenated hemoglobin changes from dark red or violet to bright red, whereas methemoglobin remains brown.

Serum levels of nitrites or other offending drugs may be determined. Often, these results are not immediately available, and treatment may have to be started empirically if the index of suspicion is high.

The presence of methemoglobin can falsely elevate the calculated oxygen saturation when arterial blood gases (ABGs) are obtained. One possible clue to the diagnosis of methemoglobinemia is the presence of a “saturation gap.” This occurs when there is a difference between the oxygen saturation measured on pulse oximetry and the oxygen saturation calculated on the basis of ABG results.

The partial pressure of oxygen (PO2) value of the ABG measurement reflects plasma oxygen content and does not correspond to the oxygen-carrying capacity of hemoglobin. It should be within the reference range in patients with methemoglobinemia.

Co-oximetry

Co-oximetry should be performed if available. The co-oximeter is an accurate device for measuring methemoglobin and is the key to diagnosing methemoglobinemia. It is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light and thus is capable of differentiating methemoglobin from carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin. Newer co-oximeters can also measure sulfhemoglobin, which can be confused with methemoglobin by older devices.

Availability of appropriate equipment may be a problem. Lipemic specimens may result in a falsely elevated methemoglobin level. In addition, the presence of methylene blue interferes with the accurate measurement of methemoglobin by co-oximetry, hence this method cannot be used to monitor methemoglobin levels after treatment with methylene blue is initiated. Blood substitutes can cause co-oximetry to yield unreliable results.

Pulse oximetry

Pulse oximetry is used extensively in the evaluation of patients with cyanosis and respiratory distress. However, findings of bedside pulse oximetry in the presence of methemoglobinemia may be misleading. Pulse oximetry measurements with low-levels of methemoglobinemia often result in falsely low values for oxygen saturation and are often falsely high in those with high-level methemoglobinemia. The reason for these inaccuracies is as follows.

The pulse oximeter only measures the relative absorbance of 2 wavelengths of light (660 nm and 940 nm) to differentiate oxyhemoglobin from deoxyhemoglobin. The ratio of absorption of light at each of these wavelengths is converted into oxygen saturation by using calibration curves. Methemoglobin increases absorption of light at both wavelengths (more at 940 nm) and therefore offers optical interference to pulse oximetry by falsely absorbing light.

As a result, oxygen saturations by pulse oximetry in methemoglobinemia plateau at about 85%; therefore, a patient with a methemoglobin level of 5% and a patient with a level of 40% have approximately the same saturation values on pulse oximetry (~85%). The severity of the cyanosis does not correspond to the pulse oximetry reading: a patient may appear extremely cyanotic but still have a pulse oximetry reading in the high 80s.

However, newer multiwavelength pulse oximeters have been developed that can detect methemoglobinemia with an accuracy comparable to that achievable with co-oximeters.

Potassium cyanide test

This test can distinguish between methemoglobin and sulfhemoglobin. Methemoglobin reacts with cyanide to form cyanomethemoglobin, which has a bright red color. Sulfhemoglobin does not react with cyanide and therefore does not change to a bright red color.

Diagnostic imaging

Imaging studies of the chest and echocardiography may be helpful to exclude pulmonary or cardiac disease.

Prompt recognition of the condition and initiation of treatment, as indicated (especially in acquired methemoglobinemia), are critical in the management of methemoglobinemia. However, at the same time, it may be imperative to initiate extensive and sometimes invasive investigations to rule out cardiac and pulmonary abnormalities that often result in a similar clinical picture with cyanosis. Once the diagnosis is confirmed, management should be instituted as indicated. Initial care includes administration of supplemental oxygen and removal of the offending oxidizing substance.

Patients with methemoglobinemia who have asymptomatic cyanosis resulting from ingestion of a known substance are the only patients who should be considered for early discharge. They may be discharged after a 6-hour observation period only if the implicated cause has been eliminated and is not known to cause rebound methemoglobinemia.

Symptomatic patients with methemoglobinemia or those with a significantly elevated methemoglobin level should be admitted to the hospital. A lower threshold for hospital admission should occur for patients with complicating factors, such as underlying anemia, chronic cardiopulmonary disease, or peripheral vascular disease. The specific symptoms determine the level of care that is needed.

Intravenous (IV) methylene blue is the first-line antidotal agent. Intravenous vitamin C, exchange transfusion, and hyperbaric oxygen treatment are second-line options for patients with severe methemoglobinemia whose condition does not respond to methylene blue or who cannot be treated with methylene blue (eg, those with glucose-6-phosphate dehydrogenase [G6PD] deficiency).[72]

Patient transfer should occur when life-threatening methemoglobinemia that is refractory to treatment occurs in a facility that cannot provide the appropriate critical care.

