Abstract

Methemoglobinemia occasionally causes cyanosis particularly in congenital methemoglobinemia. Avoidance of exposure to oxidizing agents is important for patients with congenital methemoglobinemia because of their deficient enzymatic pathways and decreased oxygen-carrying capacity. Here, we present a patient with preoperatively undiagnosed congenital methemoglobinemia who underwent uterine myomectomy under general anesthesia. The patient was a 35-year-old woman who displayed a low pulse oximetry reading of 91% prior to induction of anesthesia.Methemoglobinemia was first suspected intraoperatively because of a mismatch of SpO2 of finger pulse oximetry and SaO2 of arterial blood, and was later confirmed by multiplewavelength CO-oximetry. The pathophysiology, etiology, clinical manifestations, anesthetic considerations, and treatment options of methemoglobinemia are discussed.

Keywords

methemoglobinemia: congenital; oxygen: saturation;

1. Introduction

Methemoglobinemia is a rare disorder which is the result of oxidation of the iron molecules of hemoglobin, changing from the ferrous state (Fe²⁺) to a ferric state (Fe³⁺). This reaction continuously occurs in vivo and is reduced predominantly by cytochrome-b5 reductase, and so the methemoglobin concentration remains less than 2% in healthy humans. Hemoglobin in the ferric state is incapable of binding oxygen and without reversion to the ferrous state it may lead to life-threatening hypoxemia.^1,2 There are two types of methemoglobinemia—acquired and congenital. Acquired methemoglobinemia is more common than congenital methemoglobinemia.

Acquired methemoglobinemia is produced from the oxidation of hemoglobin by drugs or chemicals, usually exogenous oxidants, such as nitrites, local anesthetics, and sulfonamides. When the production of methemoglobin exceeds its reduction, methemoglobinemia occurs and potentially compromises tissue oxygenation. Congenital methemoglobinemia is caused by a deficiency of cytochrome-b5 reductase, and patients with congenital methemoglobinemia are susceptible to exogenous oxidants because of their deficient enzymatic pathways. We report a patient with preoperatively undiagnosed congenital methemoglobinemia undergoing uterine myomectomy. The pathophysiology, etiology, clinical manifestations, anesthetic considerations, and treatment options of methemoglobinemia are discussed.

2. Case Report

A 35-year-old female patient, with a height of 173 cm and weight of 63 kg, with American Society of Anesthesiology class Ι and no history of drug allergies, was scheduled for uterine myomectomy. The patient’s past medical history was unremarkable. The findings at physical examination were also unremarkable, except for mildly cyanotic lips and nails. Preoperative laboratory data showed a hematocrit of 42%, hemoglobin of 14.6 g/dL and white blood cell count of 8.5 × 10³ /μL. Electrocardiography showed normal sinus rhythm. Chest radiography showed clear lung fields and a heart of normal size and contour. There were no abnormalities of the hilar, mediastinal, pleural, or bony structures.

In the operating room, the patient’s initial pulse oximetry reading was 91% upon breathing ambient air. Following preoxygenation with 100% oxygen for 3 minutes, anesthesia was induced with 2.5 mg midazolam, 75 μg fentanyl, 50 mg lidocaine, 2 mg/kg propofol and 50 mg rocuronium. Initially, anesthesia was maintained with sevoflurane 2−3% in a mixture of 50:50 oxygen and air. The SpO₂ at this point was 93%. Vital signs were stable but no improvement in SpO₂ was seen following the switch to oxygen supplementation of 100%. When the operation began, chocolate-brown colored blood was noted by the operating gynecologist, while the patient’s fingers and lips were found to be cyanotic. An arterial blood sample was obtained for gas analysis, which revealed a pH of 7.522, arterial oxygen saturation (SaO₂) of 99.9%, PaO₂ of 454.7 mmHg and base excess of 1.2 mmol/L. After half an hour, a repeated arterial blood gas analysis revealed a pH of 7.464, SaO₂ of 99.9%, PaO₂ of 599.5 mmHg and base excess of 0.3 mmol/L, while the SpO₂ readings were around 93−94%. Methemoglobinemia was suspected because of the mismatch of SpO₂ and SaO₂. Therefore, at this juncture, a blood sample was drawn for hemoglobin analysis and a methemoglobin level of 13.6% was confirmed by CO-oximetry. The surgery lasted for 2 hours and the endotracheal tube was removed smoothly. The SpO₂ read 93% in the recovery room with oxygen support by facemask at a concentration of 40%, and oxygen was continuously used in the ward. The gynecologist warned that the patient should avoid exposure to oxidizing agents. The postoperative course was uneventful and the patient was discharged 2 days later. The patient’s methemoglobin level was rechecked at follow-up visits. The methemoglobin levels on postoperative day 4, 1 month, and 2 months later were 15.5%, 8.6%, and 11.9%, respectively. The pulse oximetry examined during follow-up visits remained at 91% without clinical signs of cyanosis.

The findings suggested that this patient had congenital methemoglobinemia.

3. Discussion

Monitoring arterial oxygenation by pulse oximetry is a standard method in anesthetic practice. A low pulse oximetry reading of 91% in an asymptomatic patient with neither cardiovascular nor pulmonary disease upon breathing ambient air was an unexpected finding. We focused our attention on the airway, pulmonary and cardiovascular systems in search of the cause, but nothing remarkable was noted.

