Methemoglobinemia: Pathogenesis, Diagnosis, and

Review Article

Methemoglobinemia: Pathogenesis, Diagnosis, and Management Anna Skold,

MD, MPH,

Dominique L. Cosco,

MD,

Abstract: The diagnosis of methemoglobinemia should be considered in patients presenting with cyanosis and hypoxia. A variety of frequently used medications are capable of inducing methemoglobinemia, with dapsone and benzocaine being common culprits. Unique features, such as a saturation gap and chocolate-brownYcolored blood, can raise suspicion for methemoglobinemia. Typically, symptoms correlate with the methemoglobin level, and treatment with methylene blue is reserved for patients with significantly elevated methemoglobin levels. In the presence of comorbid conditions that impair oxygen transport, however, low-grade methemoglobinemia can become symptomatic and may warrant treatment. Key Words: dapsone, methemoglobinemia, methemoglobin, methylene blue

M

ethemoglobinemia occurs when hemoglobin is oxidized to form methemoglobin (MetHb), rendering it incapable of oxygen transport; if severe, it leads to tissue hypoxia.1 Protective mechanisms typically keep MetHb levels in check; however, a variety of medications are capable of inducing methemoglobinemia (Table). Healthy patients can tolerate low levels of MetHb without difficulty. Cyanosis is often the first sign of an underlying methemoglobinemia. Hypoxia as measured by pulse oximetry is observed frequently as patients manifest a misleading reduction in peripheral oxygen saturation measurements. As MetHb levels rise, symptoms of dyspnea, headache, and dizziness can occur. Elevations in MetHb 950% can lead to arrhythmias, acidosis, seizures, coma, and even death.2 Methemoglobinemia should be considered in the differential diagnosis of patients who present with cyanosis and reduced peripheral oxygen saturation. Early recognition of met-

and Robin Klein,

MD

hemoglobinemia is vital because withdrawal of the offending agent is the first step in treatment. In this review, we examine the pathophysiology of methemoglobinemia, review the unique features physicians can use to diagnose methemoglobinemia, and discuss the management of patients with symptomatic methemoglobinemia.

Pathophysiology Methemoglobinemia is characterized by high levels of MetHb in the blood. It occurs when the iron moiety of hemoglobin is oxidized from the ferrous state (Fe2+) to the ferric state (Fe3+), forming MetHb.1 This change renders MetHb incapable of oxygen transport and shifts the oxygen dissociation curve leftward.1,2 This reduces oxygen delivery, thereby increasing the risk of tissue hypoxia. MetHb forms normally in the body in response to oxidative stress at a rate of 3%/day.1 This action typically is counteracted quickly by multiple protective mechanisms that keep MetHb levels below 1%.2 The major enzymatic counterregulatory system is the cytochrome b5-MetHb reductase pathway. In this pathway, cytochrome b5 reductase reduces MetHb to hemoglobin using nicotinamide adenine dinucleotide as a cofactor.1 This enzyme system is responsible for the removal of 95% to 99% of endogenously produced MetHb and reduces MetHb at a rate of 15%/hour.2,3 A second pathway, involving nicotinamide adenine dinucleotide phosphate (NADPH)-MetHb reductase, uses NADPH

Key Points & A variety of compounds can induce an acquired methemo-

From the Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA. Reprint requests to Robin Klein, MD, Division of General Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303. Email: [email protected] The authors have no financial relationships to disclose and no conflicts of interest to report. Accepted July 12, 2011. Copyright * 2011 by The Southern Medical Association 0038-4348/0Y2000/104-757 DOI: 10.1097/SMJ.0b013e318232139f

Southern Medical Journal

globinemia, with dapsone and benzocaine being the most common culprits. & In healthy patients, symptoms correlate with methemoglobin (MetHb) level. In patients with comorbidities that affect oxygen transport, symptoms can occur even with low MetHb levels. & Unique features such as the chocolate-brown color of blood, poor response to supplemental oxygenation, and presence of a saturation gap can raise suspicion for methemoglobinemia. & Treatment with methylene blue should be considered in patients with significant symptoms, elevated MetHb levels, or comorbid conditions that compromise oxygen delivery.

& Volume 104, Number 11, November 2011

Copyright © 2011 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.

