Methemoglobinemia

INTRODUCTION — Methemoglobin is a form of hemoglobin wherein its heme iron has been oxidized, changing its iron configuration from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. Unlike normal hemoglobin, methemoglobin does not bind oxygen and as a result cannot deliver oxygen to the tissues.

Methemoglobinemia can be congenital or acquired:

●The majority of people with congenital methemoglobinemia are asymptomatic except for cyanosis (only of cosmetic significance), but some forms may have serious morbidity and can be fatal in neonates.

●Acquired methemoglobinemia can be severe or even fatal, depending on the proportion of methemoglobin.

This topic discusses the pathogenesis, causes, epidemiology, clinical presentation, diagnosis, differential diagnosis, and management of methemoglobinemia.

Separate topic reviews discuss other causes of cyanosis:

●Newborn – (See "Approach to cyanosis in the newborn".)

●Child – (See "Approach to cyanosis in children".)

●Adult – (See "Approach to the adult with dyspnea in the emergency department", section on 'Emergency stabilization of patients with danger signs' and "Measures of oxygenation and mechanisms of hypoxemia", section on 'Mechanisms of hypoxemia'.)

PATHOPHYSIOLOGY

What is methemoglobin? — In normal hemoglobin, iron is in the ferrous (Fe²⁺) state, which allows reversible binding of oxygen gas (O₂) in the lungs and its release to the tissues.

Methemoglobin is an altered state of hemoglobin in which the heme iron is oxidized from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. Oxidation differs from oxygenation in that it changes the redox state of heme iron (causes removal of an electron), whereas oxygenation involves reversible binding of O₂ without a redox change.

The ferric hemes of methemoglobin do not bind O₂. The ferric heme in the hemoglobin tetramer also causes the remaining normal ferrous hemes within the same tetrameric hemoglobin molecule to have increased O₂ affinity [1]. This produces a left shift of the hemoglobin oxygen dissociation curve and in turn further decreases O₂ delivery to the tissues (figure 1). As a result of these two changes (inability to bind oxygen and left-shifting of the oxygen-hemoglobin curve), methemoglobin causes decreased oxygen delivery from the same amount of hemoglobin, producing "functional anemia." (See "Structure and function of normal hemoglobins", section on 'Oxygen affinity'.)

The consequences of methemoglobin depend on whether it is chronically or acutely increased:

●Children and adults with chronically increased methemoglobin levels and associated functional anemia can develop compensatory erythrocytosis and are asymptomatic except for cyanosis (which is primarily of cosmetic concern). However, some congenital forms of methemoglobinemia are associated with severe and generally fatal developmental abnormalities and other non-erythroid pathologies [2]. (See 'Congenital methemoglobinemia' below.)

●People with acute toxic methemoglobinemia can be severely ill and can die from severe hypoxia despite administration of supplemental oxygen. (See 'Acquired methemoglobinemia' below.)

How are the levels regulated? — Formation of methemoglobin and conversion back to the normal ferrous state (by reduction [addition of an electron]) occurs continuously during normal red blood cell (RBC) metabolism. Normally, the formation and reduction of methemoglobin are balanced, and the steady-state level of methemoglobin is <1 percent of total hemoglobin.

●Formation of methemoglobin – The following processes contribute to oxidation of heme (removal of an electron) and formation of methemoglobin [3]:

•Auto-oxidation converts a small portion of the available hemoglobin to methemoglobin per hour [4,5]. The process occurs during hemoglobin release of oxygen in the tissues (hemoglobin deoxygenation; physiologic release of molecular oxygen) and involves the formation of a ferric-superoxide anion complex (Fe³⁺-O₂^-) followed by release of the superoxide radical (O₂^-), oxidizing the heme iron to the ferric (Fe³⁺) state [6].

•Reactions with endogenous free radicals and compounds including hydrogen peroxide(H₂O₂), nitric oxide (NO)_,O₂^-, and hydroxyl radical (OH•) also generate methemoglobin [7,8].

•Exogenous chemicals can increase methemoglobin, either directly or by means of a metabolic derivative or by generating O₂^- and H₂O₂ during their metabolism.

●Reduction of methemoglobin – Methemoglobin levels are kept low (approximately 1 percent) by the RBC enzyme cytochrome b5 reductase (Cyb5R), which oxidizes NADH to NAD and reduces (adds an electron to) the heme in hemoglobin, converting it back to the ferrous (Fe²⁺) state (figure 2).

•Cyb5R – The only physiologically important pathway for methemoglobin reduction is via Cyb5R (previously called methemoglobin reductase, NADH methemoglobin reductase, and methemoglobin diaphorase). Cyb5R is a housekeeping enzyme, a member of the flavoenzyme family of dehydrogenases-electron transferases present in all cells; it reduces ferric heme to ferrous heme in RBCs and has additional functions in non-erythroid cells [9-13]. This reaction is coupled to the transfer of electrons from NADH to FAD and in turn to cytochrome b5 [14].

-Congenital deficiency of Cyb5R is the principal form of inherited methemoglobinemia. (See 'Cytochrome b5 reductase deficiency' below.)

-Certain acute/toxic exposures can overwhelm the ability of Cyb5R to reduce methemoglobin. Heterozygotes for pathogenic variants in Cyb5R may be at increased risk for methemoglobinemia following these exposures. (See 'Acquired causes' below.)

•NADPH methemoglobin reductase and G6PD – An alternative pathway for methemoglobin reduction, which is not physiologically active, uses NADPH methemoglobin reductase. In this pathway, electrons are derived from NADPH that is generated by glucose-6-phosphate dehydrogenase (G6PD) in the hexose monophosphate (pentose phosphate) shunt (figure 2). However, there is normally no electron acceptor present in RBCs to interact with NADPH. As a result, the pathway can only be activated by extrinsic electron acceptors such as methylene blue (MB) and riboflavin [15-17]. This is the mechanism by which MB therapy reverses methemoglobinemia in severely affected individuals. (See 'Methylene blue (MB)' below.)

The requirement of G6PD for generating NADPH explains why MB therapy is ineffective in individuals with G6PD deficiency. MB should be avoided in people with G6PD deficiency because it can also act as an oxidant and cause severe hemolysis [18]. Ascorbic acid can be used instead. (See 'Ascorbic acid (vitamin C)' below.)

Since MB and riboflavin are not normally present in RBCs, this source of electron transfer is not operative in vivo, and NADPH methemoglobin reductase deficiency does not cause congenital methemoglobinemia [19].

•Other pathways – Other compounds that can promote reduction of methemoglobin include electron donors such as ascorbic acid, reduced glutathione, riboflavin, tetrahydropterin, cysteine, cysteamine, 3-hydroxyanthranilic acid, and 3-hydroxykynurenine [7].

Clinically significant methemoglobinemia occurs when there is an imbalance between two processes, increased production of methemoglobin or decreased reduction [20]. Acquired causes of methemoglobinemia are far more common than congenital causes. In some cases, an underlying genetic predisposition to methemoglobin formation can greatly exacerbate methemoglobinemia after an exposure to an oxidant.

Mechanisms of cyanosis — Cyanosis (bluish discoloration of the skin and mucous membranes) is a common feature of acute/toxic methemoglobinemia and may or may not be present in congenital methemoglobinemia.

Cyanosis is not specific for methemoglobinemia; it can be caused by high levels of deoxygenated hemoglobin (>4 g/dL), sulfhemoglobin (>0.5 g/dL), or methemoglobin (>1.5 g/dL). A comparison of the features of methemoglobinemia, sulfhemoglobinemia, and carboxyhemoglobinemia is presented in the table (table 1).

In methemoglobinemia, development of cyanosis correlates with the total amount of methemoglobin (total hemoglobin x percent methemoglobin = total methemoglobin), not the percentage. Total methemoglobin >1.5 g/dL causes cyanosis.

●An individual with a total hemoglobin of 10 g/dL who has 10 percent methemoglobin will have a total methemoglobin of 1 g/dL and will not be cyanotic.

●An individual with a total hemoglobin of 18 g/dL who has 10 percent methemoglobin will have a total methemoglobin of 1.8 g/dL and will be cyanotic.

