Services on Demand
Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.58 no.6 Campinas Nov./Dec. 2008
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
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
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
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.
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.
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.
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.
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 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 polycythemia8,33. 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 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.
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.
- 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
01. Udeh C, Bittikofer J, Sum-Ping STJ - Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth, 2001;13:128-130. [ Links ]
02. Yang JJ, Lin N, Lv R et al. - Methemoglobinemia misdiagnosed as ruptured ectopic pregnancy. Acta Anaesthesiol Scand, 2005; 49:586-588. [ Links ]
03. Greer FR, Shannon M - Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics, 2005;116:784-786. [ Links ]
04. Spraycar M - Stedman's Medical Dictionary, 26th Ed, Philadelphia, Williams & Wilkins, 1995;1101-1102. [ Links ]
05. Chui JSW, Poon WT, Chan KC et al. - Nitrite-induced methaemoglobinaemia aetiology, diagnosis and treatment. Anaesthesia, 2005;60:496-500. [ Links ]
06. Johnson D - Perioperative methemoglobinemia. Can J Anaesth, 2005;52:665-668. [ Links ]
07. Aepfelbacher FC, Breen P, Manning WJ - Methemoglobinemia and topical pharyngeal anesthesia. N Engl J Med, 2003;348: 85-86. [ Links ]
08. Kern K, Langevin PB - Methemoglobinemia after topical anesthesia with lidocaine and benzocaine for a difficult intubation. J Clin Anesth, 2000;12:167-172. [ Links ]
09. Haymond S, Cariappa R, Eby CS et al. - Laboratory assessment of oxygenation in methemoglobinemia. Clin Chem, 2005;51: 434-444 [ Links ]
10. Silva SS, Sajan IS, Underwood III, JP - Congenital methemoglobinemia: a rare cause of cyanosis in the newborn a case report. Pediatrics, 2003;112:e158-161. [ Links ]
11. Baraka AS, Ayoub CM, Kaddoum RN et al. - Severe oxyhemoglobin desaturation during induction of anesthesia in a patient with congenital methemoglobinemia. Anesthesiology, 2001;95: 1296-1297. [ Links ]
12. Prchal JT, Gregg XT - Red cell enzymes. Hematology 2005; 2005:19-23. [ Links ]
13. Suyama H, Morikawa S, Noma-Tanaka S et al. - Methemoglobinemia induced by automobile exhaust fumes. J Anesth, 2005; 19:333-335. [ Links ]
14. Jacka MJ, Kruger M, Glick N - Methemoglobinemia after transesophageal echocardiography: a life-threatening complication. J Clin Anesth, 2006;18:52-54. [ Links ]
15. Barker SJ, Curry J, Redford D et al. - Measurement of carboxyhemoglobin and methemoglobin by pulse oximetry. A human volunteer study. Anesthesiology, 2006;105: 892-897. [ Links ]
16. Rehman HU - Methemoglobinemia. West J Med, 2001;175:193-196. [ Links ]
17. Baraka AS, Ayoub CM, Yazbeck-Karam V et al. - Prophylactic methylene blue in a patient with congenital methemoglobinemia. Can J Anaesth, 2005;52:258-261. [ Links ]
18. Viallon A, Page Y, Bertrand JC - Methemoglobinemia due to riluzole. N Engl J Med, 2000;343:665-666. [ Links ]
19. Nguyen ST, Cabrales RE, Bashour A et al. - Benzocaine-induced methemoglobinemia. Anesth Analg, 2000;90:369-371. [ Links ]
20. Talarico JF, Metro DG - Presentation of dapsone-induced methemoglobinemia in a patient status post small bowel transplant. J Clin Anesth, 2005;17:568-570. [ Links ]
21. Noyes CD, Olufolabi AJ, Habib AS - Subtle desaturation and perioperative methemoglobinemia. The need for continued vigilance. Can J Anaesth, 2005;52:771-772. [ Links ]
22. Tsai TC, Peng SK, Shih YR et al. - Sulfadiazine-induced methemoglobinemia in a boy with thalassemia. Can J Anaesth, 2005; 52:1002-1003. [ Links ]
23. Kreeftenberg Jr HG, Braams R, Nauta P - Methemoglobinemia after low-dose prilocaine in an adult patient receiving barbiturate comedication. Anesth Analg, 2007;104:459-460. [ Links ]
