Methemoglobinemia

Objectives

1. Understand the pathophysiology of methemoglobinemia.
2. Identify the typical clinical features of methemoglobinemia.
3. Clarify the diagnosis of methemoglobinemia in light of laboratory and bedside tests, exposure to causative agents, and clinical symptoms.
4. Recognize the limitations of the pulse oximeter and standard blood gas measurement when evaluating oxygen saturation in the presence of methemoglobin.
5. Understand the rationale for, and pitfalls in, methylene blue therapy.

Key words

cyanosis; co-oximeter; hemolysis; methemoglobinemia; methylene blue; poisoning

Abbreviations

G6PD = glucose-6-phosphate dehydrogenase; Mhgb = methemoglobinemia; NADH = nicotinamide-adenine dinucleotide; NADPH = the reduced form of nicotinamide-adenine dinucleotide phosphate

Methemoglobin is a type of dyshemoglobin in which iron molecules in the hemoglobin of circulating erythrocytes are in the oxidized ferric (Fe³⁺) state rather than the normally reduced ferrous (Fe²⁺) state. Methemoglobin is incapable of carrying oxygen. In healthy adults, about 1% of total hemoglobin is normally present in the methemoglobin form. Methemoglobinemia (Mhgb) is defined as an increase in methemoglobin formation above this normally low level. Mhgb is an unusual but potentially life-threatening condition that can present a significant challenge to the treating clinician. A thorough understanding of the pathophysiology of Mhgb, together with its diagnostic and therapeutic pitfalls, is essential for prompt recognition and appropriate treatment of this disorder.

Pathophysiology

Hemoglobin is a complex comprised of four polypeptide chains, each with an embedded iron atom. This configuration serves to protect the ferrous (Fe²⁺) iron from oxidation. Hemoglobin is capable of transporting oxygen and carbon dioxide only when the hemoglobin is in the ferrous (Fe²⁺) state. During transport, the ferrous iron forms a reversible complex with the oxygen atom by temporarily donating one electron to the oxygen atom. Once the hemoglobin molecule releases the oxygen atom, the iron atom retrieves its electron, maintaining its normal reduced ferrous state. Thus it is again available to transport oxygen.

Methemoglobin is a form of hemoglobin wherein the iron atom is oxidized to the ferric (Fe³⁺) state. Not only is methemoglobin incapable of transporting oxygen and carbon dioxide, it also causes a left shift of the oxygen-hemoglobin dissociation curve. This compromises the ability of the remaining hemoglobin subunits on the affected molecule to release oxygen to tissues, thus further exacerbating tissue hypoxia.¹

Normally, approximately 1% methemoglobin is present in the body due to endogenous oxidation of the iron atom to the Fe³⁺ state. This may occur as a result of intracellular hydrogen peroxide formation, other free radical formation, or, rarely, when the iron atom spontaneously retains the oxygen atom during its release from hemoglobin.

Several intracellular mechanisms exist to maintain a low level (1%) of methemoglobin under normal conditions. The primary mechanism utilizes nicotinamide-adenine dinucleotide (NADH), cytochrome, b₅and cytochrome b₅ reductase. This NADH pathway is predominant in normal homeostasis.² Another mechanism utilizes reduced glutathione and ascorbic acid (vitamin C) as electron donors converting methemoglobin to hemoglobin. This mechanism accounts for only a small amount of regenerated hemoglobin. Because it is a slow process and a minor pathway, it is of little value in the context of clinically significant Mhgb. The last mechanism is normally dormant in the body and is only functional with the exogenous addition of methylene blue or some other substrate acting as an electron carrier. This enzymatic pathway utilizes the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) and NADPH methemoglobin reductase to convert methylene blue to leukomethylene blue. Leukomethylene blue reduces methemoglobin to hemoglobin.³

Mhgb and hemolysis both occur as a result of oxidant stress. They can be interrelated, but differ in several key respects. Mhgb is a reversible phenomenon that occurs as a result of an oxidant stress solely on the iron atom in hemoglobin. Hemolysis is an irreversible event that occurs as a result of an oxidant stress compromising the erythrocyte membrane, either directly or secondarily through hemoglobin precipitates (Heinz bodies). By these linked mechanisms, potent oxidants can cause both severe Mhgb and concomitant RBC hemolysis, although both processes need not occur together. There are numerous reports of hemolysis following methemoglobin formation after exposure to aniline dyes, phenazopyridine, nitrites, and dapsone. These morbidities are most likely to occur simultaneously when the intracellular antioxidant mechanisms have been exhausted (i>eg, glutathione, ascorbic acid, NADH, or NADPH depletion).⁴ Because of the potential role of NADPH depletion in this process, combined Mhgb and NADPH compromise (most importantly through NADPH-reductase deficiency) is a particular risk factor for hemolysis.