Stated another way, for the same percentage of methemoglobin, erythrocytosis will accentuate cyanosis and anemia can mask cyanosis. Individuals with erythrocytosis will develop cyanosis at a lower percentage of methemoglobin, whereas individuals with anemia will develop cyanosis at a higher percentage of methemoglobin.

However, anemic individuals have a reduced oxygen-carrying capacity at baseline. This is why some individuals with acquired methemoglobinemia in the setting of baseline anemia can be quite ill despite lack of cyanosis. (See 'Clinical presentation (acquired/toxic)' below.)

The appearance of cyanosis can also be affected by skin pigmentation and dermal thickness, which affect the visibility of the superficial dermal capillaries [21,22].

CAUSES OF METHEMOGLOBINEMIA

Hereditary/genetic causes — There are three genetic causes of hereditary methemoglobinemia.

●The majority of affected individuals are deficient in the enzyme cytochrome b5 reductase (Cyb5R) due to pathogenic variants in the CYB5R3 gene; this is an autosomal recessive disorder. (See 'Cytochrome b5 reductase deficiency' below.)

●Less commonly, methemoglobinemia can be caused by hemoglobin M (Hb M) disease, due to a pathogenic variant affecting one of the three globin genes (encoding alpha, beta, or gamma globin); this is an autosomal dominant disorder. (See 'Hemoglobin M disease and cytochrome b5 deficiency' below.)

●Deficiency of cytochrome b5 (the electron acceptor), which is rare. (See 'Hemoglobin M disease and cytochrome b5 deficiency' below.)

The earliest report of congenital methemoglobinemia was likely in an 1845 description of chronic congenital cyanosis without obvious cardiac or pulmonary disease [23]. A familial form of "autotoxic cyanosis" and methemoglobinemia was later described in 1932 [24]. Historic accounts of early work on this disorder are available [25-27].

Cytochrome b5 reductase deficiency — Cyb5R deficiency accounts for the majority of cases of hereditary methemoglobinemia. This is an autosomal recessive condition; affected individuals are homozygous (typically in consanguineous offspring) or compound heterozygous for a pathogenic variant in the cytochrome b5 reductase 3.

Although biallelic variants in CYB5R3 are required for the disease to manifest, heterozygotes may be more susceptible to acquired (toxic) methemoglobinemia due to their lower baseline levels of the Cyb5R enzyme. (See 'Acquired causes' below.)

Most deficient variants in CYB5R3, referred to as type I, only affect the activity of the enzyme in RBCs (via reduced stability of the enzyme). Other less common variants, referred to as type II, affect enzyme function in cells of all tissues in the body and are associated with high morbidity and mortality.

●Type I (RBC type) – Type I disease is restricted to RBCs (methemoglobinemia alone). This accounts for approximately 90 percent of CYB5R3 disease variants.

Type I disease is caused by variants in RBC-specific isoform CYB5R3 that affect the stability of soluble form, which is easily degraded and cannot be readily replenished because mature RBCs cannot synthesize new proteins. These variants affect the stability of the Cyb5R enzyme, not its catalytic activity. Many variants have been reported in patients with type I deficiency; all are missense mutations that result in a single amino acid substitution [2,21,28,29].

The RBC-specific isoform of Cyb5R is a truncated protein generated by alternative splicing that initiates transcription of the CYB5R3 gene at exon 2. As a result, most of the RBC-specific isoform of Cyb5R enzyme lacks a membrane-targeting sequence and is soluble in the cytoplasm of RBCs [30-34].

There is also a smaller component of a membrane-bound Cyb5R in RBCs of unknown function that constitutes approximately 20 percent of enzyme activity in adult RBCs (more in infants) and another membrane-bound form in the endoplasmic reticulum and mitochondrial membrane of reticulocytes; the function of these forms of Cyb5R in RBCs and reticulocytes is unknown [30,35,36].

Homozygous or compound heterozygous individuals with type I disease generally have methemoglobin concentrations of 10 to 35 percent, and many but not all are cyanotic. Most individuals are asymptomatic, even with methemoglobin levels up to 40 percent [37-39].

●Type II – Type II disease causes methemoglobinemia along with developmental delay and neurologic manifestations related to loss of Cyb5R function in non-erythroid cell types. This accounts for approximately 10 percent of CYB5R3 disease variants. These variants affect the catalytic activity or decrease the transcription of the Cyb5R enzyme.

The isoform of Cyb5R in other (non-RBC) cells is a membrane-bound protein; the membrane-targeting peptide is encoded by exon 1 [40-42]. The function of Cyb5R in the central nervous system is not fully known; it may involve abnormal lipid elongation and desaturation or redox alterations in other cellular proteins [43,44].

Individuals with type II disease have developmental delay, intellectual disability, and failure to thrive [45]. Other neurologic findings are often present, including microcephaly, opisthotonus, athetoid movements, strabismus, seizures, and spastic quadriparesis. Life expectancy is significantly shortened; most die in infancy [46].

A common variant found in >40 percent of African Americans (T116S) does not appear to be pathogenic based on in vitro studies and is the most frequent African-specific genetic polymorphism [47]. This variant modifies the severity of malaria and sickle cell disease [48].

Hemoglobin M disease and cytochrome b5 deficiency

●Hemoglobin M (Hb M, for methemoglobin) disease is caused by selected variants in the alpha, beta, or (rarely) gamma globin genes [49-52]. At least 12 Hb M disease variants have been described [51]. Most result in substitution of a tyrosine for histidine in either the proximal or distal site in the heme pocket. This leads to formation of a complex of an iron with phenolate. This iron-phenolate complex resists reduction of Fe³⁺ heme iron to the divalent state. Individuals with Hb M disease have chronic methemoglobinemia and may have cyanosis but are usually otherwise asymptomatic. Transmission is autosomal dominant.

The phenotype of hemoglobin M disorders differs by age; gamma globin M variants are expressed at birth and disappear in first few months of infancy; beta globin M variants are asymptomatic at birth and the become evident at approximately six months of age; and alpha globin M variants are evident throughout the lifespan [2].

●Cytochrome b5 deficiency is the rarest form of congenital methemoglobinemia that may be also associated with ambiguous genitalia; it has been described in only a few families [53,54]. Cytochrome b5 is a substrate for the enzyme Cyb5R. It serves as an electron donor in the conversion of methemoglobin to hemoglobin and plays roles in fatty acid metabolism in cells with mitochondria, transferring electrons to stearyl-CoA in the outer mitochondrial membrane and endoplasmic reticulum [55].

One case report described an individual born from a consanguineous marriage who was homozygous for a variant that affected splicing of cytochrome b5 and produced a truncated protein [53,56]. Another family with probable cytochrome b5 deficiency was described prior to the recognition of this entity; although the inheritance pattern was autosomal dominant, the diagnosis could not be confirmed [57].

The phenotype, aside from cyanosis, is poorly described, but in a kindred from China, hypergonadotropic hypogonadism and infertility was described in an affected female but not in males with the same CYB5A variant [58].

Acquired causes — Most cases of methemoglobinemia are acquired, resulting from increased methemoglobin formation induced by various exogenous substances (table 2). These may include idiosyncratic medication reactions or overdoses or poisoning in some cases. In some instances, hemolysis can also co-occur with medications given at standard doses.

The most commonly implicated medications include topical anesthetic agents (eg, benzocaine, lidocaine, prilocaine) [49,52,59-61]. These agents are commonly added to heroin, cocaine, and other "street drugs" and may be a cause for otherwise unexplained acquired methemoglobinemia [62,63]. Exceedingly rare cases of methemoglobinemia have been reported with acetaminophen overdose/toxicity, although causality has not been clearly demonstrated and a mechanism has not been defined [64,65]. A triggering substance may be present in a chemical product but not listed on the data safety sheet. (See 'Aniline dyes and other chemicals' below.)

Individuals with the greatest susceptibility are those with lower baseline Cyb5R activity (typically individuals heterozygous for pathogenic variants in CYB5R3) [66,67]:

●Infants, especially premature infants, have baseline activity of approximately 50 to 60 percent of that in adults [68-70].