24. Jansen T, Barnung S, Mortensen CR et al. - Isobutyl-nitrite-induced methemoglobinemia; treatment with an exchange blood transfusion during hyperbaric oxygenation. Acta Anaesthesiol Scand, 2003;47:1300-1301. [ Links ]
25. Yazbeck-Karam VG, Aouad MT, Kaddoum RN et al. - Methemoglobinemia after a blast injury. Anesthesiology 2004;100:448-449. [ Links ]
26. FDA Public Health Advisory. Benzocaine sprays marketed under different names, including Hurricaine, Topex, and Cetacaine. February 10, 2006. [ Links ]
27. Gupta SK, Gupta RC, Seth AK et al. - Methaemoglobinemia in areas of high nitrate concentration in drinking water. Natl Med J India, 2000;13:58-61. [ Links ]
28. Gupta SK, Gupta RC, Seth AK et al. - Adaptation of cytochrome-b5 reductase activity and methaemoglobinaemia in areas with a high nitrate concentration in drinking-water. Bull World Health Organ, 1999;77:749-753. [ Links ]
29. Askew GL, Finelli L, Genese CA et al. - Boilerbaisse: an outbreak of methemoglobinemia in New Jersey in 1992. Pediatrics. 1994; 94:381-4. [ Links ]
30. König MW, Dolinski SY - A 74-year-old woman with desaturation following surgery. Chest, 2003;123:613-616. [ Links ]
31. Sather JE, Tantawy H - Toxins. Anesthesiol Clin, 2006;24:647-670. [ Links ]
32. Hegedus F, Herb K - Benzocaine-induced methemoglobinemia. Anesth Prog, 2005;52:136-139. [ Links ]
33. Maurtua MA, Emmerling L, Ebrahim Z - Anesthetic management of a patient with congenital methemoglobiemia. J Clin Anesth, 2004;16:455-457. [ Links ]
34. Stucke AG, Riess ML, Connoly LA - Hemoglobin M (Milwaukee) affects arterial oxygen saturation and makes pulse oximetry unreliable. Anesthesiology 2006;104:887-888. [ Links ]
35. Barker SJ, Tremper KK - Pulse Oximetry, em: Ehrenwerth J, Eisenkraft J Anesthesia Equipment. Principles and Applications. Mosby 1993:249-264. [ Links ]
36. Barker SJ, Tremper KK, Hyatt J - Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology, 1989;70:112-117. [ Links ]
37. Burgoyne LL, Jay DW, Bikhazi GB et al. - Isosulfan blue causes factitious methemoglobinemia in an infant. Ped Anesth, 2005; 15:1116-1119. [ Links ]
38. Zijlstra WG - Clinical assessment of oxygen transport-related quantities. Clin Chem, 2005;51:291-292. [ Links ]
39. Meier J, Pape A, Lauscher P et al. - Hyperoxia in lethal methemoglobinemia: Effects on oxygen transport, tissue oxygenation, and survival in pigs. Crit Care Med, 2005;33:1582-1588. [ Links ]
40. Meier J, Kemming GI, Kisch-Wedel H et al. - Hyperoxic ventilation reduces 6-hour mortality at the critical hemoglobin concentration. Anesthesiology, 2004;100:70-76. [ Links ]
41. Woodman A, Bright J, Marrs T - The effect of oxygen on in vitro studies on methemoglobin production in man and dog blood using 4-dimethylaminophenol. Hemoglobin 1988; 12:53-60. [ Links ]
42. Sharma D, Pandia MP, Bithal PK - Methylene blue in congenital methemoglobinemia: prophylactic or on demand? Can J Anesth., 2005; 52:884-885. [ Links ]
43. Matisoff AJ, Panni MK - Methylene blue treatment for methemoglobinemia and subsequent dramatic bispectral index reduction. Anesthesiology, 2006;105:228. [ Links ]
44. Siebert C, Kroeber S, Lutter N - Prolonged postoperative disorientation after methylene blue infusion during parathyrodectomy. Anesth Analg, 2005;101:608-609. [ Links ]
45. Maddali MM, Fahr J - Postoperative methemoglobinemia with associated G-6-P-D deficiency in infant cardiac surgery enigmas in diagnosis and management. Ped Anesth, 2005;15: 334-337. [ Links ]
46. Baraka AS, Ayoub CM, Yazbeck-Karam V et al. - Prophylactic methylene blue in a patient with congenital methemoglobinemia. Can J Anaesth, 2005;52:258-261. [ Links ]
Correspondence to: Submitted em 16
de janeiro de 2008 *
Received from Serviço de Anestesiologia do Instituto Nacional de Cardiologia,
Rio de Janeiro, RJ
Dra. Tatiana Souza do Nascimento
Av. Pref. Dulcídio Cardoso, 1.200/1606 - Bl. 01 - Barra da Tijuca
22620-311 Rio de Janeiro, RJ
Accepted para publicação em 18 de agosto de 2008
Submitted em 16
de janeiro de 2008
* Received from Serviço de Anestesiologia do Instituto Nacional de Cardiologia, Rio de Janeiro, RJ