Early clinical recognition of methemoglobinemia is paramount, as patients often have only vague, nonspecific complaints, especially in the initial phase. High levels of methemoglobinemia can be life-threatening and necessitate emergency therapy. Patients with chronic mild increases in methemoglobin level may be completely asymptomatic and require no specific therapy (provided that they have no evidence of end-organ damage).

Once the diagnosis of methemoglobinemia has been confirmed and appropriate management has been initiated, the underlying etiology should be sought. In acquired methemoglobinemia, if the toxin or drug is not known from the history, it may be identified by obtaining blood levels, performing gastric lavage, or both. In asymptomatic patients with low levels of methemoglobin, monitoring serial serum levels may be all that is necessary. The levels normalize over time unless recurrent or chronic exposure to the offending agent occurs.

Treatment is advisable for patients with acute exposure to an oxidizing agent who have methemoglobin levels of 20% or higher. Patients with significant comorbidities (eg, coronary artery disease [CAD] or anemia) may require therapeutic intervention at lower methemoglobin levels (eg, 10%), especially if end-organ dysfunction (eg, cardiac ischemia) is present.

If methemoglobinemia is the result of toxin exposure, then removal of this toxin is imperative. Further ingestion or administration of the drug or chemical should be avoided. If the substance is still present on the skin or clothing, the clothing should be removed and the skin washed thoroughly. These patients may be unstable and should be cared for in a closely monitored situation, with oxygen supplementation provided as needed.

Methylene blue is the primary emergency treatment for documented symptomatic methemoglobinemia. It is given in a dose of 1-2 mg/kg (up to a total of 50 mg in adults, adolescents, and older children) as a 1% solution in IV saline over 3-5 minutes. Administration may be repeated at 1 mg/kg every 30 minutes as necessary to control symptoms. Methylene blue is itself an oxidant at doses greater than 7 mg/kg and thus may cause methemoglobinemia in susceptible patients; hence, careful administration is essential.

Methylene blue is contraindicated in patients with G6PD deficiency. Because it requires G6PD to work, it is ineffective in G6PD-deficient patients with methemoglobinemia. Additionally, methylene blue administration may cause hemolysis in these patients.

Methylene blue is also not effective in patients with hemoglobin M (Hb M). Other conditions in which methylene blue may be ineffective or even deleterious include nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase (ie, diaphorase II) deficiency and sulfhemoglobinemia.

Methylene blue is listed as a category X teratogen. However, given that the data on the teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration, it is possible that in life-threatening cases of methemoglobinemia during pregnancy, the benefits of methylene blue may outweigh the risk.[73]

The US Food and Drug Administration (FDA) warns against using methylene blue concurrently with serotonergic psychiatric drugs, unless such usage is indicated for life-threatening or urgent conditions. Methylene blue may increase central nervous system (CNS) serotonin levels as a result of monoamine oxidase (MAO)-A inhibition, thus increasing the risk of serotonin syndrome.[74]

Intravenous ascorbic acid has been recommended as a treatment for methemoglobinemia when methylene blue is unavailable or contraindicated, such as in pregnant patients or those with G6PD deficiency. Dosing is not standardized, however, and has ranged widely in published reports.[72]  

Exchange transfusion (which replaces abnormal hemoglobin with normal hemoglobin) may be considered for G6PD-deficient patients who are severely symptomatic or unresponsive to methylene blue. Patients who are on long-acting medication (eg, dapsone) may have initial treatment success with subsequent relapse of symptoms. Gastric lavage followed by charcoal administration may decrease this prolonged drug effect. These patients should be monitored closely and retreated with methylene blue as necessary.

Hyperbaric oxygen treatment is another option for situations where methylene blue therapy is ineffective or contraindicated. This approach permits tissue oxygenation to occur through oxygen dissolved in plasma, rather than through hemoglobin-bound oxygen.

Infants with methemoglobinemia due to metabolic acidosis should be treated with IV hydration and bicarbonate to reverse the acidosis. The NADPH-dependent methemoglobin reductase enzyme system requires glucose for the clearance of methemoglobin. Therefore, IV hydration with dextrose 5% in water (D5W) is often effective.

Patients with mild chronic methemoglobinemia due to enzyme deficiencies may be treated with oral medications in an attempt to decrease cyanosis. These medications include methylene blue, ascorbic acid, and riboflavin. The methylene blue dosage in this setting is 100-300 mg/day, which may turn the urine blue in color. The ascorbic acid dosage is 200-500 mg/day; unfortunately, long-term oral ascorbic acid therapy can cause the formation of sodium oxalate stones. The riboflavin dosage is 20 mg/day.

Cimetidine can be used in dapsone-induced methemoglobinemia to prevent further formation of its metabolite. N-acetylcysteine has been shown to reduce methemoglobin in some studies but is not currently an approved treatment for methemoglobinemia.