Sulfhemoglobin is another dyshemoglobin that is closely related to methemoglobin. This dyshemoglobin occurs when a sulfur atom is incorporated into the porphyrin ring of the hemoglobin moiety. First, hemoglobin is oxidized to methemoglobin, then the sulfur atom is covalently bound to the heme moiety. Like methemoglobin, sulfhemoglobin is incapable of transporting oxygen and carbon dioxide. In contrast to Mhgb, sulfhemoglobinemia causes a right shift of the oxygen-hemoglobin dissociation curve. Therefore, the remaining hemoglobin more readily releases oxygen atoms to oxygenate tissues. It may be for this reason that patients suffering from sulfhemoglobinemia are not typically as symptomatic as those suffering from an equivalent degree of Mhgb.⁵ Unlike Mhgb, however, sulfhemoglobinemia is not reversible.

Hereditary and Acquired Methemoglobinemia

Mhgb can be divided into two broad categories: hereditary and acquired. Often, a combination of both factors is involved in the clinical presentation of Mhgb. A number of congenital disorders within the erythrocyte can result in Mhgb, which can be present at birth or be elicited after exposure to an oxidizing agent.⁶ Hereditary disorders responsible for Mhgb are listed in Table 1.

Acquired Mhgb is more common by far than congenital forms. Acquired Mhgb occurs from exposure to oxidizing agents, which can include many widely used drugs and chemicals. Exposure to these agents can occur by ingestion, by inhalation, and through absorption across skin and mucous membranes. Although certain agents (such as dapsone) produce Mhgb in a predictable dose-related fashion, other scenarios, such as Mhgb related to topical anesthetic administration, appear to have an idiosyncratic component with poorly characterized susceptibility factors. Patients with the enzymatic deficiencies are more susceptible to oxidant stresses at lower levels of exposure. Often, patients are diagnosed with an enzymatic disorder only after exposure to an oxidizer results in Mhgb. Finally, in some scenarios the precise mediators of oxidant stress or methemoglobin homeostasis disruption remain unclear, eg, in the well-described syndrome of acute illness-associated Mhgb in children and infants.

Some agents causing Mhgb are direct oxidizers that react directly with hemoglobin to form methemoglobin. Indirect oxidizers reduce oxygen or water to O₂^- or H₂O₂, respectively, which in turn oxidize hemoglobin to methemoglobin. Other agents have to be converted to an oxidizing metabolite. A classic example is aniline, a dye once used extensively in industry. Aniline is metabolized by the cytochrome P-450 system to phenylhydroxylamine, an intermediary that binds with O₂ to form the oxygen free radical, O₂^- , which then produces methemoglobin. Dapsone and benzocaine also are metabolized to oxidizing metabolites. The ongoing redox reaction between the parent compound and the metabolites can result in prolonged, cyclical Mhgb that can persist for days. Dapsone overdose can be further complicated by the concurrent formation of sulfhemoglobinemia,⁷ for which no effective antidotal therapy exists. Nitrates, which are not oxidizers, are converted nonenzymatically to the oxidizing nitrites by bacteria colonizing the gut or burned skin (as with dermal application of silver nitrate). Table 2 is a partial list of some of the most commonly reported causes of acquired Mhgb. 

Table 2—Common Causative Agents in Acquired Methemoglobinemia

Infants, as noted above, are especially susceptible to acquired Mhgb, with or without exposure to known oxidizers. There are several possible reasons for this increased susceptibility: (1) fetal hemoglobin is more easily oxidized than those of adults; (2) levels of RBC cytochrome-b₅ reductase in infants is only 50 to 60% of adult levels; and (3) the higher intestinal pH of infants may promote the growth of nitrite-forming bacteria, such as Escherichia coli or Campylobacter jejuni. Mhgb in infants has been associated with ingestion of well water high in nitrates, and, historically, with dermal exposure to aniline ink used on cloth diapers.⁸ Mhgb has been reported in infants with diarrhea-induced dehydration and acidosis, although this is a sporadic observation.^9,10 Some oxidizing chemicals and drugs, including local anesthetics used for epidural analgesia, can cross the placental barrier and cause fetal Mhgb.