●Heterozygous individuals for a pathogenic variant in CYB5R3 have approximately half-normal activity. (See 'Cytochrome b5 reductase deficiency' above.)

Dapsone — Dapsone is a common cause of acquired methemoglobinemia.

●In a series of 138 cases of methemoglobinemia, dapsone accounted for 42 percent, with a mean methemoglobin level of 7.6 percent (range 2 to 34 percent) [60].

●In a series of 167 children with hematologic malignancy or aplastic anemia receiving dapsone for Pneumocystis (PCP) prophylaxis, 32 (19 percent) developed methemoglobinemia (median level: 9 percent, range 3.5 to 22 percent) [71]. The child with 22 percent methemoglobin also had G6PD deficiency.

●Topical dapsone (eg, a treatment for acne, sweet syndrome, and other conditions) has been associated with methemoglobin levels as high as 20 percent [72].

●(See 'Acquired causes' above.)

Dapsone undergoes enterohepatic recirculation and as a result has a long half-life (30 hours or more) [73]. Serial methemoglobin levels should be followed, and retreatment (with MB or ascorbic acid) may be needed if symptoms persist. (See 'Management (acquired/toxic)' below.)

Cimetidine may be used to reduce methemoglobin production during chronic use of dapsone. (See 'Initial treatment decisions' below.)

Antimalarial agents — Some antimalarial drugs including chloroquine, primaquine, and diaminodiphenylsulfone have been associated with development of methemoglobinemia in military recruits [66].

Methemoglobinemia due to chloroquine and hydroxychloroquine occurred during the early stages of the coronavirus disease 2019 (COVID-19) pandemic [74,75].

Topical anesthetics — Topical anesthetics, especially benzocaine spray, are a common cause of methemoglobinemia [61,76,77]. These agents are used during bronchoscopy, endoscopy, transesophageal echocardiography (TEE), and other procedures. In 2006, the United States Veterans Health Administration announced its decision to stop using benzocaine spray.

Over-the-counter oral health care products and infant teething products may also contain benzocaine; these are often marketed under different brand names (Hurricaine, Anbesol, Topex). This was stressed in a 2006 US Food and Drug Administration (FDA) Public Health Advisory and a 2011 FDA Safety Announcement (2011 FDA Drug Safety Communication).

The incidence of methemoglobinemia from benzocaine is relatively low in adults:

●A retrospective series of 28,478 TEE studies documented 19 cases of benzocaine-induced methemoglobinemia (0.067 percent) [61]. The mean methemoglobin level was 32 percent. Compared with a random sample of 190 patients undergoing TEE who did not develop methemoglobinemia, those with methemoglobinemia were more likely to be inpatients (90 versus 58 percent), anemic (84 versus 45 percent), and showing signs of active systemic infection (68 versus 7 percent).

●A retrospective case-control study involving 94,694 procedures (bronchoscopy, nasogastric tube placement, esophagogastroduodenoscopy, TEE, and endoscopic retrograde cholangiopancreatography) documented 33 cases of methemoglobinemia (0.035 percent) [78]. The mean initial methemoglobin level was 32 percent. On multivariate analysis, only the use of benzocaine-containing anesthetics and inpatient status were significantly associated with an increased risk of methemoglobinemia.

●Case reports have described infants and children developing methemoglobinemia after a single benzocaine spray, especially those with underlying airway or cardiac disease, who may absorb a higher dose [79-81]. Cases of significant adverse outcomes and very high methemoglobin levels in otherwise healthy adults have also been reported [82,83].

The mechanism by which topical anesthetics cause methemoglobinemia is unclear. Benzocaine does not directly oxidize hemoglobin. Hypothesized explanations include an inconsistently present solvent or alterations in hepatic metabolism that favor production of metabolites with oxidant potential [61,84-86]. This is supported by observations that subsequent exposure to the same topical anesthetic in the same individual has not resulted in methemoglobinemia [2,51,61].

Inhaled nitric oxide (NO) — Inhaled NO is used as a pulmonary vasodilator to treat pulmonary hypertension. Methemoglobin can form during the binding and release of NO from hemoglobin, although methemoglobinemia is unusual when inhaled NO is administered within the accepted dose range of 5 to 80 ppm [87].

In one study of 163 infants treated with inhaled NO, one had a methemoglobin level >5 percent and 16 had levels of 2.5 to 5 percent [88]. (See "Inhaled nitric oxide in adults: Biology and indications for use", section on 'Adverse effects' and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Inhaled nitric oxide (iNO)' and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Side effects'.)

It has been alleged that nitrous oxide (N₂O), used during dental procedures or as an illicit drug, can also cause methemoglobinemia. However, in most instances this association has been poorly documented, and affected individuals were exposed to N₂O gas with multiple impurities [89].

Rasburicase — Rasburicase is a recombinant urate oxidase used for the treatment of hyperuricemia in patients with malignancy and tumor lysis syndrome [90]. Rasburicase converts uric acid to allantoin and generates hydrogen peroxide. The formation of this reactive oxygen species may precipitate hemolysis, methemoglobinemia, or both.

In clinical trials, methemoglobin has been reported in <1 percent of individuals treated with rasburicase [91].

In individuals with G6PD deficiency, however, RBCs have decreased capacity to protect against oxidative damage; there are a number of cases of severe hemolysis with methemoglobinemia in individuals with G6PD deficiency treated with rasburicase [92-98].

Consequently, rasburicase is contraindicated in individuals with G6PD deficiency due to the risk of hemolysis and methemoglobinemia [99].

Nitrates and nitrites (from foods, drugs, preservatives, and chemicals) — High levels of ingested nitrates and nitrites have been associated with methemoglobinemia (table 2). Nitrates do not oxidize hemoglobin directly, but intestinal bacteria (or in some cases, a method of food preparation) can convert the nitrates to nitrites, which can oxidize hemoglobin to methemoglobin.

●Well water – Well water may be contaminated by nitrates [100]. In the United States, formula and food prepared from well water contaminated with nitrates poses the greatest risk of developing methemoglobinemia in infants and children ("blue baby syndrome") [101-103].

For those using private water supplies to prepare formula and food for infants and children, annual or semiannual testing should be performed to assure that nitrate levels are <10 ppm (<10 mg/L) and nitrite levels are <1 ppm (<1 mg/L) [103,104].

Methemoglobinemia does not occur in breastfed infants of mothers who ingest nitrate-contaminated water because nitrates do not concentrate in breast milk.

●Other contaminated water – A report described methemoglobinemia in 10 neonates in the maternity ward and neonatal intensive care unit (NICU) of a hospital where the formula was prepared using tap water that was contaminated with nitrites [105]. Three required methylene blue therapy, and all 10 recovered. It was determined that a malfunctioning valve had allowed water used in the hospital heating system that contained an anticorrosion agent to enter the general water supply.

●Root vegetables and leafy-green vegetables – Some root vegetables have been reported to cause methemoglobinemia, including carrots, beetroot, and radish juices; other reports cite leafy-green vegetables as a source of nitrates [106-110]. Factors such as fertilizer use, method of storage, bacterial contamination, and method of preparing (eg, removal of stems, peeling, blanching, juicing of raw vegetables) may be responsible [111-114]. A study from Italy that included 19 infants with acquired methemoglobinemia found that 16 of the poisonings (84 percent) were caused by ingestion of homemade vegetable broth that had been poorly preserved (eg, frozen and thawed in the refrigerator) or other vegetable sources [115].

●Mushrooms – Mushrooms that contain gyromitrin can cause methemoglobinemia, although this is often of lesser importance than other manifestations of mushroom poisoning. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Delayed symptom onset (>6 hours after ingestion)'.)

●Other foods – Methemoglobinemia may occur in certain frozen-dried foods that use nitrites as a preservative. Such a case was reported in a woman who ate frozen-dried mudfish [116].

●Sodium nitrite poisoning – Sodium nitrite is used as a food preservative, and cases of intentional ingestion have resulted in severe methemoglobinemia [117-119]. Treatment is similar to other acquired methemoglobinemias, but early transfusion of RBCs can be helpful in severe cases (eg, hemodynamic instability) while awaiting antidotal administration or onset of effect. (See 'Management (acquired/toxic)' below.)

