Methemoglobinemia: from diagnosis to treatment

Abstracts

JUSTIFICATIVAS E OBJETIVOS: A metemoglobina é a forma oxidada da hemoglobina, que além de não se ligar ao oxigênio, aumenta a afinidade deste pela porção parcialmente oxidada da hemoglobina. A concentração aumentada da metemoglobina no sangue decorre de alterações congênitas e de exposição a agentes químicos diversos, resultando em quadro com múltiplos diagnósticos diferenciais, que se não tratado pode levar ao óbito. Foi feita revisão sobre o assunto, dando ênfase às informações relevantes para o manuseio clínico dos pacientes. CONTEÚDO: Quando a concentração sangüínea de metemoglobina está acima de 1,5% surge a cianose, característica principal da doença. Os pacientes apresentam sangue arterial de coloração marrom-escuro com a PaO2 normal. O diagnóstico deve ser suspeitado em pacientes que apresentem cianose e baixa leitura de saturação ao oxímetro de pulso (SpO2), sem que haja comprometimento cardiopulmonar significativo. A co-oximetria é o método padrão-ouro e define o diagnóstico. No tratamento dos pacientes devem ser considerados o caráter agudo ou crônico da síndrome (etiologia) e a gravidade dos sintomas. A concentração sangüínea de metemoglobina é importante, sobretudo nos casos agudos. O tratamento básico consiste na remoção do agente causador, administração de oxigênio e observação. Casos graves devem ser tratados com azul-de-metileno, antídoto específico, porém ineficaz em algumas situações. CONCLUSÃO: A metemoglobinemia é condição potencialmente grave, cujo diagnóstico depende do alto grau de suspeição. Em geral, os anestesiologistas, no período perioperatório, são os primeiros a detectarem o problema e devem liderar a condução do tratamento.

COMPLICAÇÕES; MONITORIZAÇÃO; MONITORIZAÇÃO

MISCELLANEOUS

Methemoglobinemia: from diagnosis to treatment^*

Metahemoglobinemia: del diagnóstico al tratamiento

Tatiana Souza do Nascimento, M.D.^I; Rodrigo Otávio Lami Pereira, TSA, M.D.^II; Humberto Luiz Dias de Mello, TSA, M.D.^III; José Costa, TSA, M.D.^IV

^IAnestesiologista; Médico do Serviço de Anestesiologia do Instituto Nacional de Cardiologia

^IIAnestesiologista do Instituto Nacional do Câncer, Rio de Janeiro, RJ

^IIIAnestesiologista; Responsável pelo CET/SBA Prof. Bento Gonçalves do Hospital Universitário Clementino Fraga Filho - UFRJ

^IVAnestesiologista; Responsável pelo CET Hospital Naval Marcílio Dias

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Methemoglobin is the oxidized form of hemoglobin, which does not bind oxygen and increases the affinity of oxygen for the partially oxidized portion of hemoglobin. Increased levels of methemoglobin in the blood are secondary to congenital changes and exposure to several chemical agents, resulting in a disorder with several differential diagnoses, which it can lead to death if it is not treated. The objective of this report was to review this subject, emphasizing relevant information for the clinical management of patients with methemoglobinemia.

CONTENTS: When the concentration of methemoglobin in the blood is above 1.5%, the patient develops cyanosis, the main characteristic of this disorder. The color of the arterial blood changes to dark brown with normal PaO₂. One should suspect the diagnosis in patients with cyanosis and low saturation (SpO₂) without significant cardiopulmonary dysfunction. Co-oximetry is the gold standard and defines the diagnosis. Treatment should be based on whether the syndrome is acute or chronic (etiology) and on the severity of symptoms. Blood levels of methemoglobin are important, especially in acute cases. Basic treatment includes removal of the agent responsible for the disorder, administration of oxygen, and observation. Severe cases should be treated with the specific antidote, methylene blue, which is not effective in some situations.

CONCLUSIONS: Methemoglobinemia is a potentially severe disorder, whose diagnosis depends on a high degree of suspicion. In general, anesthesiologists are the first to detect the problem in the preoperative period and should lead the treatment.