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Table. Causes of acquired methemoglobinemia Chemicals

Medications

Aniline dyes

Acetaminophen

Fava beans

Acetanilide

Fumes (wood, plastic, automobile exhaust)

Amyl nitrate Benzocaine

Ginkgo biloba Herbicides

Chloramine

Mothballs

Chloroquine

Nitrate containing foods Pesticides Petrol octane booster Well-water nitrates

Copper sulfate Dapsone EMLA Flutamide Metoclopramide Nitric oxide Nitroethane Nitrofurans Nitroglycerin Nitroprusside Paraquat Phenacetin Phenazopyridine Prilocaine Primaquine Silver nitrite Sodium nitrite Sulfonamides Zopiclone

as a cofactor. NADPH production, in turn, requires glucose6-phosphate dehydrogenase (G6PD). This pathway normally quantitatively accounts for a small amount, about 5%, of MetHb reduction3; however, it can be activated pharmacologically by exogenous cofactors, such as methylene blue, to dramatically increase its reducing activity.3 Other mechanisms, such as intracellular glutathione and ascorbic acid, reduce oxidant compounds, thereby decreasing the production of MetHb.3

Causes Methemoglobinemia can be hereditary or acquired. Hereditary forms are caused by deficiencies of cytochrome b5 reductase or the presence of an abnormal hemoglobin, hemoglobin M, that is incapable of being reduced.4 Often, patients with hereditary forms of methemoglobinemia tolerate high levels of MetHb without prominent symptoms.2 Deficiencies of NADPH-MetHb reductase do not typically lead to methemoglobinemia because of the relatively minor role it plays in normal MetHb reduction.2 Patients with G6PD deficiency are unable to use the NADPHMetHb reductase pathway. Methemoglobinemia is not a common problem in these patients, again because of the relatively small contribution overall of the NADPH-MetHb reductase pathway in normal MetHb reduction.2

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More commonly, acquired methemoglobinemia can arise after exposure to an exogenous oxidizing agent. Inciting compounds accelerate the rate of formation of MetHb, overwhelming the protective enzyme systems leading to methemoglobinemia.3 A variety of compounds are capable of inducing methemoglobinemia (Table). Toxins and environmental contaminants, most notably nitrates, chlorates, and aniline compounds, are frequent causes of methemoglobinemia. Cases have been reported of ingestion of contaminated well water and exposure to common household products.2,3 Many commonly used medications can cause acquired methemoglobinemia. Because of individual variability in metabolism, not every patient develops methemoglobinemia after exposure.2 Dapsone and benzocaine are the most studied and cited culprits.1 In a retrospective review of 138 cases of acquired methemoglobinemia, dapsone accounted for 42% of all of the cases, followed by benzocaine (4%) and primaquine (4%).5 Dapsone is an antimicrobial and anti-inflammatory agent used in autoimmune disorders such as dermatitis herptiformis and as prophylaxis in immunocompromised states, most notably to prevent Pneumocystis jiroveci pneumonia. Methemoglobinemia has been reported after both dapsone overdose and therapeutic dosing. Case reports detail severe methemoglobinemia, with MetHb levels ranging from 28.7% to 55% after dapsone overdose.6Y9 At normal therapeutic doses, dapsone can induce a low-grade methemoglobinemia.10Y15 Ash-Bernal and colleagues reported the mean peak MetHb in therapeutic dapsone-induced methemoglobinemia as 7.6%.5 In a review of pediatric patients with dapsone-induced methemoglobinemia, the mean duration of therapy was 6.6 weeks and the mean peak MetHb level in symptomatic patients was 11.67%.16 Benzocaine is a local anesthetic used during procedures such as endotracheal intubation, transesophageal echocardiogram, bronchoscopy, and esophagogastroduodenoscopy. In a review of 242 cases of anesthetic-induced methemoglobinemia, more than 60% were caused by benzocaine.17 Cases of methemoglobinemia have been reported after a single dose of benzocaine.5,17,18 Doses as low as 150 to 300 mg have induced methemoglobinemia from spraying a 20% solution.19 In a series of 19 patients with benzocaine-induced methemoglobinemia after transesophageal echocardiogram, the incidence of methemoglobinemia was 0.7% and the mean peak MetHb level was 32%.19 A mean peak MetHb level of 43.8% was reported in patients with benzocaine-induced methemoglobinemia.5 Because low doses of benzocaine can induce high-level methemoglobinemia, it is of particular importance that physicians take precautions to minimize risk by ensuring that patients expectorate excess medication, avoid use on inflamed or broken skin, or use an alternative topical numbing agent.