Sodium nitrite is also part of Nithiodote, an antidote kit used for treating cyanide poisoning. Sodium nitrite is administered to therapeutically induce formation of methemoglobin, which preferentially binds cyanide. (See "Cyanide poisoning", section on 'Induction of methemoglobinemia'.)

●Drugs – Illicit drugs may contain amyl nitrite or isobutyl nitrite, which have been reported to cause methemoglobinemia [120]. Inhaled amyl nitrites may be referred to as "poppers" or marketed under names such as Pig Black, Everest Brutal, Amyl24, Pur Amyl, Jungle Juice, Extreme Formula, HardWare, Quick Silver, Double Scorpio, RUSH, Super RUSH, and many others.

●Antifreeze – Antifreeze may contain nitrites or nitrates. A case report described an individual who drank antifreeze and was found to have methemoglobinemia due to nitrites or nitrates that were in the specific antifreeze product but were not listed as ingredients on the safety data sheet because they were present at concentrations below 1 percent [121]. Cases of methemoglobinemia due to unintentional ingestion of antifreeze (mistakenly thought to be water) have also been reported [122].

Aniline dyes and other chemicals — Although rare, certain solvents, dyes, pesticides, and other chemicals may cause methemoglobinemia (table 2).

Aniline and its derivatives (eg, aniline dyes, aminophenol, phenylhydroxylamine) are highly toxic oxidant compounds used in industry.

A case report described fatal methemoglobinemia in a woman working in a paint and dye-casting factory [123]. Another case report described methemoglobinemia due to aniline in recreational drugs [124].

In addition to accidental or deliberate ingestion, aniline dyes and other chemicals can be absorbed systemically through the skin or lungs, which can lead to extremely high concentrations of methemoglobin that may persist for up to 20 hours after exposure and may be relatively resistant to treatment [124].

Another case report described methemoglobinemia in an individual who drank chlorhexidine 0.5 percent in a 70 percent ethanol skin disinfectant (as a means of obtaining alcohol); the authors noted that chlorhexidine is degraded to p-chloroaniline [125].

INITIAL EVALUATION

Overview of evaluation — Methemoglobinemia is suspected in a child or adult with unexplained cyanosis or hypoxia that does not resolve with supplemental oxygen. Cyanosis with normal oxygen saturation should always raise suspicion for methemoglobinemia. Concern for the diagnosis of methemoglobinemia is further increased by any of the following:

●Prior history of methemoglobinemia

●Positive family history for methemoglobinemia

●Positive genetic testing for a disease variant in one of the methemoglobinemia genes

●Known exposure to methemoglobinemia-inducing substance

Other conditions that do not resolve with supplemental oxygen include right to left shunting due to cardiac disease and sulfhemoglobinemia. (See 'Differential diagnosis' below.)

Once the diagnosis of methemoglobinemia is suspected, the evaluation focuses on:

●Detect methemoglobin – This testing should be done immediately to confirm the diagnosis and determine the need for treatment. (See 'How to detect (measure) methemoglobin' below.)

●Determine need for treatment – Need for treatment is based on clinical status and methemoglobin level. Chronic cyanosis from congenital methemoglobinemia can be treated for cosmetic purposes but is not an emergency. Acquired methemoglobinemia can be life-threatening if severe. (See 'Initial treatment decisions' below.)

●Eliminate exposures – Potential exposures (eg, medications, chemicals) are reviewed and eliminated. (See 'Acquired causes' above.)

●Evaluate genetic causes – Genetic testing takes longer and can be done after the individual recovers. This is important for future avoidance of precipitating factors and genetic counseling and testing of first-degree relatives. (See 'Evaluation and diagnosis (congenital)' below.)

How to detect (measure) methemoglobin — Misconceptions are common in the practical aspects of detecting methemoglobin. These are related to the unusual behavior of methemoglobin in various tests and the evolution of technologies used for arterial blood gas analysis and pulse oximetry.

In the United States, the best first test is simple blood gas analysis with review of the methemoglobin level. This and options for testing are summarized below and listed in the table (table 3).

●Blood gas – The vast majority of blood gas analyzers in use in the United States are able to detect methemoglobin by its absorbance spectrum at 631 nm. An arterial or venous sample can be used. In many cases, this will be reported with the blood gas results, but in some cases a specific request for the information may be required. A fresh sample should be used because methemoglobin levels increase with storage. Generally, the result is expressed as a percentage of methemoglobin.

The method of assaying methemoglobin on a blood gas is measurement of the absorption spectrum using co-oximetry [126]. Methemoglobin has a peak absorbance at 631 nm. Some instruments interpret all readings in the 630 nm range as methemoglobin; thus, false positives may occur in the presence of other pigments, including sulfhemoglobin, MB, and certain drugs [127-129]. This makes the follow-up of patients treated with MB challenging.

The partial pressure of arterial oxygen (PaO₂; also called arterial oxygen tension) on the blood gas reflects the amount of oxygen dissolved in the blood. The oxygen saturation of hemoglobin (SaO₂), which is the critical parameter for tissue oxygen delivery, is calculated using the PaO₂ (see "Arterial blood gases", section on 'Transport and analysis'); this calculated oxygen saturation is falsely elevated in methemoglobinemia.

If the blood gas analyzer used is unable to detect methemoglobin, either a certain type of pulse oximeter that can perform co-oximetry or a direct assay for methemoglobin (the Evelyn-Malloy method) can be used [130]. Not all types of pulse oximeter can perform co-oximetry for methemoglobin.

●Pulse oximetry and co-oximetry – Routine pulse oximetry cannot detect methemoglobin. The reason is that methemoglobin absorbs light at the pulse oximeter's two wavelengths, and this leads to error in estimating the percentages of reduced and oxyhemoglobins. A high concentration of methemoglobin causes the oxygen saturation to display as approximately 85 percent, regardless of the true hemoglobin oxygen saturation [131].

The finding of an SaO₂ of approximately 85 percent and failure of the SaO₂ to improve with administration of supplemental oxygen are clues that may raise the suspicion for methemoglobinemia [132]. Blood gas measurements are then required for diagnosis.

Co-oximetry (multiple wavelength oximetry) is a specialized modification of standard pulse oximetry in which absorbance is also measured at a fixed wavelength of 630 nm. Most co-oximeters interpret all readings in the 630 nm range as methemoglobin; thus, they may be falsely positive in the presence of other hemoglobins such as sulfhemoglobin, other pigments such as MB, and certain drugs.

The Rad-57pulse oximeter uses eight wavelengths of light instead of the usual two and is thereby reported to be able to distinguish methemoglobin from carboxyhemoglobin and MB, although the reliability of this approach has been questioned [133-135].

●Specialized testing (direct assay) – Methemoglobin can be quantified using a reaction with cyanide (the Evelyn-Malloy method). Cyanide binds to the positively charged methemoglobin, eliminating its peak absorbance at 630 to 635 nm. The subsequent addition of ferricyanide converts the entire specimen to cyanomethemoglobin for measurement of the total hemoglobin concentration.

This method may be especially useful if there is a need to re-measure the methemoglobin level following administration of MB, since co-oximeters typically read MB as if it were methemoglobin. However, the availability of this assay is declining in most clinical laboratories. In those instances, the methemoglobin quantitation by the Rad-57 pulse oximeter is the preferred method of detection. If needed, testing may be sent out to a specialty laboratory such as the Mayo Clinic [136].

The exact (quantified) results are not required for diagnosis and treatment of methemoglobinemia; results from the blood gas measurement are generally sufficient. However, direct quantification may be helpful in selected cases. If an individual is acutely ill from methemoglobinemia, appropriate treatment should not be withheld while awaiting the results of this testing.

Distinguishing congenital from acquired methemoglobinemia — It is important to determine whether an individual has a genetic predisposition to methemoglobinemia. However, for any acutely ill individual, this distinction is not required to initiate treatment, and treatment of an acutely ill individual should not be delayed while the cause of methemoglobinemia is being investigated.