Key Words: COMPLICATIONS: methemoglobinemia; MONITORING: pulse oximetry, co-oximetry.

RESUMEN

JUSTIFICATIVAS Y OBJETIVOS: La metahemoglobina es la forma oxidada de la hemoglobina, que, además de no vincularse con el oxígeno, aumenta su afinidad por la porción parcialmente oxidada de la hemoglobina. La concentración aumentada de la metahemoglobina en la sangre, proviene de las alteraciones congénitas y de la exposición a agentes químicos diversos, trayendo como resultado, un cuadro con múltiples diagnósticos diferenciales, que si no se trata, puede conllevar al deceso. Se hizo una revisión sobre el asunto, dándole énfasis a las informaciones relevantes para el manejo clínico de los pacientes.

CONTENIDO: Cuando la concentración sanguínea de metahemoglobina está por encima de 1,5% surge la cianosis, característica principal de la enfermedad. Los pacientes presentan sangre arterial de coloración marrón oscuro con la PaO₂ normal. El diagnóstico debe suponerse en pacientes que presenten cianosis y una baja lectura de saturación al oxímetro de pulso (SpO₂), sin que exista un comprometimiento cardiopulmonar significativo. La co-oximetría es el método estándar de oro y define el diagnóstico. En el tratamiento de los pacientes, deben ser considerados el carácter agudo o crónico del síndrome (etiología) y la gravedad de los síntomas. La concentración sanguínea de metahemoglobina es importante principalmente en los casos agudos. El tratamiento básico consiste en la retirada del agente causador, administración de oxígeno y observación. Casos graves deben ser tratados con azul de metileno, antídoto específico, sin embargo ineficaz en algunas situaciones.

CONCLUSIÓN: La Metahemoglobinemia es una condición potencialmente grave, cuyo diagnóstico depende del alto grado de sospecha. En general, los anestesiólogos, en el período perioperatorio, son los primeiros que detectan el problema y deben liderar el tratamiento.

INTRODUCTION

Methemoglobinemia (MetHba) is a clinical syndrome caused by an increase in the blood levels of methemoglobin (MetHb) ¹ secondary to both congenital (chronic) changes in hemoglobin (Hb) synthesis or metabolism, or acute imbalances in reduction and oxidation reactions (redox imbalance) induced by the exposure to several chemical agents ^2,3. Central cyanosis unresponsive to the administration of oxygen ^4-7, which can cause a reduction in oxygen delivery (DO₂), is the main characteristic of MetHba. Its prevalence is difficult to determine because it encompasses mild cases, which are probably underdiagnosed, and fatal cases; it frequently presents in the preoperative period and should be known to every anesthesiologist.

ETIOPATHOGENY

The molecule of Hb is a tetramer composed of alpha, beta, gamma, or delta chains. The most common form of Hb in adults (HbA) consists of two α and two β chains. Each Hb chain is formed by a globin polypeptide linked to a prosthetic heme group, which is formed by a complex of a protoporfirin IX ring and one atom of ferrous iron (Fe⁺²). Thus, each Hb molecule has four atoms of iron. Each ferrous iron can reversibly link one O₂ molecule, for a total of four molecules of O₂ transported by each Hb molecule ⁸.

Methemoglobin, along with carboxyhemoglobin (COHb) and sulfhemoglobin (SHb), represents a dyshemoglobin (dysHb), i.e., a type of hemoglobin that does not bind O₂. Methemoglobin is the oxidized form of Hb, whose heme Fe⁺² is oxidized to ferric iron (Fe⁺³) and, for this reason, cannot bind oxygen. Ferric iron also causes an allosteric change in the heme portion of partially oxidized Hb, increasing its O₂ affinity. Thus, besides the inability to bind O₂, MetHb shifts the dissociation curve of partially oxidized Hb to the left ^8-11, hindering the release of O₂ in the tissues. Tissue hypoxia caused by MetHba is secondary to a reduction in free Hb to transport O₂ (relative anemia) and the difficulty to release O₂ in the tissues ¹¹.