Clinical Presentation In healthy patients, symptoms of methemoglobinemia correlate in general with MetHb level. Cyanosis occurs at a MetHb * 2011 Southern Medical Association


Review Article

level of 1.5 g/dL, which in nonanemic patients is 15% of total hemoglobin.2 Anxiety, headache, and dizziness can occur at MetHb levels 920%.2 Levels between 30% and 50% can produce fatigue, confusion, and tachypnea.2 At levels 950%, arrhythmias, acidosis, seizures, and coma can occur.2

Diagnosis The diagnosis of methemoglobinemia can be difficult because of its nonspecific symptoms. Many unique features can raise suspicion of methemoglobinemia in certain patients. The color of blood containing high levels of MetHb is a chocolate brown, in contrast to the dark red color of deoxygenated blood.1,2 The chocolate-brown color does not change with the exposure of blood to oxygen, as seen with nonmethemoglobinemic blood. An easy bedside test involves applying a drop of blood to filter paper to assess its color change after exposure to air.18 Blood that is rich in MetHb remains the chocolate-brown color. Patients with methemoglobinemia often present with cyanosis that is out of proportion to oxygen saturation. This discrepancy results from the unique effects of MetHb on standard oxygenation assessments. Standard pulse oximetry measures light absorbance at 2 distinct wavelengths, 660 and 940 nm, and determines the ratio of oxyhemoglobin to deoxyhemoglobin.4 MetHb absorbs light at both wavelengths, distorting this ratio. As a result, the presence of MetHb lowers the measured saturation value determined by pulse oximetry. When MetHb levels rise above 30%, the measured saturation by pulse oximetry plateaus around 85%, irrespective of the true oxygen content.4 The saturation value determined by pulse oximetry is largely unresponsive to supplemental oxygenation.4 In contrast, the oxygen saturation that is reported with arterial blood gas is calculated from the partial pressure of oxygen dissolved in blood.4 This value varies with inspired oxygen content, ventilation, perfusion, and diffusion capacity, but it is independent of the MetHb level.4 As a result, the calculated saturation from the blood gas often differs greatly from the saturation measured from pulse oximetry, producing a ‘‘saturation gap.’’4 A saturation gap 95% is abnormal.5 At high MetHb levels, the saturation gap can be upwards of 15%.18 The chocolate-brown color of blood, lack of improvement in peripheral oxygen saturation with supplemental oxygenation, and presence of a saturation gap are valuable clues to the diagnosis of methemoglobinemia. Methemoglobinemia can be confirmed by direct measurement of MetHb levels in the blood. Advanced cooximetry may be helpful in monitoring MetHb. Cooximetry uses multiple wavelengths of light to correctly distinguish the fractions of MetHb, carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin.4 Because of its cost and availability, cooximetry is not used widely in hospitals.2 Another test, the Evelyn-Malloy test, is used often as a confirmatory test when methemoglobinemia is suspected. Cyanide is added to bind the positively charged MetHb. This binding eliminates the absorption at 630 to 635 nm in direct proportion to the MetHb concentration, which allows for quantification Southern Medical Journal