Further, children with congenital methemoglobinemia can have a superimposed acquired exposure, and adults with acquired methemoglobinemia may be heterozygous for a disease variant in a congenital methemoglobinemia gene. Thus, the evaluation of an acutely ill individual should consider both acquired and hereditary causes.

We fully review the family history and personal history of cyanosis, polycythemia, and prior episodes, and we evaluate any possible exposures (dietary, chemical, medications). (See 'Acquired causes' above.)

In individuals with a suspected genetic cause, additional testing is discussed below. (See 'Evaluation and diagnosis (congenital)' below.)

The family history and presence of erythrocytosis is useful in evaluating hereditary causes. Typically, Cyb5R enzyme deficiency inheritance is autosomal recessive, and hemoglobin M disease is autosomal dominant. Cytochrome b5 (the heme containing protein) deficiency is autosomal recessive. (See 'Hereditary/genetic causes' above.)

CONGENITAL METHEMOGLOBINEMIA

Epidemiology (congenital) — The prevalence of congenital methemoglobinemia is not well-defined.

●Cyb5R deficiency – As discussed above, the most common cause of congenital methemoglobinemia is deficiency of cytochrome b5 reductase (Cyb5R) caused by biallelic pathogenic variants in the CYB5R3 gene. (See 'Cytochrome b5 reductase deficiency' above.)

Cyb5R deficiency is typically seen in certain isolated populations such as the following:

•Evenk people in Yakutia, Siberia [137]

•Athabascan peoples from Alaska [138,139]

•Navajo peoples [140]

•Puerto Ricans [141]

The Navajo and Athabascan peoples are known to share a common ancestor. Thus, the high frequency of Cyb5R deficiency may be due to an early founder effect; however, it remains to be determined whether the Yakut CYB5R3 806C>T variant is also causative of type I methemoglobinemia in the Aleutian and Navajo peoples, whose ancestors migrated to North America from Siberia. As of yet, the author has not received permission to determine the Navajo CYB5R3 mutation from the Navajo Nation Council.

In other ethnic and racial groups, pathogenic variants occur sporadically, and typically affected individuals are compound heterozygous for two different CYB5R3 variants. Consanguineous unions increase the likelihood of homozygosity for a CYB5R3 variant.

Clinical presentation (congenital) — The most common presentation is an infant or child with cyanosis (slate-blue color of the skin and mucous membranes) caused by chronic methemoglobinemia. Cyanosis is observable when the absolute concentration of methemoglobin exceeds 1.5 g/dL, equivalent to 8 to 12 percent methemoglobin at normal hemoglobin concentrations (lower in those with erythrocytosis) [39,52]. (See 'Mechanisms of cyanosis' above.)

●Cyb5R deficiency – In Cyb5R deficiency, the presence or absence of other clinical findings depends on whether the function of the enzyme is only deficient in red blood cells (RBCs; type I) or in all tissues (type II). (See 'Cytochrome b5 reductase deficiency' above.)

•In type I Cyb5R deficiency (RBCs only; most common), the typical clinical presentation is of a cyanotic child who is relatively well. They may be short of breath but often are not, as they have compensatory erythrocytosis. Some have reported nonspecific symptoms of headache, exertional dyspnea, and easy fatigability.

In most instances, cyanosis is only of cosmetic significance, even with methemoglobin levels as high as 40 percent of total hemoglobin [39]. Mild erythrocytosis is often present (compensatory and appropriate), but severe erythrocytosis is only rarely observed. Life expectancy is normal, and there is no increased risk during pregnancy.

•Rare cases of type II disease (Cyb5R deficiency in all cells) present as severe illness with developmental and neurologic abnormalities including microcephaly, opisthotonus, athetoid movements, strabismus, cognitive impairment, developmental delay, seizures, spastic quadriparesis, failure to thrive; these abnormalities predominate over methemoglobinemia [45,142]. Life expectancy is significantly shortened; in most cases disease is fatal in the first year of life [43,143].

●Hemoglobin M disease – Children with hemoglobin M (Hb M) disease present with isolated methemoglobinemia. Inheritance is autosomal dominant. Those with a pathogenic variant affecting alpha globin present at birth, those with a variant affecting beta globin present at approximately six months of age, and those with a variant affecting gamma globin present at birth and generally resolve by approximately six months due to beta globin switching [51].

Evaluation and diagnosis (congenital)

Diagnosis — A general evaluation of the cyanotic infant or child is presented separately. (See "Approach to cyanosis in the newborn" and "Approach to cyanosis in children".)

The diagnosis of congenital methemoglobinemia may be suspected in any infant or child with otherwise unexplained cyanosis and/or elevated methemoglobin levels. Once methemoglobinemia is suspected, measurement of methemoglobin levels is appropriate. Testing methods, including the option of prenatal testing for type II disease in subsequent pregnancies, are presented above. (See 'How to detect (measure) methemoglobin' above.)

The diagnosis of methemoglobinemia is made in the appropriate clinical context when the methemoglobin level is elevated (typically >5 percent). Other abnormal hemoglobins such as sulfhemoglobin should be excluded if appropriate. (See "Pulse oximetry", section on 'Sulfhemoglobin'.)

Testing to determine the cause — Subsequent testing is important to determine the underlying cause. Testing can include genetic testing for disease variants and biochemical testing for enzyme activity.

Genetic testing and biochemical testing are complementary. Genetic testing may be more complicated to interpret (eg, if the pathogenicity of a variant has not been clearly established). To distinguish type I methemoglobinemia from type II (erythroid-specific versus all body cells), the enzyme assay must be performed not only in erythrocytes but also in non-erythroid cells such as granulocytes, lymphocytes, buccal mucosa cells, or cultured skin fibroblasts.

●Genetic testing – Genetic testing is helpful because it facilitates counseling (see 'Avoidance of precipitating exposures' below), including in heterozygotes for CYB5R3 variants, and it informs treatment, because certain treatments such as methylene blue (MB) and ascorbic acid are effective in reducing cyanosis in cytochrome b5 reductase (Cyb5R) deficiency but not Hb M disease. We performed genetic testing on a series of eight consecutive cases of methemoglobinemia and found CYB5R3 variants in five of them [20].

For those from a family known to have familial methemoglobinemia, testing for the familial condition is appropriate. The choice of testing is individualized, based on knowledge of the familial disease variant and may include testing for already known genetic variants for those with a well-characterized familial variant and/or biochemical testing. Genetic testing for M hemoglobins is also available, although hemoglobin analysis may be pursued first if M hemoglobin is suspected.

Genetic testing of globin chains is available at several reference laboratories as well as other laboratories that specialize in globin chain abnormalities. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity", section on 'Resources (p50, genetic testing)'.)

●Biochemical testing – An assay for the enzymatic function of Cyb5R and genetic testing for variants in CYB5R3 (the gene that encodes Cyb5R). Several assays have been used that vary in their methods and technical difficulty [37,38,52,144-152].

●Hemoglobin analysis – Hemoglobin analysis (electrophoresis or high-performance liquid chromatography [HPLC]) is used to detect M hemoglobins. M hemoglobins differ from other hemoglobins in their spectrophotometric absorbance, migration on hemoglobin electrophoresis, and reactivity to cyanide and azide [51]. They may migrate abnormally on hemoglobin electrophoresis, especially if this is performed at pH 7.1, a pH at which the imidazole groups of histidine have a net positive charge. However, a normal hemoglobin electrophoresis does not rule out the presence of Hb M.

Involvement of a hematologist, genetic counselor, or clinical geneticist is appropriate to direct this testing. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)

Prenatal testing — Genetic testing can be performed prenatally in families with previous offspring(s) with type II methemoglobinemia. Measurement of Cyb5R activity in cultured amniotic cells may also be performed if needed (eg, if the familial variant has not been identified) [153,154]. (See "Diagnostic amniocentesis" and "Chorionic villus sampling".)