In theory, any oxidizing agent can lead to the formation of MetHb ⁶. Hemoglobin is constantly being oxidized; however, natural reducing systems maintain the levels of MetHb under 2% ^5,13. NADH-Methemoglobin reductase (NADH-NR) ⁹, a system with two enzymes, cytochrome B5 and cytochrome B5-reductase (CB5R), is responsible for the endogenous reduction of MetHb, corresponding to 99% of the reducing activity. NADH-Methemoglobin reductase transfers one electron from NADH to MetHb, changing it into reduced hemoglobin (HHb) (Figure 1). Other systems also help to maintain a low level of MetHb; among them, ascorbic acid, gluthation, and NADPH dehydrogenase should be mentioned. Gluthation reduces several oxidizing substances in the blood before they attack the Hb ¹⁴. However, under normal conditions those pathways are less significant, but become important when NADH-MR is disrupted ⁹. Methemoglobinemia results from a redox imbalance, either due to excessive oxidization of Hb (increased production) or a decrease in the activity of reducing enzymes (decreased metabolism) ^19,10,12.

CLASSIFICATION

Methemoglobinemia can be congenital or acquired. Acquired (acute) MetHba results from the exposure to several oxidizing agents (Charts I and ^II), and occasionally are secondary to pathologic conditions, such as sepsis, sickle cell crisis, and gastrointestinal infections in children ¹⁵. The exact prevalence is not currently available, but it is believed that acquired cases are more frequent than congenital ones ¹⁶. Oxidizing agents accelerate 100 to a 1,000 times the oxidation of Hb, and eventually overwhelm the capacity of reducing endogenous systems ¹⁷; they include several drugs ^{1,5,7,14,18-23,} , intoxication with pesticides, herbicides, and fertilizers ³, automobile exhaust fumes ¹³, and industrial chemicals ^24,25. Drugs implicated more often include local anesthetics (benzocaine, lidocaine, and prilocaine), dapsone, phenacetin derivatives, and drugs used in the treatment of malaria ¹⁶. Several cases of MetHba related with the use of benzocaine sprays during endoscopies led the Food and Drug Administration (FDA), a regulating agency in the USA, to ban the topical oropharyngeal use of this drug ²⁶. A large proportion of intoxication-induced MetHba is secondary to the use of nitrites and nitrates ^2,3,5,27-29. Those drugs are powerful oxidants widely used as preservatives and dyes in the food industry ^2,5. They can be found in industrialized baby foods, barbecue-flavored foodstuffs, and other products ^2,3,29. Nitrates can also be present, as a contaminant, in drinking water. Cases of acute MetHba have been reported in rural areas of the USA and several residential areas in India for some years ^3,27,28. Poor people who use water from irregular water wells are affected more often by this problem ³.

Infants are particularly susceptible to MetHba since, until 4 months of age, the activity of CB5R is reduced (50% to 60% of adults) and fetal hemoglobin (HbF) is more easily oxidized than HbA ^3,20. Besides, the elevated intestinal pH facilitates the growth of Gram-negative bacteria that convert food nitrates in nitrites that have higher oxidative capacity ¹⁶. Early weaning of infants, before 4 months of age, exposes them to nitrate-contamination from several sources, including natural sources (carrot, beets, fava beans, green beans, spinach, and pumpkin) ³. Intoxication of infants causes the production of MetHb at a rate above the reduction capacity, and the severity of the case depends on the amount of toxin the patient has been exposed to, individual metabolic capacity, intestinal absorption, and enterohepatic circulation ⁹.

Deficiency of CB5R is the most common cause of congenital MetHba ^10,12. It is an autosomal recessive disorder divided in two types: type I affects only mature red blood cells; and type II affects all cell types. Type I CB5R deficiency is found worldwide, but it is endemic in specific populations, such as Athabasca and Navajo Native Americans, in the USA, and the Yakutsk, Siberian natives ¹². In other ethnical groups this disorder is sporadic. Homozygous have fMetHb (fraction of MetHb relative to total Hb expressed in percentage, which varies from 10% to 35%) and usually present cyanosis and polycythemia, and other symptoms only develop with MetHb levels greater than 40% ^10,12. The life expectancy of those patients is not lower than the general population and pregnancies develop normally. Heterozygous individuals have CB5R with 50% of the activity observed in healthy subjects. Although this level of activity is enough to maintain fMetHb under 1%, conditions of acute oxidative stress can occasionally overwhelm the ability of the erythrocyte to reduce MetHb, leading to acute symptomatic MetHba, and one can infer that at least part of the patients who develop the acute syndrome are probably undiagnosed heterozygous for CB5R deficiency ³². Due to the sudden development, this disorder is probably harder in heterozygous than in homozygous individuals, since the latter develop tolerance mechanisms since birth ^12,32.