of MetHb, expressed as a percentage of total concentration of hemoglobin.20

Treatment The mainstay of the treatment of acquired methemoglobinemia is identification and withdrawal of the offending agent. With continuous endogenous reduction of MetHb, removing the culprit medication often is sufficient in mild cases.21 Methylene blue accelerates the reduction of MetHb via the NADPHMetHb reductase pathway and is the treatment of choice in severe cases of methemoglobinemia.21 Methylene blue should be given intravenously at a dose of 1 to 2 mg/kg for 5 minutes.2 The maximum effect of methylene blue occurs quickly, at 30 minutes.22 Additional doses of methylene blue may be given after 1 hour if response is inadequate.22 Methylene blue can be given orally, but absorption is variable, ranging from 53% to 97%.22 It is eliminated in bile, feces, and urine as the metabolite leukomethylene blue, and patients should be warned that their urine and feces may turn a blue-green color.22 Because of the long half-life of inciting medications and the short half-life of methylene blue, rebound increases in MetHb levels may occur up to 12 hours after the administration of methylene blue.2 Serial monitoring of MetHb levels with the Evelyn-Malloy test posttreatment is indicated.20 Cooximetry is not helpful in monitoring these patients because it does not have the ability to distinguish between MetHb and methylene blue. Methylene blue should be used with caution because it is not without risk. High doses (7 mg/kg) can lead to hemolysis and a paradoxical rise in MetHb levels of up to 10%.3 Methylene blue also can increase the risk of dapsone-induced hemolysis.22 Aniline dyeYinduced methemoglobinemia is less responsive to methylene blue because the metabolite phenylhydroxylamine blocks its uptake.22 Methylene blue is ineffective in patients with G6PD deficiency. G6PD is required for the NADPH-MetHb reductase pathway to function. In addition, methylene may be potentially dangerous in patients with G6PD deficiency because there is an increased risk of hemolysis and paradoxical methemoglobinemia in these patients.2 Methylene blue should be avoided in patients with known G6PD deficiency and its use should be cautioned in groups that have a higher incidence of G6PD deficiency such as people of African, Asian, Mediterranean, or Middle Eastern descent.3 When G6PD activity is unknown, methylene blue treatment still may be warranted when the risk of significant symptomatic methemoglobinemia outweighs the risk of inciting hemolytic anemia in a previously undiagnosed G6PD-deficient individual. Patients prescribed medications known to induce methemoglobinemia, such as dapsone, should undergo G6PD testing. Other treatment options for methemoglobinemia have been tried with varying success. Cimetidine, a P450 inhibitor, has been beneficial in reducing the incidence of methemoglobinemia in



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patients taking dapsone; however, its role in the acute care setting is unproven.2 N-Acetylcysteine and ascorbic acid also have been suggested, given their role in cellular detoxification. Their benefit in acute methemoglobinemia is unclear, however.2,3 The decision to initiate treatment with methylene blue often is based largely on MetHb levels. Methylene blue is recommended in symptomatic patients with MetHb levels 920% and in asymptomatic patients with levels 930%.2,3 Treatment with methylene blue may be considered in symptomatic patients with low-grade methemoglobinemia and concomitant conditions that impair oxygen delivery (Fig.).21

Role of Comorbidities Low-grade methemoglobinemia can become symptomatic in the right setting. Likened to a multiple-hit hypothesis, comorbid conditions that impair oxygen transport, such as anemia, heart disease, and pulmonary conditions, can exacerbate a low level MetHb.21 Patients with anemia are more susceptible to methemoglobinemia because of their reduced oxygen-carrying capacity. Anemia is a significant risk factor for methemoglobinemia and was cited in 94% of patients with methemoglobinemia.5 Although anemia does not alter the susceptibility of hemoglobin to oxidation, a lower hemoglobin level means that there is less of a reserve when exposed to precipitating agents. Cardiac and respiratory conditions affect oxygen delivery and can exacerbate methemoglobinemia.21 Symptomatic lowgrade methemoglobinemia is associated with pneumonia, chronic obstructive pulmonary disease, and heart disease.23Y26 In these cases, MetHb levels ranged from 8.0% to 13%, and in the majority, the patients also were noted to be anemic.23Y26

Understanding the impact of comorbid conditions is important in diagnosing and managing this condition. In contrast to high levels of MetHb, patients with low-grade methemoglobinemia may not present with dramatic hypoxia or a large saturation gap. Small discrepancies in oxygenation saturation may go unnoticed easily or simply be attributed to error. Physicians need to maintain suspicion for methemoglobinemia in patients taking dapsone and other agents that can cause lowlevel methemoglobinemia. The presence of comorbid conditions and severity of symptoms should be considered along with MetHb level when determining treatment. Treatment with methylene blue has been successful in patients with low-level symptomatic methemoglobinemia complicated by pneumonia and anemia.23,24 A treatment threshold as low as 10% has been suggested in patients with comorbid conditions21; however, the paradoxical effect that methylene blue can cause a methemoglobinemia as high as 10% also can be more significant in patients with comorbidities that impair oxygen delivery. Therefore, the use of methylene blue should be considered carefully and advised only for patients with significant symptoms.

Conclusions Acquired methemoglobinemia can arise from exposure to many commonly encountered compounds. As MetHb levels rise, serious symptoms can develop. Prompt recognition of methemoglobinemia is crucial and may be aided by clinical features that are unique to methemoglobinemia, such as a saturation gap. Management includes the withdrawal of offending medications and methylene blue in certain patients. Treatment

Fig. Treatment approaches for the patient with suspected methemoglobinemia.

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with methylene blue should be considered in patients with significant symptoms, elevated MetHb levels, or comorbid conditions that compromise oxygen delivery.

14. 15.

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