No pharmacologic treatment exists for hereditary forms of methemoglobinemia.

Rarely, the patient’s diet may include a substance that is the source of the methemoglobinemia. Well water contamination with inorganic nitrates can be a particular problem with infants whose formula is prepared with this water. Methemoglobinemia due to the ingestion of homemade fennel puree has been reported in infants. Some vegetables (eg, beets, spinach, carrots, borage, and chard) are high in nitrite or nitrate content and may have to be avoided by susceptible patients.[75]

Curcumin, the main curcuminoid in turmeric, has been shown experimentally to reduce methemoglobinemia in rats treated with dapsone.[76]

No change in activity is indicated.

Recognition and avoidance of precipitating factors are important for prevention of methemoglobinemia, especially in susceptible populations. Monitoring of well water levels may be needed. Individuals with known G6PD deficiency or methemoglobin reductase enzyme deficiencies should use great care with the ingestion of oxidizing medications and endeavor to minimize or prevent toxin exposure.

Consultation with a toxicologist should be obtained for those who are not familiar with or who are not comfortable with the treatment of methemoglobinemia. Consultation with other specialists (eg, a hematologist, cardiologist, or pulmonologist) may be required to assist in the search for the cause of the methemoglobinemia.

In patients with severe symptoms, consultation with a critical care specialist should be obtained. If the methemoglobinemia is severe, it may be life-threatening; hence, an American Association of Poison Control Centers (AAPCC)–certified regional poison control center or a medical toxicologist should be consulted.

Close outpatient follow-up care is required in patients treated for methemoglobinemia. Discharged patients should be reevaluated by a physician within 24 hours for any signs or symptoms of recurring disease. Patients should also be provided with strict discharge instructions detailing symptoms that should prompt immediate medical reevaluation, such as shortness of breath, increasing fatigue, or chest pain.

Once appropriate treatment has been instituted for acquired methemoglobinemia, identification and removal of the precipitating cause is all that is often necessary. Clear instructions to avoid future exposure to the precipitating agent (and related agents) should be given to the patient. If treatment is indicated on an ongoing basis, patients should be observed for therapeutic and toxic effects of treatment.

Outpatient medications for the treatment of cyanosis that is associated with chronic mild methemoglobinemia include oral methylene blue, ascorbic acid, and riboflavin.

Unless methemoglobinemia is severe or symptomatic, treatment is purely for cosmetic or psychological reasons. Various agents can reduce the methemoglobin levels to within the reference range (~1%) or at least to acceptable levels (5-10%).

Methylene blue is the first-line antidotal therapy. Ascorbic acid and riboflavin have been used. N -acetylcysteine reduces methemoglobin levels but is not yet approved for the treatment of methemoglobinemia. Cimetidine can be used in dapsone-induced methemoglobinemia. Hyperbaric oxygen and exchange transfusion should be considered when methylene blue treatment is ineffective or contraindicated.

Class Summary

Antidotes (eg, methylene blue) are used to counteract methemoglobinemia, acting as cofactors in the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent methemoglobin reductase system. Cimetidine may be used in dapsone-induced methemoglobinemia.

Methylene blue

Methylene blue increases the activity of nicotinamide adenine dinucleotide (NADH)-methemoglobin reductase in red blood cells (RBCs), assisting in the conversion of ferric (Fe3+) to ferrous (Fe2+) iron. It is available as a 1% solution (10 mg/mL). Most patients require only 1 dose. Resolution of toxicity should be seen within 1 hour, often within 20 minutes.

The US Food and Drug Administration (FDA) warns against using methylene blue concurrently with serotonergic psychiatric drugs, unless such usage is indicated for life-threatening or urgent conditions. Methylene blue may increase central nervous system (CNS) serotonin levels as a result of monoamine oxidase (MAO)-A inhibition, increasing the risk of serotonin syndrome.

Class Summary

Vitamins are essential for normal metabolic functioning of the body. Important: they act as cofactors in erythrocyte glutathione reductase and NADH dehydrogenase.

Ascorbic acid (Vita-C, Ascocid-500, C-Gel, Chew-C)

Ascorbic acid is an antioxidant and coenzyme for reduction. It may be helpful in the treatment of congenital methemoglobinemia if used daily and on a continual basis. 

Riboflavin (Ribo-100)

Riboflavin can reduce the cyanosis associated with chronic methemoglobinemia but has no role in the treatment of acute severe acquired methemoglobinemia.

Class Summary

Cytochrome P-450 inhibitors are recommended only for patients with methemoglobinemia secondary to dapsone.

Cimetidine (Tagamet HB 200)

Cimetidine inhibits conversion of dapsone to its oxidizing metabolite, dapsone hydroxylamine, by the P-450 system, thereby preventing further development of dapsone-induced methemoglobinemia.