Type II disorder affects 10% to 15% of the individuals with congenital deficiency of CB5R, which is caused by enzymatic deficiency in all cell types, including non-erythroid cells like fibroblasts, lymphocytes, and central nervous system cells. This disorder, which is sporadic all over the world, manifests as mental retardation and developmental delay. Life expectancy is reduced due to neurologic complications. Treatment with reducing agents is not effective for those complications and does not change the prognosis of this disorder ^10,12.

Hemoglobin M (HbM) disease is another cause of congenital MetHba ^9,32,33. In this condition, mutations affect the globin chain of Hb, stabilizing the iron of the heme radical as oxidized Fe³⁺. Usually thyrosine replaces the histidine in the alpha or beta chain. Those aberrations cause the formation of an iron-phenolate complex, which is resistant to reduction and, for this reason, HbM cannot be reduced by NADH-MR ⁸. Several variants of HbM have been identified and characterized (Boston, Iwate, Kankakee, Saskatoon, Hyde Park, Osaka, Fort Ripley) ⁹. When mutation affects the alpha chain, cyanosis is present at birth; when it affects the beta chain, cyanosis starts at six months of age, period that most of HbF has been substituted by HbA ^8,32. Patients with HbM are cyanotic but are usually asymptomatic. However, exposure to drugs or toxins capable of oxidizing Hb can increase fHbM and lead to clinical decompensation ⁸. Life expectancy is not affected in HbM, which is an autosomal dominant disorder. It is believed that homozygosis is incompatible with life ³³.

CLINICAL MANIFESTATIONS

Clinical manifestations of MetHba reflect the reduction in O₂-carrying capacity, leading to tissue hypoxia ⁵. In general, fMetHb under 15% causes only a grayish pigmentation of the skin, but the condition is frequently overlooked. Anemia makes patients more sensitive to MetHba by reducing the functional stores of Hb ⁶. Above 12% to 15%, the blood is brown (a chocolate color) and patients have central cyanosis non-responsive to the administration of O₂, which is not proportional to the discrete general symptoms ⁵. Neurologic and cardiovascular symptoms (dizziness, headache, anxiety, dyspnea, symptoms of low cardiac output, somnolence, and seizures) are commonly present with fMetHb above 20% to 30%. As levels of MetHb increase, the patient evolves with reduction in the level of consciousness, respiratory depression, shock, and death. Levels of fMetHb above 70% are usually fatal.

As mentioned before, patients with congenital disease develop physiological adaptations and can tolerate elevated levels (up to 40%) without symptoms. Those adaptations include changes in the concentration of 2,3-DPG and pH, synthesis of globin chains, and polycythemia^8,33. But those patients can present clinical decompensation when exposed to agents that also oxidize hemoglobin, increasing fMetHb ⁸, or in diseases that increase the metabolic demand, such as those that manifest with systemic inflammatory response syndrome (SIRS). Table I shows the correlation of fMetHb and clinical manifestations.

DIAGNOSTIC AND MONITORING METHODS

One should suspect MetHba in patients with central cyanosis and low saturation on pulse oximetry (SpO₂) once more common causes, like cardiopulmonary dysfunctions, are ruled out ¹⁷. Arterial blood analysis shows a high partial pressure of O₂ (PaO₂) with normal Hb saturation (SaO₂), with values well above those indicated by pulse oximetry ^21,29.