Differential diagnosis — The differential diagnosis includes other causes of cyanosis such as hypoxia from respiratory or cardiovascular conditions, peripheral vasoconstriction (eg, from cold temperatures or Raynaud phenomenon), or less common conditions such as sulfhemoglobinemia (generally seen when the concentration of sulfhemoglobin exceeds 0.5 g/dL) or erythrocytosis. (See "Approach to cyanosis in children", section on 'Life-threatening causes' and "Approach to cyanosis in children", section on 'Other causes'.)

Management (congenital methemoglobinemia) — Important aspects of management include the following:

●Do not perform phlebotomy to "normalize" the hemoglobin level. The increase in erythrocyte mass is what allows these individuals to provide normal tissue oxygenation [66]. This is exemplified by the observation that following phlebotomy, erythropoietin increases, indicating tissue hypoxia.

●The cyanosis is of cosmetic significance only (see 'Mechanisms of cyanosis' above), but it may cause significant distress.

•For individuals with Cyb5R deficiency, cyanosis can be treated with oral MB after G6PD deficiency is ruled out, or ascorbic acid (vitamin C) if G6PD deficiency is present, both of which facilitate the reduction of methemoglobin. Both therapies are likely to be effective, but no formal comparison trial exists.

-MB is given at 1 to 2 mg/kg intravenously or 100 to 300 mg orally per day. (See 'Methylene blue (MB)' below.)

-Ascorbic acid is given at typically 1000 mg three times per day. (See 'Ascorbic acid (vitamin C)' below.)

The choice of agent and dose may be individualized. Controlled trials have not been performed, and an optimal effective dose has not been established for either agent.

•For those with hemoglobin M disease, MB and ascorbic acid are not effective and should be avoided (unless being used to treat superimposed acquired methemoglobinemia). Individuals with hemoglobin M disease should be counseled about the benign nature of their condition and the lack of effective treatment for cyanosis [155].

●For individuals with type II Cyb5R deficiency (reduced enzyme activity in all tissues, with neurologic defects and developmental delay), there is no effective treatment for the neurologic defects. Hypothetically, a hematopoietic stem cell transplant or liver transplant might alleviate abnormalities of lipid processing, but these approaches have not been tested.

●Individuals with congenital methemoglobinemia (as well as unaffected heterozygous carriers) are likely to have greater susceptibility to acquired methemoglobinemia when exposed to a substance that induces methemoglobin formation (table 2). Counseling is appropriate, and attention should be paid to avoiding implicated substances when possible, maintaining a high index of suspicion for acquired methemoglobinemia, and rapidly evaluating and treating superimposed acquired methemoglobinemia. (See 'Avoidance of precipitating exposures' below and 'Management (acquired/toxic)' below.)

●First-degree relatives should be informed of the diagnosis and offered the opportunity to pursue testing and counseling if appropriate. We advise heterozygotes for Cyb5R deficiency to avoid substances that can induce methemoglobinemia.

A case report described treatment of congenital methemoglobinemia with riboflavin (vitamin B2) at a dose of 20 to 30 mg/day, but experience is limited [156]. We have also used this approach with only moderate improvement [141].

ACQUIRED METHEMOGLOBINEMIA

Clinical presentation (acquired/toxic) — Prompt clinical suspicion and evaluation is critical to identify acquired methemoglobinemia because the condition is rare but potentially life-threatening. In a series of 828 patients admitted to a hospital with acute poisoning due to deliberate self-harm, only seven (0.8 percent) had methemoglobinemia [157].

The typical presentation is of relative abrupt development of symptoms of hypoxia (low tissue oxygen) upon exposure to an oxidizing substance that induces methemoglobin formation (table 2). In contrast to tissue hypoxia, hypoxemia is typically absent (the partial pressure of oxygen in the blood [PaO₂] may be normal). (See 'How to detect (measure) methemoglobin' above.)

Symptoms may range from cyanosis, dyspnea, or nonspecific symptoms (headache, lightheadedness, fatigue, irritability, lethargy) to shock, severe respiratory depression, or neurologic deterioration (coma, seizures) due to tissue hypoxia, which can be fatal [3,59].

Typically, the severity of symptoms correlates with the methemoglobin level, as summarized in the table (table 4). In some cases, toxicity may be exacerbated by pre-existing conditions such as anemia, heart disease, and lung disease, or by coexistent glucose-6-phosphate dehydrogenase (G6PD) deficiency and ensuing hemolysis.

Common scenarios include the following:

●An infant fed formula made with well water that was not tested for nitrite levels. (See 'Nitrates and nitrites (from foods, drugs, preservatives, and chemicals)' above.)

●A child with leukemia and tumor lysis syndrome and undiagnosed G6PD deficiency treated with rasburicase. (See 'Rasburicase' above.)

●A member of the military who is administered malarial prophylaxis. (See 'Dapsone' above.)

●An individual undergoing endoscopy or bronchoscopy who is treated with a topical anesthetic agent prior to the procedure (benzocaine, lidocaine, prilocaine) [158]. (See 'Topical anesthetics' above.)

Additional clues to the diagnosis include [3]:

●Cyanosis with pale, gray or blue colored skin, lips, and nail beds, in the presence of a normal arterial oxygen pressure (PaO₂).

●Symptoms of hypoxia that do not improve with administration of oxygen.

●Discoloration of the blood (dark red, chocolate, or brownish to blue) that does not resolve upon oxygenation. This may be seen in the videoscopic field (during endoscopy or bronchoscopy), in the blood collection tube (picture 1) or a piece of absorbent paper (picture 2)[159].

Risk factors for acquired methemoglobinemia include:

●Heterozygosity for a pathogenic variant in CYB5R3 – Individuals who are heterozygous for a CYB5R3 variant are sometimes uncovered upon exposure to one of the above exogenous agents [141]. (See 'Acquired causes' above.)

In these individuals, the baseline methemoglobin level is normal, and exposure to a precipitating agent may lead to cyanosis and/or other symptoms. (See 'Cytochrome b5 reductase deficiency' above.)

●Infants – Cyb5R activity is decreased in infants; infants are susceptible to methemoglobinemia after exposure to precipitating agents. In addition, infants have been described who have developed methemoglobinemia in association with diarrheal illnesses and low weight or failure to thrive [160-163].

The mechanism of methemoglobinemia in these infants is unknown and may relate to an unappreciated exposure to a precipitating substance, increased endogenous nitrite production, milk intolerance, or unique bacterial pathogens [164].

●G6PD deficiency – Individuals with G6PD deficiency are at risk for methemoglobinemia when treated with rasburicase. (See 'Rasburicase' above.)

Individuals with G6PD deficiency and methemoglobinemia can develop hemolysis and worsening methemoglobinemia when treated with MB. (See 'Methylene blue (MB)' below.)

Evaluation and diagnosis (acquired/toxic)

History and laboratory testing — As noted above, in any individual who is acutely ill from suspected or documented methemoglobinemia, evaluation for acquired/toxic causes is critical to initiation treatment, regardless of whether the individual also has an underlying genetic cause. (See 'Distinguishing congenital from acquired methemoglobinemia' above.)

The history should review any potential exposures, including dietary (eg, well water), medications, and chemicals. (See 'Acquired causes' above.)

The following laboratory testing should be obtained:

●Observation of the color of the blood (from an arterial blood gas or phlebotomy sample).

●Arterial blood gas with methemoglobin level (available at virtually all medical institutions in the United States). In other jurisdictions, an alternative test may be ordered. (See 'How to detect (measure) methemoglobin' above.)

•Methemoglobinemia is diagnosed if the methemoglobin level is >5 percent.

•Affected individuals may become symptomatic when methemoglobin comprises more than 10 percent of total hemoglobin. Those with anemia or lung disease (eg, emphysema) may become symptomatic at lower percentages as they already have reduced oxygen delivery.

•Levels of methemoglobin >30 to 40 percent, unless chronic and due to congenital methemoglobinemia, are associated with severe symptoms and are considered life-threatening.

●Complete blood count (CBC). Typically, individuals with acquired methemoglobinemia have a normal hemoglobin level. They do not have time to develop compensatory erythrocytosis, although they may have relative erythrocytosis if they are severely dehydrated. The peripheral blood smear is not helpful in diagnosing methemoglobinemia, although some individuals with G6PD deficiency and dapsone exposure may have Heinz bodies.

