Methemoglobinemia

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Practice Essentials

Methemoglobinemia occurs when red blood cells (RBCs) contain methemoglobin at levels higher than 1%. Methemoglobin results from the presence of iron in the oxidized ferric form (Fe3+) instead of the usual reduced ferrous form (Fe2+). This results in a decreased availability of oxygen to the tissues. This condition can be congenital or acquired.[1]

Symptoms are proportional to the methemoglobin level. At levels up to 20%, changes can occur in the color of blood (see the image below) and skin. As levels rise above 20%, neurologic and cardiac symptoms arise as a consequence of hypoxia. Levels higher than 70% are usually fatal.



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

Key elements of the history include the following:

Symptoms are proportional to the fraction of methemoglobin and the resulting hypoxia. A normal methemoglobin fraction is about 1% (range, 0-3%). Symptoms associated with higher levels of methemoglobin are as follows:

Physical findings may include the following:

See Presentation for more detail.

Diagnosis

Laboratory studies that may be ordered include the following:

Oxygen-carrying capacity of the blood may be determined with the help of the following:

There may be a discrepancy between the SpO2  and the oxygen concentration calculated in arterial blood gas (SaO2). If the methemoglobin level is above 10-15%, SpO2 will remain depressed, at approximately 85% even if the patient is on 75-90% oxygen; however, SaO2 will be falsely nomal, as this technology considers all hemoglobin to be oxyhemoglobin or deoxyhemoglobin.[3]  

Other studies that may be considered are as follows:

See Workup for more detail.

Management

Early clinical recognition of methemoglobinemia is essential. Treatment is determined by the symptoms:

Initial care includes the following:

Treatment is advisable for patients who have suffered acute exposure to an oxidizing agent and have methemoglobin levels of 20% or higher, as well as for those with lower methemoglobin levels who have significant comorbidities (eg, cardiac, pulmonary, or hematologic disease), especially in the presence of end-organ dysfunction.

Treatment modalities include the following:

See Treatment and Medication for more detail.

Background

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.[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.[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.[2]

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.)

Pathophysiology

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.[6, 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 intellectual disability, 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] :

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.



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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.

Etiology

Congenital (hereditary) methemoglobinemia

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

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:

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:

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]

Methemoglobinemia has been reported in infants fed purées of vegetables (borage and chard) with high levels of nitrates.[26] Tests confirmed that vegetables with the highest nitrate levels Consumption of vegetables (eg, spinach, beets, carrots) that were contaminated with bacteria and inadequately cooked has been associated with methemoglobinemia.[27] 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.[28] Favism has been reported in breastfed infants with G6PD deficiency whose mother consumed fava beans.[29]

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.[30]

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, 31] lidocaine,[32] prilocaine, phenazopyridine,[33, 34] cerium nitrate, and silver sulfadiazine[35] ) 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.[36]  

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.[37]

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[38] ), 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, 39]

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.[40, 41, 42] 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.[43] 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).[44]  

Other substances that can cause methemoglobinemia include the following:

COVID-19

Many case reports have documented methemoglobinemia in patients with COVID-19. Most of these patients had taken hydroxychloroquine and were critically ill.[60]  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.[61, 62, 63]

Epidemiology

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, 64, 65]

A large retrospective cohort study found a high incidence of methemoglobinemia (up to 19.8%) in 167 pediatric patients receiving dapsone for PCP prophylaxis.[66] 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.[67]

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.

Prognosis

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.[68]

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.

Patient Education

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.

History

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:

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

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.

Physical Examination

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:

Skeletal abnormalities and intellectual disability 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.[69]

Laboratory Studies

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.

Arterial Blood Gas Determination

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.

Oximetry

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.

Other Studies

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.

Approach Considerations

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 brief 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 preferred agent. Intravenous vitamin C, riboflavin, 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).[4]

Methylene blue carries a Black Box warning for risk of serious or fatal serotonergic syndrome when used in combination with serotonergic drugs (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and monoamine oxidase inhibitors [MAOIs]) or opioids. Coadministration with those agents should be avoided. Methylene blue should be used with high caution in patients with signficant hemolysis, as methylene blue itself may cause hemolysis.[73]

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

Initial Management

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 the 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 setting, with oxygen supplementation provided as needed.

Pharmacologic Therapy, Exchange Transfusion, and Hyperbaric Oxygen

Methylene blue is the primary emergency treatment for documented symptomatic methemoglobinemia. Although randomized trials have not been conducted, observational studies have consistently shown resolution or alleviation of methemoglobinemia in patients treated with methylene blue.[74]  

Methylene blue is given in a dose of 1-2 mg/kg IV (up to a total of 50 mg in adults, adolescents, and older children) as a 1% solution in 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 requires G6PD to work, so it is ineffective in patients with G6PD deficiency. Additionally, it may cause hemolysis in these patients. About 2% of the United States population has G6PD deficiency; however, the emergency physician may have no way of knowing that a patient has this condition.[74]

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.[75]

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.[76]

Exchange transfusion (which replaces abnormal hemoglobin with normal hemoglobin) is the preferred second-line treatment for severely symptomatic patients for whom methylene blue is contraindicated or ineffective. Patients who are on long-acting medication (eg, dapsone) may have initial treatment success but 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.