Co-oximetry is the gold standard for the diagnosis of MetHba ^{9,15,29,33,34}. The co-oximeter is capable of measuring the concentration of different types of Hb in the blood through spectrophotometry, using different wavelengths. This technology is based on the Lambert-Beer law that correlates the concentration of a dissolved substance to the intensity of the light transmitted through a solution (Figure 2) ³⁵. The different molecular structure of the heme radical in different species of Hb has characteristic absorbance spectra called extinction coefficient. Since absorbance is an addictive property, measuring in n wavelengths one obtains the concentration of n substances, individualizing the types of Hb ^9,35.

Until the middle of the decade of 1980 co-oximeters were capable of measuring fractions of HHb, O₂Hb (oxyhemoglobin), COHb, MetHb, and SHb using six wavelengths. Current models measure light absorbance of up to 128 wavelengths, increasing the precision of the equipment, minimizing interferences from undesirable substances, and allowing the detection of a larger number of substance ⁹.

Despite recent advances, co-oximeters cannot be considered the perfect MetHb quantification method ⁹. It is possible that the absorbance spectrum of totally oxidized forms of Hb is discretely different from partially oxidized forms. It has not been determined whether co-oximeters discriminate those molecules; thus, it is possible that total MetHb (the sum of complete and partially oxidized forms) is underdetected. Structural variations in the globin chain of HbM, and its variants, make their absorbance spectrum significantly different from the typical MetHb, causing problems to quantify fMetHb, especially when using older co-oximeters. In HbM, fMetHb can be underestimated, while fCOHb and/or fSHb are artificially increased ⁹. Methylene blue can also be a source of error when measuring MetHb in the co-oximeter ^2,5,6,8. Since the absorbance characteristics of methylene blue are similar to MetHb, it can be interpreted as MetHb, overestimating its concentration after the treatment ⁸. Therefore, it is recommended to analyze a sample in the co-oximeter before using methylene blue. Despite the different particularities and possible sources of error, the co-oximeter is still the only laboratorial tool capable of providing data on the O₂-carrying capacity of the different forms of MetHb ⁹. The set of clinical information that should guide the steps to be taken is more important than the level of fMetHb showed by the co-oximeter.

The pulse oximeter is a simplified photometer that estimates the arterial saturation of Hb by measuring the ratio of pulsatile luminous transmission in a vascular bed using two wavelengths usually 600 nm (red light) and 940 nm (almost infrared light). The use of only two wavelengths limits the discriminatory capacity of the oximeter to O₂Hb and HHb. In fact, both O₂Hb and HHb absorb light in the wavelengths used. The determination of saturation is based on the absorbency ratio (R) in the pulsatile phases, called AC, and non-pulsatile, called DC (Figure 3). The value of R obtained corresponds to a value of arterial Hb saturation obtained from an empirical calibration curve stored in the memory of the device. Thus, the value of SpO₂ is a true approximation of the functional Hb saturation in arterial blood (Figure 4-a). Since significant amounts of Hb species, besides HHb and O₂Hb, are rare in daily practice, SpO₂ is a satisfactory representation of hemoglobin saturation in most patients. However, in the presence of dysHb the monitor is incapable of measuring precisely the concentration of any specie of Hb, providing wrong saturation readings. In the presence of additional species of Hb, the O₂-carrying capacity of the blood can only represent the fractional saturation (Figure 4-b), which considers the different species of Hb, and not the functional saturation ^9,35.

According to experimental demonstrations ³⁶, increases in fMetHb produce progressive reduction of the fO₂Hb measured by co-oximetry, while SpO₂ shows a less marked reduction, stabilizing at approximately 85% with fMetHb above 35%. Above those levels, SpO₂ overestimates the real Hb saturation (fO₂Hb), concealing possible tissue hypoxia. Although it is an important device for the bedside follow up of O2 carrying capacity in critical and surgical patients, the pulse oximeter is useless in the presence of dysHb, and can lead to wrongful decision-making by the ill-judged physician ^9.34,35. In 2005, two models of co-oximeter were introduced in the North-American market. Those devices use eight wavelengths and are capable of measuring fMetHb and fCOHb ³⁵. They have been approved by the FDA to be used in suspected cases of MetHb and carbon monoxide intoxication.