●Results of testing for G6PD activity, if available. MB should not be administered to individuals with G6PD deficiency. (See 'Initial treatment decisions' below.)

Differential diagnosis — The differential diagnosis of acquired methemoglobinemia includes other causes of cyanosis and other poisonings, as discussed separately. (See "Approach to cyanosis in the newborn" and "Approach to cyanosis in children" and "Approach to the adult with dyspnea in the emergency department".)

Carbon monoxide poisoning (producing carboxyhemoglobin) and sulfhemoglobinemia (table 1) deserve special consideration because like methemoglobin, these are both abnormal hemoglobins that cannot be reliably detected by pulse oximetry and can be potentially life-threatening at high levels. The table lists distinguishing characteristics between methemoglobin and these other hemoglobins (table 1). Sulfhemoglobin can be distinguished from methemoglobin in a specialty laboratory by virtue of its peak absorption at 620 nm which, unlike methemoglobin, is not abolished by the addition of cyanide.

Management (acquired/toxic)

Initial treatment decisions — Acute toxic methemoglobinemia with methemoglobin levels above 30 percent (or lower if symptomatic from hypoxia) is a medical emergency with potentially life-threatening complications. Early identification and treatment are crucial.

●Management – The following is appropriate in any individual with suspected or confirmed methemoglobinemia due to a toxic exposure (algorithm 1):

•Discontinue precipitating agents – The offending drug or medication should be discontinued (table 2).

•Supportive care – Institute appropriate supportive care as needed. This may include intravenous access, hydration for hypotension, ventilator support for respiratory compromise, or treatments targeted to neurologic complications (antiseizure medications). (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication' and "Evaluation and management of the first seizure in adults", section on 'When to start antiseizure medication therapy'.)

Individuals with concerning symptoms, those who require pressors or ventilation, or those whose clinical status appears to be deteriorating should be managed in the intensive care unit.

•Therapies for very high methemoglobin levels – Individuals with methemoglobin levels >30 percent or those with levels of 20 to 30 percent who are symptomatic require additional treatment, especially if they have underlying cardiac or pulmonary disease (algorithm 1).Typical symptoms at different levels of methemoglobin are listed in the table (table 4).

-MB – Individuals with any symptoms of concern (eg, more than mild headache or lethargy) and/or a methemoglobin level >30 percent are usually treated with methylene blue (MB). MB acts faster than ascorbic acid (vitamin C) and thus is the treatment of choice for symptomatic acute toxic methemoglobinemia. The effectiveness of MB is also better established than that of ascorbic acid and its use more widespread. (See 'Methylene blue (MB)' below.)

-Ascorbic acid – MB should be avoided in individuals with G6PD deficiency (in whom MB can precipitate hemolysis) and those taking serotonergic medications (in whom MB can precipitate serotonergic syndrome); in these cases, ascorbic acid is used instead. (See 'Ascorbic acid (vitamin C)' below.)

MB or ascorbic acid often are not needed for those who are asymptomatic (or only mildly symptomatic) and have methemoglobin levels <20 percent. However, if symptoms develop during observation, this decision should be re-evaluated.

•Exchange transfusion and hyperbaric oxygen – Exchange transfusion and hyperbaric oxygen have been reported to be beneficial in severe disease according to case reports, but there are no controlled trials of these approaches [165,166]. The Centers for Disease Control and Prevention (CDC) suggest consideration of hyperbaric oxygen in individuals with aniline dye exposure who do not improve with MB [167]. (See 'Aniline dyes and other chemicals' above.)

For individuals who have persistent methemoglobinemia, blood transfusion may be used, especially if the patient is anemic.

●Evidence for efficacy – MB and ascorbic acid have not been directly compared in a randomized trial; available evidence on their relative efficacy comes from case reports or small series. MB works faster than ascorbic acid and is generally preferred due to its rapid onset of action and dramatic improvements observed with treatment, especially for those with clinically worrisome symptoms and/or higher levels of methemoglobin (>30 percent) [60,168-170]. In contrast, ascorbic acid generally requires multiple doses and may take 24 or more hours to lower methemoglobin levels [157,168,171].

●Monitoring – Clinical status is monitored closely according to the severity and pace of improvement.

Cimetidine may be effective in increasing patient tolerance to dapsone, chronically lowering the methemoglobin level by more than 25 percent [172-174]. Since it works slowly, cimetidine is not helpful for the management of acute symptomatic methemoglobinemia arising from the use of dapsone. (See 'Dapsone' above.)

Methylene blue (MB)

●Indications – MB is the treatment of choice for acute toxic methemoglobinemia with methemoglobin levels >30 percent. MB is also appropriate for those who are symptomatic with methemoglobin levels between 20 and 30 percent, especially those with pulmonary or cardiac comorbidities. For asymptomatic patients with methemoglobin levels <30 percent, with or without cyanosis, it is prudent to follow the patient without therapy after the offending drug or agent is withdrawn.

MB can also be used for cosmetic considerations to lessen cyanosis in individuals with congenital (chronic) methemoglobinemia due to cytochrome b5 reductase (Cyb5R) deficiency.

●Contraindications – MB should not be used in the following:

•Individuals with G6PD deficiency – MB can precipitate hemolysis in individuals with G6PD deficiency [18,92]. A paradoxical case of methemoglobinemia caused by MB in an individual with G6PD deficiency has also been reported [175]. If an individual's G6PD status is unknown and there is concern about possible G6PD deficiency, such as in individuals of Mediterranean, Puerto Rican, African, or Southeast Asian descent (figure 3), it may be possible to start with a low dose of MB (eg, 100 mg) and monitor closely, although higher doses given rapidly are preferred, as discussed below [141,168].

MB is not effective for treatment of methemoglobinemia in individuals with G6PD deficiency. In order for MB to reduce methemoglobin to hemoglobin, it must first be reduced to leukomethylene blue by electrons transferred from NADPH. In individuals with G6PD deficiency, RBCs have depleted pools of NADPH and an impaired capacity to generate the active MB metabolite leukomethylene blue (figure 2). MB in its unreduced form can act as an oxidizing agent and can precipitate hemolysis in individuals with G6PD deficiency.

•Individuals receiving serotonergic agents – MB can precipitate serotonin syndrome (potentially life-threatening) in individuals receiving serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) and other serotonergic antidepressants (table 5). This is because MB acts as a potent monoamine oxidase inhibitor (MAOI) [176-178]. A literature review from 2018 identified 50 cases of MB-induced serotonin syndrome in individuals receiving serotonergic antidepressants, one of which was fatal [179]. (See "Serotonin syndrome (serotonin toxicity)".)

●Dosing

•Severe (toxic exposure with concerning symptoms and/or methemoglobin >30 percent) – 1 to 2 mg/kg intravenously, given over five minutes [180]. The optimal dose is unknown, and other doses have been used.

May be repeated in one hour if the methemoglobin level remains high (eg, >20 percent) and/or is increasing. However, administration of more than 2 to 3 doses (>7 mg/kg) is generally avoided due to the possibility of causing hemolysis, even in individuals who do not have G6PD deficiency [181,182].

•Mild (toxic exposure with less-concerning symptoms and methemoglobin 20 to 30 percent) – It may be reasonable to start with 1 mg/kg.

•Chronic (congenital disorder with desire to reduce cyanosis as a cosmetic concern) – (See 'Management (congenital methemoglobinemia)' above.)

●Expected response – Most individuals have rapid clinical improvement with MB and reduction of methemoglobin levels to <10 percent within 10 to 60 minutes. (See 'Initial treatment decisions' above.)

Those who improve rapidly (as most do) and whose cyanosis subsides do not need to have their methemoglobin level rechecked as the accuracy of methemoglobin measurement is impaired by MB interference at the same absorption wavelength. For those whose cyanosis returns and symptoms of hypoxia recur (likely due to continuous presence of offending agent), repeated doses of MB may be needed.

Since co-oximetry detects MB as methemoglobin, this technique cannot be used to follow the response of methemoglobin levels to treatment with MB. If available, the specific Evelyn-Malloy method will discriminate between methemoglobin and MB. (See 'How to detect (measure) methemoglobin' above.)