Clinical Presentation

The severity of signs and symptoms seen in Mhgb is directly proportional to the percentage of hemoglobin that has been oxidized to methemoglobin. The higher the methemoglobin formation, the more severe the findings. At concentrations < 10 to 15% methemoglobin, there may be no obvious abnormality other than cyanosis by physical examination. In Mhgb, the skin classically has a gray-blue discoloration. With higher methemoglobin concentrations, symptoms of anoxia become more pronounced. At Mhgb levels > 30 to 40%, the patient may complain of headache, dizziness, fatigue, tachycardia, exertional dyspnea, tachypnea, and blurred vision. At even higher levels, anaerobic conditions are associated with severe metabolic acidosis, weakness, dyspnea, and altered mental status. At methemoglobin levels > 60 to 70%, symptoms may include seizures, coma, cardiovascular collapse, and death.^11,12

The methemoglobin concentrations and corresponding symptoms described above apply to normal, healthy, nonanemic individuals. However, patients who are anemic, are immunocompromised, or have underlying cardiac, pulmonary, or hematologic conditions are at risk for more severe symptoms at lower methemoglobin concentrations. First and foremost, the anemic host has an even smaller amount of available hemoglobin, further compromising tissue oxygenation. For any given percentage of methemoglobin concentration, the concomitant presence of anemia dictates that, in absolute terms, a smaller amount of hemoglobin is available to oxygenate tissues. Thus, the methemoglobin concentration reported as a percentage out of context does not reflect the potential severity of the physiologic compromise that is present.

Diagnosis

Appearance

One of the most important clues in diagnosing Mhgb is when a cyanotic patient shows no clinical improvement despite 100% oxygen administration. As noted above, even at relatively low levels of Mhgb, the patient may have a cyanotic appearance, yet have no clinical symptoms. Whether at low or high methemoglobin levels, administration of 100% oxygen will not result in any clinical improvement of cyanosis nor increase the oxygen-carrying capacity of the blood to any substantive degree.

Bedside Tests

There are several bedside tests that are of some historical interest and are widely cited in various reviews of the subject or in older texts. First, the venous blood in Mhgb is classically a dark, chocolate-brown color. This brown color will remain unchanged even when oxygen is bubbled through it in a test tube. In contrast, normal venous blood, even if it appears dark, will turn bright red after this procedure. Second, a drop of blood may be placed on a piece of white filter paper alongside a normal drop of blood. The methemoglobin-containing blood will appear dark brown in color. Third, lysis of the RBCs may be carried out by adding deionized water (1:100 dilution) and then one crystal of potassium cyanide. If methemoglobin is present, cyanomethemoglobin will be formed and the blood will turn bright red.¹³ This test is particularly useful in differentiating between sulfhemoglobin and methemoglobin, since there will be no color change for sulfhemoglobin.¹⁴ In a practical sense, these bedside tests are rarely used today because of concerns relating to bloodborne pathogens and toxic chemical exposure.

Laboratory Tests

The co-oximeter is the only reliable method to quantify oxygen saturation in a methemoglobin-poisoned patient. The co-oximeter uses spectrophotometric techniques to directly measure four different wavelengths of light corresponding to the absorbance of oxyhemoglobin, deoxyhemoglobin, methemoglobin, and carboxyhemoglobin. Co-oximetry measurement is available at most medical centers with intensive care capabilities.

Both the pulse oximeter and standard blood gas analysis will falsely report elevated oxygen saturation values in the methemoglobin-poisoned patient.¹⁵ The pulse oximeter relies on measurements at only two wavelengths of light typical for absorbance by oxyhemoglobin (660 nm) and deoxyhemoglobin (940 nm). Its computational algorithms assume that there are no other forms of hemoglobin present.^16,17 Methemoglobin absorbs more light at the 660-nm wavelength (oxyhemoglobin) than at the 940-nm wavelength (deoxyhemoglobin). Therefore, when the ratio of oxy/deoxyhemoglobin is calculated, an inaccurate result is reported. The reported oxygen saturation will be decreased, but reaches a plateau around 82 to 85% in the methemoglobin-poisoned patient.^17,18 The presence of methylene blue also leads to inaccuracies in pulse oximetry saturation estimates.