Arterial gas anlaysis cannot be used as parameters to assess the O₂-carrying capacity in dyshemoglobinemias. In conventional arterial blood gas analyzers, the PaO₂ measured is correlated mathematically with the value of Hb saturation (SaO₂) as a function of the pH, and a standardized Hb dissociation curve. Thus, those devices do not measure, but estimate, the Hb saturation. If the standard (normal) Hb dissociation curve is inaccurate in sick individuals, in patients with MetHb, COHb, or SHB intoxications those parameters are markedly wrong ^9,35.

Although family history is important and frequently defines the diagnosis of congenital MetHba, additional methods are occasionally necessary to confirm the diagnosis¹⁶. The presence of HbM can be confirmed by hemoglobin electrophoresis, while CB5R deficiency is confirmed with the determination of its activity by spectrophotometry ^9,10.

TREATMENT

Treatment of patients with MetHba should be guided, primarily, by the severity of the disorder ^{2,6,17,19,20,32}. Blood levels of MetHb represent a secondary parameter in the definition of the treatment.

Usually, the symptoms are mild. In those cases, treatment consists of removing the inducing agent, administration of high-flow O₂, observation, and evolutive co-oximetric assessment ^6,9,20. After discontinuation of the causative agent, fMetHb returns to baseline levels within 36 hours ²⁵. The use of supplementary O₂ increases plasma levels of dissolved O₂, contributing, discretely, to the improvement of DO₂ and oxygen consumption (VO₂) during tissue hypoxia. Hyperoxic pulmonary ventilation (inspired fraction of O₂ of 1.0) can accelerate the degradation of MetHb and prolong the survival of pigs submitted to lethal acute MetHba ^{2,3,5,7,9,20-29}

In situations of significant clinical manifestations (e.g., dizziness, headache, anxiety, dyspnea, symptoms of low cardiac output, somnolence, and seizures), besides the basic conduct mentioned, methylene blue should be used as a specific antidote. Several authors suggest that methylene blue should be used with MetHb above 30%, regardless of the presence or absence of symptoms ^{2,3,5,7,9,20,25,29}. This is especially recommended when the patient is unconscious (e.g., head trauma, deep sedation, or general anesthesia). Evidence of tissue hypoxia obtained by the usual monitoring - metabolic acidosis, hyperlactatemia, tachycardia, changes in ST segment, cardiovascular shock - can be a late development and might result in severe damages and irreversible sequela ²⁰.

As mentioned before, cases of congenital MetHba evolve with elevated levels of fMetHb (up to 35% to 40%) without symptoms of hypoxia ^8-10,12. However, several conditions leading to imbalances in the global supply/demand ratio of O₂ in those individuals (SIRS, cardiopulmonary disorders, anemia, etc.) can cause clinical decompensation ^6,31,32. Similarly, exposure to oxidizing drugs can increase the levels of MetHb, leading to the development of acute symptoms ^8,12,32. Therefore, the decision to treat or not should be individualized and oriented according to the clinical presentation ^41,42.

Methylene blue is a thiazine dye with dose-dependent antiseptic and oxidizing properties ⁵. During its use, the alternative enzymatic system (NADPH methemoglobin reductase) becomes fundamental in the reduction of MetHb. Methylene blue activates NADPH methemoglobin reductase, which reduces methylene blue to methylene leucoblue, which transforms MetHb in HHb by a non-enzymatic mechanism (Figure 1). In reality, methylene blue is an oxidizer; it is its metabolic by-product - methylene leucoblue - that reduces MetHb ¹.

The recommended dose of methylene blue ranges from 1 to 2 mg.kg^-1, administered intravenously as a 1% solution over 5 minutes ^9,31. It can also be administered by the oral or intra-osseous routes in selected cases ¹³. The subcutaneous administration of this drug is associated with abscess formation at the injection site ⁵. The levels of fMetHb fall significantly 30 to 60 minutes after the first dose ^9,24. Additional doses can be administered every hour if necessary, up to a maximum total dose of 7 mg.kg^-1. Fast intravenous administration or the use of doses above the recommended dose can cause thoracic pain, dyspnea, hypertension, diaphoresis, and paradoxal increase of fMetHb ^5,6,9,43,44. Doses above 15 mg.kg^-1 cause direct damage of red blood cells and hemolysis with Heinz bodies ⁵. This drug should be administered carefully in patients with renal failure, since both methylene blue and leucoblue are slowly excreted by the kidneys ⁵. During treatment, the urine has a bluish tint. The same occurs, in varying degrees, to the skin and mucous membranes, hindering the interpretation of cyanosis after the treatment ^5,17. Gastrointestinal symptoms may also be seen and, rarely, anaphylactic reaction ³⁰. The bispectral index (BIS) may show marked reduction after treatment with ethylene blue ⁴³.