If rapid improvement does not occur, confirm that the original diagnosis is correct (see 'Evaluation and diagnosis (acquired/toxic)' above), and consider other interventions such as transfusion, exchange transfusion, or hyperbaric oxygen. (See 'Initial treatment decisions' above.)

Ascorbic acid (vitamin C) — Ascorbic acid (vitamin C), has reducing potential and may be helpful in settings in which MB cannot be used. (See 'Initial treatment decisions' above.)

●Indications – Ascorbic acid can be used to treat severe or symptomatic methemoglobinemia when MB is unavailable or contraindicated (eg, due to suspected or proven G6PD deficiency or in a person receiving a serotonergic agent such as an SSRI). It can also be used cosmetically to lessen cyanosis in individuals with congenital (chronic) methemoglobinemia due to cytochrome b5 reductase (Cyb5R) deficiency.

●Dosing – Acute/toxic exposure with concerning symptoms and/or methemoglobin level >30 percent; up to 10 grams intravenously, given as a single dose or in divided doses.

One report described a series of five individuals in Argentina (where MB was unavailable) who were treated with three to four infusions of 1.5 to 2 grams per infusion [171]. One report described administration of multiple 10 gram doses of ascorbic acid to an individual with a methemoglobin level of 64 percent; recovery took 54 hours [183]. Another report described use of 40 grams intravenously three times per week plus 20 to 40 grams orally per day in an individual with G6PD deficiency and HIV infection; he developed severe hemolysis when the intravenous dose was increased to 80 grams [184].

Congenital (chronic) disorder with desire to reduce cyanosis (cosmetic concern) – (See 'Management (congenital methemoglobinemia)' above.)

●Expected response – Case reports have described recovery in individuals with severe methemoglobinemia treated with ascorbic acid, but improvement appears to take one to three days depending on their methemoglobin level [185].

●Adverse effects – Kidney stones (oxalate crystal deposition) and kidney failure have been reported in individuals taking extremely high doses of ascorbic acid, generally over prolonged periods of time [186-188]. A causal association remains speculative. (See "Crystal-induced acute kidney injury", section on 'Oxalate'.)

Other therapies for MB refractoriness — If methemoglobinemia does not respond to the therapies above, it is worthwhile to reevaluate the diagnosis. While data are limited, other therapies may be appropriate (algorithm 1):

●Transfusions – Blood transfusion and/or exchange transfusion has been used in individuals with severe methemoglobinemia that does not respond to MB [189].

●Hyperbaric oxygen – Hyperbaric oxygen has also been used in these cases [190].

Avoidance of precipitating exposures — Avoidance of oxidant substances that can precipitate methemoglobinemia (table 2) is critical to prevention.

We counsel avoidance for any individual with a history of congenital or acquired methemoglobinemia, as well as individuals who are heterozygous for CYB5R3 variants. Infants are especially susceptible to methemoglobinemia and should not be exposed to precipitating substances. For infants and children fed food or formula prepared using well water, the water should be tested, as noted above. (See 'Acquired causes' above and 'Nitrates and nitrites (from foods, drugs, preservatives, and chemicals)' above.)

First-degree relatives (parents, siblings, and children) of individuals with congenital methemoglobinemia have a chance of being heterozygous and may be advised to be tested and/or to avoid these substances.

SUMMARY AND RECOMMENDATIONS

●Definition and regulation – Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe²⁺) iron in heme is oxidized to the ferric (Fe³⁺) state (figure 2). Cyanosis occurs with methemoglobin levels >8 to 12 percent. (See 'What is methemoglobin?' above and 'How are the levels regulated?' above and 'Mechanisms of cyanosis' above.)

●Causes – Congenital methemoglobinemia can be caused by biallelic pathogenic variants in the CYB5R3 gene (encodes Cyb5R) or by heterozygosity for a pathogenic variant in a globin gene (encoding alpha, beta, or gamma chains) that generates an M hemoglobin. Cyanosis may be present, but clinically significant tissue hypoxia is rare due to compensatory erythrocytosis. (See 'Hereditary/genetic causes' above.)

Most individuals with pathogenic variants in CYB5R3 have reduced Cyb5R in RBCs only. Rarely, reduced enzyme activity in other cells (type II disease) causes severe neurologic and developmental abnormalities. Cytochrome b5 deficiency is a rare cause of congenital methemoglobinemia.

Acquired methemoglobinemia can occur with dapsone, antimalarial drugs, topical benzocaine, nitrites, nitrates, rasburicase, and aniline dyes (table 2). Heterozygosity for Cyb5R deficiency is likely to confer increased susceptibility to these medications and compounds. (See 'Acquired causes' above.)

●Evaluation – Methemoglobinemia is suspected in a child or adult with unexplained cyanosis or hypoxia that does not resolve with oxygen supplementation. (See 'Overview of evaluation' above.)

•Blood gas – Methemoglobin is detected on the majority of arterial blood gas machines, or, if not available, by multiple wavelength co-oximetry or the Evelyn-Malloy assay (typically a send-out test) (table 3). Routine pulse oximetry (oxygen saturation) and blood gas (PaO₂) cannot be used. (See 'How to detect (measure) methemoglobin' above.)

•Genetic testing – Cyb5R enzyme assays, hemoglobin analysis, and genetic testing for pathogenic variants in CYB5R3 or variants in globin that cause M hemoglobins are important but not required to initiate treatment. (See 'Distinguishing congenital from acquired methemoglobinemia' above.)

•Differential diagnosis – A comparison of methemoglobinemia, sulfhemoglobinemia, carboxyhemoglobinemia and is presented in the table (table 1). Other causes of cyanosis are discussed separately. (See "Approach to cyanosis in the newborn" and "Approach to cyanosis in children" and "Approach to the adult with dyspnea in the emergency department".)

●Congenital methemoglobinemia treatment – Cyb5R deficiency can be treated for cosmetic considerations with oral methylene blue (MB) at a dose of 100 to 300 mg daily or with ascorbic acid (vitamin C) at a dose of 1000 mg orally three times daily. Phlebotomy should not be used to "normalize" the hemoglobin if elevated. (See 'Congenital methemoglobinemia' above.)

●Acquired methemoglobinemia – Acquired methemoglobinemia is a medical emergency.

•Diagnostic clues:

-Exposure (table 2)

-Cyanosis out of proportion to pulse oximetry

-Respiratory or neurologic symptoms; shock if severe

-Dark red or brownish to blue blood that does not turn red with oxygenation (picture 1 and picture 2)

-Pulse oximetry of approximately 85 percent SaO₂ that does not improve with oxygen

Symptoms generally occur with methemoglobin levels >10 percent, and levels >30 to 40 percent can be life-threatening (table 4). (See 'Acquired methemoglobinemia' above.)

•Treatment – Stop the exposure, give supplemental oxygen, and provide supportive care. Severe symptoms and/or methemoglobin levels >30 percent are treated with MB or ascorbic acid (algorithm 1). For asymptomatic methemoglobin levels <30 percent, we suggest observation (Grade 2C). (See 'Initial treatment decisions' above.)

-For symptomatic or severe methemoglobinemia in individuals without G6PD deficiency, we recommend MB rather than ascorbic acid (Grade 1B). A common dose is 1 to 2 mg/kg intravenously; improvement should occur rapidly. (See 'Methylene blue (MB)' above.)

-MB is not used in individuals with G6PD deficiency (causes hemolytic anemia and worsening of methemoglobinemia) or taking a serotonergic medication (causes serotonergic syndrome).

-For individuals with severe or symptomatic methemoglobinemia who should not receive MB, we suggest ascorbic acid (Grade 2B). A common dose is 1.5 to 2 (up to 10) g intravenously. Judgment is needed for those with suspected G6PD deficiency awaiting testing. Improvement may take ≥24 hours. (See 'Ascorbic acid (vitamin C)' above.)

●Prevention – Avoidance of precipitating exposures is critical. For infants and children ingesting well water, the water should be tested to assure low nitrate and nitrite levels. (See 'Avoidance of precipitating exposures' above.)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.