Intravenous ascorbic acid has been used 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. American Heart Association guidelines recommend against its use in patients with life-threatening methemoglobinemia, noting that most case reports describe its administration in combination with other treatments and that its onset of action is slow; multiple doses over several hours may be necessary for it have any significant effect.[4]  

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. Hyperbaric oxygen treatment is relatively slow acting, requiring several hours to take effect, and so is used with other treatments.[74]

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.

A case report describes successful use of plasmapheresis in a patient with extremely severe methemoglobinemia (methemoglobin level 82%) that had not responded to standard treatment options.[77]

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 promote 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.

Treatment with N-acetylcysteine (NAC) has been reported in the past. However, in a randomized controlled crossover trial, NAC failed to improve methemoglobin levels in healthy volunteers with methemoglobinemia induced by infusing sodium nitrite.[78] ​

No pharmacologic treatment exists for hereditary forms of methemoglobinemia.

Diet and Activity

Rarely, the patient’s diet may include a substance that is the source of the methemoglobinemia. Water from wells contaminated with inorganic nitrates can be a particular problem with infants whose formula is prepared with this water. Methemoglobinemia due to the ingestion of homemade purées of vegetables high in nitrates (borage, chard) has been reported in infants. Likewise, susceptible patients may have to avoid vegetables (eg, beets, spinach, carrots, borage, and chard) that have high nitrite or nitrate contents.[26]

Curcumin, the main curcuminoid in turmeric, has been shown experimentally to reduce methemoglobinemia in rats treated with dapsone.[79]

No change in activity is indicated.

Prevention

Recognition and avoidance of precipitating factors are important for prevention of methemoglobinemia, especially in susceptible populations.

Monitoring of nitrate levels in well water 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.

Occupational exposure to analine, paint thinner, and other oxidant chemicals should be prevented with appropriate personal protective equiptment. 

Consultations

Clinicians who are not familiar with or who are not comfortable with the treatment of methemoglobinemia should consult with a toxicologist. Consultation with other specialists (eg, hematologist, cardiologist, 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. Severe methemoglobinemia may be life-threatening, so an American Association of Poison Control Centers (AAPCC)–certified regional poison control center or a medical toxicologist should be consulted.

Long-Term Monitoring

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.

Guidelines Summary

American Heart Association (AHA) guidelines strongly recommend methylene blue for treatment of life-threatening methemoglobinemia. For methemoglobinemia that is unresponsive to methylene blue, the AHA suggests that treatment with exchange transfusion or hyperbaric oxygen therapy may be reasonable. The AHA guidelines recommend against using N-acetylcysteine or ascorbic acid to treat acute life-threatening methemoglobinemia.[74]

European guidelines on the diagnosis and treatment of methemoglobin include the following recommendations[4] :

Medication Summary

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.

Methylene blue

Clinical Context:  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

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.

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

Clinical Context:  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)

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

Class Summary

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

Cimetidine (Tagamet HB 200)