The standard blood gas machine uses the Pao₂ and the oxygen dissociation curve to calculate, rather than directly measure, the oxygen saturation. As with the pulse oximeter, the standard blood gas machine calculation is based on the presumption that no other forms of hemoglobin are present. Pao₂ reflects the total amount of oxygen present in blood, but it does not differentiate between oxygen bound to hemoglobin vs oxygen dissolved in blood yet not available for transport to the tissues; as a result, this measurement results in a falsely elevated value. Therefore, both of these methods, pulse oximetry and standard blood gas measurement, are unreliable methods for testing true oxygen saturation in the presence of Mhgb.

In contrast to methemoglobin, sulfhemoglobin is more challenging to quantify. Its measurement requires spectrophotometry or other laboratory methods that may not be readily available.

Treatment

Once a diagnosis of Mhgb has been made, it is important to recognize that cyanosis alone in an otherwise asymptomatic Mhgb patient does not necessarily require antidotal treatment. Removal of the offending agent is often the only treatment needed. Decontamination of skin and mucous membranes (for dermal exposures), activated charcoal for recent ingestions, and multiple-dose activated charcoal for drugs with long half-lives and enterohepatic recirculation, such as dapsone,¹⁹ are very important for preventing prolonged toxicity. Dextrose is essential for the glycolysis needed for production of NADH in erythrocytes, and it should be administered as soon as possible.

Patients with Mhgb levels > 30% or symptomatic patients with lower levels may be treated with methylene blue. Patients with underlying cardiovascular disease or anemia are candidates for treatment at lower Mhgb levels. Methylene blue is actually a potent oxidizer that is reduced to leukomethylene blue by NADPH-methemoglobin reductase. Leukomethylene blue then reduces methemoglobin, for which it has a high affinity, regenerating hemoglobin. The dose of methylene blue is 1 to 2 mg/kg of body weight administered IV over 3 to 5 min. Rapid disappearance of cyanosis should be noted within 30 min to 1 h. If not, a repeat dose of 1 mg/kg can be given, cautiously.²⁰ Patients who do not respond to methylene blue may have glucose-6-phosphate dehydrogenase (G6PD)²¹ or NADPH-methemoglobin reductase deficiencies or hemoglobin M, or may be suffering from sulfhemoglobinemia.

A potentially dangerous adverse reaction to methylene blue can occur in patients with G6PD deficiency. The sole source of NADPH in the erythrocyte is the hexose monophosphate shunt, of which G6PD is a key enzyme. Patients with G6PD deficiency are unable to produce NADPH normally in the erythrocytes. Therefore, they may not be able to convert methylene blue to leukomethylene blue, the active form of the antidote, rendering methylene blue ineffective for treatment of Mhgb. In addition, because methylene blue itself is an oxidizer, it can exacerbate oxidative stress in patients with G6PD deficiency, causing hemolysis and/or worsening Mhgb. Exchange transfusion may be the most effective option for G6PD-deficient patients with life-threatening Mhgb.¹

Even in patients without erythrocyte enzyme abnormalities, methylene blue may exacerbate Heinz body hemolytic anemia when used to treat patients who have taken drugs that have strong potential for causing hemolysis, such as dapsone.²² Intra-amniotic injections of methylene blue have caused hemolytic anemia in neonates, one of whom received only 3.6 mg/kg.²³ IV methylene blue used as a dye to aid in the removal of pancreatic tumors resulted in Mhgb, even at a dose of 5 mg/kg.²⁴ Treatment of chronic cyanosis from hereditary Mhgb is usually instituted for cosmetic reasons. In this context, oral ascorbic acid, 300 to 600 mg/d divided into three or four doses, has been advocated.²⁵ Use of ascorbic acid alone is not appropriate for treatment of acute, acquired Mhgb. Hyperbaric oxygen therapy was shown to improve survival in rats with sodium nitrite-induced Mhgb, but its role in human poisoning is unclear.

Treatment of hemolysis is directed toward preserving the patient’s renal function with IV fluid hydration and, in the case of massive overdoses, administration of IV sodium bicarbonate. Treatment of sulfhemoglobinemia consists of removal of the offending agent and supportive care. Methylene blue is ineffective in treating sulfhemoglobinemia. In severe cases, exchange transfusion may be utilized.

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