In cases of congenital MetHba, only patients with deficiency of CB5R reductase show consistent results to methylene blue. In HbM disease, patients do not show adequate response to exogenous electron donors because the enzymatic machinery responsible for the reductive activity of red blood cells is normal and iron oxidation is stabilized by the globin chain ⁸. In general, methylene blue is not indicated in cases of HbM ³⁴.

Other causes of unresponsiveness to methylene blue include: NADPH methemoglobin reductase deficiency, glucose-6-fosfate dehydrogenase (G6PD) deficiency, and the presence of SHb erroneously identified as MetHb by the co-oximeter ^45,46. In G6PD deficiency, red blood cells do not produce enough NADPH to reduce methylene blue to methylene leucoblue; N-acetyl-cysteine (another electron donor) has been used on those cases ⁴⁵. Other treatments for MetHba include ascorbic acid, exsanguination-transfusion, and hyperbaric oxygen therapy. Selected cases of non-severe NADH-MR deficiency can be treated with the intravenous administration 300 to 1,000 mg of ascorbic acid daily ⁹. On the other hand, acquired (acute) MetHba does not respond to ascorbic acid because its capacity to reduce MetHb is much inferior to that of endogenous enzymatic systems ¹⁰. Hyperbaric oxygen therapy increases the level of O₂ dissolved in the plasma and brings CO₂ close to the minimum necessary to maintain the metabolism, even in the of severe anemia ²⁴. With hyperbaric treatment it is possible to maintain the DO₂ temporarily, until the oxygen carrying capacity is restored with exsanguination-transfusion ^24,38. Therefore, both hyperbaric oxygen therapy and exsanguination-transfusion are reserved for severe cases that do not respond to methylene blue ²⁹. Those patients also benefit from ventilatory and cardiovascular support, and are better followed in the intensive care unit ¹³.

CONCLUSION

MetHba is a syndrome with multiple etiologies, including different congenital changes and toxic reactions to several chemical agents, but its prevalence is unknown. Since it presents frequently in the perioperative period, the diagnosis should be considered in cases of severe cyanosis non-responsive to oxygen administration, after ruling out cardiopulmonary dysfunction. Artifacts and uncertainties related with pulse oximetry and conventional arterial blood gas determination can both suggest the diagnosis and hinder institution and follow-up of the treatment. Only with the knowledge of those particularities it is possible to institute adequate conducts.

VOCABULARY

CaO₂ - arterial oxygen content

CB5R - cytochrome B5-reductase

COHb - carboxyhemoglobin

DO₂ - oxygen delivery

dysHb - dyshemoglobin

Fe²⁺ - ferrous ion

Fe³⁺ - ferric ion

fMetHb - fraction of methemoglobin

fO2Hb - fraction of oxyhemoglobin or fractional hemoglobin saturation

O2Hb - oxyhemoglobin

G6PD - glucose-6-fosfate dehydrogenase

Hb - hemoglobin

HbA - adult hemoglobin

HbF - fetal hemoglobin

HbM - hemoglobin M

HHb - reduced hemoglobin

MetHb - methemoglobin

MetHba - methemoglobinemia

NADH-MR - NADH-methemoglobin reductase

PaO₂ - partial arterial oxygen pressure

SHb - sulfhemoglobin

SaO₂ - functional saturation of arterial hemoglobin

SpO₂ - hemoglobin saturation obtained by pulse oximetry

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Publication Dates

• Publication in this collection
  14 Nov 2008
• Date of issue
  Dec 2008

History

• Received
  16 Jan 2008
• Accepted
  18 Aug 2008