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

Class Summary

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

What is methemoglobinemia?Which history findings are characteristic of methemoglobinemia?Which symptoms are associated with higher levels of methemoglobin?What are physical findings characteristic of methemoglobinemia?What is the role of lab studies in the workup of methemoglobinemia?How is oxygen-carrying capacity of the blood determined in methemoglobinemia?Which imaging studies may be considered in the workup of methemoglobinemia?What is the basis for treatment selection in methemoglobinemia?What is included in initial care of methemoglobinemia?What are the treatment options for methemoglobinemia?How does methemoglobin occur?What causes methemoglobinemia?What is the course of methemoglobinemia?Which tests are performed to diagnose methemoglobinemia?What are the most important aspects of the management of methemoglobinemia?What is the pathophysiology of methemoglobinemia?What is the physiologic mechanism for reducing methemoglobin to its original ferrous state?What is the pathophysiology of congenital (hereditary) methemoglobinemia?What are the phenotypic varieties of hemoglobin M (Hb M) in methemoglobinemia?What is the pathophysiology of acquired methemoglobinemia?What is the role of cyanosis in the pathophysiology of methemoglobinemia?What is the role of genetics in the etiology of methemoglobinemia?What are the types of hereditary methemoglobinemia due to NADH reductase deficiency?What causes acquired methemoglobinemia and what are risk factors?What is the role of nitrites in the etiology of methemoglobinemia?What is the role of dialysis in the etiology of methemoglobinemia?What is the role of chlorates in the etiology of methemoglobinemia?What is the role of anesthetics in the etiology of methemoglobinemia?What is the role of dapsone in the etiology of methemoglobinemia?What is the role of rasburicase therapy in the etiology of methemoglobinemia?What is the role of cirrhosis in the etiology of methemoglobinemia?Which patients are at highest risk for idiopathic methemoglobinemia?What is the role of inadequately cooked vegetables in the etiology of methemoglobinemia?Which substances can cause methemoglobinemia?What is the prevalence of methemoglobinemia in the US?What is the global prevalence of methemoglobinemia?How does the prevalence of methemoglobinemia vary by age?How does the prevalence of methemoglobinemia vary by sex?What are the racial predilections for methemoglobinemia?What is the prognosis of methemoglobinemia?What is the clinical course of hereditary methemoglobinemia?What is the prognosis of acquired methemoglobinemia?What is included in patient education for methemoglobinemia?What is the characteristic history of congenital (hereditary) methemoglobinemia?What should be the focus of clinical history for acute methemoglobinemia?What are the signs and symptoms of methemoglobinemia?What is included in the physical exam for methemoglobinemia?Which physical findings are characteristic of methemoglobinemia?What are diagnostic considerations for methemoglobinemia?What are the differential diagnoses for Methemoglobinemia?What is the role of lab studies in the workup of methemoglobinemia?What is the role of arterial blood gas (ABG) in the workup of methemoglobinemia?What is the role of co-oximetry in the workup of methemoglobinemia?What is the role of pulse oximetry in the workup of methemoglobinemia?What is the role of a potassium cyanide test in the workup of methemoglobinemia?What is the role of imaging studies in the diagnosis of methemoglobinemia?When is inpatient treatment indicated for methemoglobinemia?What is included in the initial management of methemoglobinemia?What is the role of methylene blue in the treatment of methemoglobinemia?What is the role of exchange transfusion in the treatment of methemoglobinemia?What is the role of hyperbaric oxygen for the treatment of methemoglobinemia?How is methemoglobinemia due to metabolic acidosis managed in infants?Which medications are used in the treatment of mild chronic methemoglobinemia due to enzyme deficiencies?What is the role of medication in the treatment of hereditary methemoglobinemia?What is the role of dietary and activity modification in the treatment of methemoglobinemia?How is methemoglobinemia prevented?Which specialist consultations are needed in the treatment of methemoglobinemia?What is involved in long-term monitoring methemoglobinemia?What is the role of medications in the treatment of methemoglobinemia?Which medications in the drug class Histamine H2 Antagonists are used in the treatment of Methemoglobinemia?Which medications in the drug class Vitamins, Water Soluble are used in the treatment of Methemoglobinemia?Which medications in the drug class Antidotes, Other are used in the treatment of Methemoglobinemia?

Author

Dipen B Khanapara, MD, Fellow in Hematology and Oncology, University of Cincinnati College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Ronald A Sacher, MD, FRCPC, DTM&H, Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

Amy Lawser Curran, MD, Fellow, Department of Hematology/Oncology, Lankenau Hospital

Disclosure: Nothing to disclose.

Deric C Savior, MD, Fellow, Department of Hematology/Oncology, Lankenau Hospital

Disclosure: Nothing to disclose.

Elizabeth DelGiacco, DO, Chief Fellow, Department of Hematology/Oncology, Main Line Health, Lankenau Medical Center

Disclosure: Nothing to disclose.

Khaled F Abouelezz, MBChB, Fellow in Hematology and Oncology, University of Cincinnati College of Medicine

Disclosure: Nothing to disclose.

Mary Denshaw-Burke, MD, FACP, Clinical Assistant Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Clinical Assistant Professor, Affiliated Clinical Faculty of the Lankenau Institute for Medical Research; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Medical Center

Disclosure: Nothing to disclose.

Mudra Kumar, MD, MRCP, FAAP, Professor of Pediatrics, Course Director, Course 6 MSII, Preclerkship Director, Clinical Integration, Department of Pediatrics, University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology

Disclosure: Nothing to disclose.

Matthew Bouchard, MD Consulting Staff, Department of Emergency Medicine, Altoona Regional Health System

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Kathy L Ferguson, DO Attending Physician, Department of Emergency Medicine, New York Hospital of Queens

Kathy L Ferguson, DO is a member of the following medical societies: American College of Emergency Physicians and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology

Disclosure: Nothing to disclose.

John Schoffstall, MD Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania

John Schoffstall, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Pennsylvania Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Verive, MD Medical Director, Pediatric Intensive Care, Department of Pediatrics, St Mary's Hospital for Women and Children

Michael J Verive, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, Pediatric Sedation, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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

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

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