Because of a mismatch between SaO₂ and SpO₂, which was not resolved after oxygen therapy, this anomaly alerted us to the possibility of abnormal hemoglobin. Methemoglobinemia and sulfhemoglobinemia should be carefully differentiated. With the typical presentation of chocolate-brown colored blood and normal arterial oxygen tension, this patient was likely to have methemoglobinemia. Because pulse oximetry makes use of only two wavelengths (660 nm and 940 nm), it can determine values of only two hemoglobin species—oxyhemoglobin and reduced hemoglobin.1,3 The pulse oximetry readings may be inaccurate or not informative if patients have higher levels of methemoglobin, carboxyhemoglobin or other abnormal hemoglobin species.^1,3 CO-oximetry, using multiple wavelengths, can mea sure the levels of hemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin, and can demonstrate values in fractional saturation. In this patient, the diagnosis of methemoglobinemia was confirmed by analysis of methemoglobin, which was found to be 13.6%.

Methemoglobin is formed by oxidation of the iron molecules of hemoglobin from a ferrous (Fe²⁺) state to a ferric (Fe³⁺) state. Hemoglobin in the ferric state is incapable of transporting oxygen, impairs the release of oxygen and shifts the oxyhemoglobindissociation curve to the left.^1,3 Methemoglobin is reduced to deoxyhemoglobin predominantly by cytochrome-b5 reductase, and so the methemoglobin concentration remains less than 2% in normal conditions. Clinically significant methemoglobinemia may occur because of one of the following conditions: (1) a greatly increased production of methemoglobin; (2) an abnormal hemoglobin which, once oxidized, is resistant to reduction; (3) decreased activity of erythrocyte NADH-cytochromeb5 reductase.^1,4

Methemoglobinemia can be classified as congenital or acquired. There are three types of congenital methemoglobinemia. Two are inherited as autosomal recessive traits—cytochrome-b5 reductase deficiency and cytochrome-b5 deficiency. The third type is an autosomal dominant disorder, hemoglobin M disease, in which there is a mutation in the globin molecule. Because of the absence of neurologic disorders, cytochrome-b5 reductase deficiency may be the cause of methemoglobinemia in this patient. It is more prevalent in certain racial and ethnic groups such as Eskimos, American Indians, Puerto Ricans and Mediterranean populations. It tends to occur sporadically in other racial groups.⁴ The carrier or heterozygous state of patients is characterized by an intermediate level of enzyme activity, and thus they are more susceptible to the effects of oxidizing agents.^2,4 Acquired methemoglobinemia is caused by oxidizing agents. Hemoglo bin is continuously oxidized in vivo from the ferrous state to the ferric state. The rate of such oxidation is accelerated by many drugs and toxic chemicals, the former including lidocaine, benzocaine, prilocaine and nitrites, which are often used in the perioperative period.⁵ There are many case reports about methemoglobinemia induced by topical anesthetics, including lidocaine, benzocaine, and prilocaine.⁶⁻⁸ The more common ones are benzocaine and prilocaine. The incidence of benzocaineinduced methemoglobinemia according to the Mayo Clinic experience was 1 in 1499 cases and the outcome was good.⁷ There are a few case reports about methemoglobinemia associated with topical use of lidocaine alone.^8,9 Lidocaine alone causing methemoglobinemia in humans is inconclusive, as the results of a human study found that intravenous lidocaine only produced clinically mild methemoglobinemia.^8,9 There was no oxygen desaturation noted after injection of lidocaine in that patient. The course of congenital methemoglobinemia is generally benign (seldom reaching methemoglobin levels above 30%), but prevention of exposure to oxidizing agents is still very important because of patients’ deficient enzymatic pathways and decreased oxygencarrying capacity.

Patients with undiagnosed congenital methemoglobinemia usually have methemoglobin levels between 15% and 30%. Cyanosis becomes apparent at methemoglobin levels over 15%, and patients generally become symptomatic only when their methemoglobin level exceeds 30%.^5,10 Severe methemoglobinemia (> 50%) usually occurs with exposure to oxidizing agents. Commonly described symptoms are dyspnea, headache, lightheadedness, confusion, and lethargy.⁵ Levels of methemoglobin exceeding 60−70% may be associated with vascular collapse, coma, and death.¹¹ Severity of symptoms may be exacerbated by complicating medical conditions and other factors, such as heart disease, anemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, infancy and old age.¹²

Therapy of methemoglobinemia is based on the degree of methemoglobin levels, severity of symptoms, the etiological process (acute or chronic), and the presence of complicating medical conditions (such as cardiovascular disease and pulmonary disease). In a patient with acute toxic methemoglobinemia, the first step in treatment consists of correcting metabolic abnormalities, discontinuing potential offending pharmaceuticals, and maintaining dextrose-containing fluids, which can adequately supply substrates for production of NADH and NADPH.

Methylene blue is an effective treatment for patients with methemoglobinemia because it activates NADPH diaphorase, an enzyme capable of reducing methylene blue to leukomethylene blue, and the latter, via a non-enzymatic pathway, reduces methemoglobin to hemoglobin. The intravenous administration of 1−2 mg/kg methylene blue over a period of 5 minutes is the preferred treatment dose. The response is prompt and a rapid decrease in methemoglobin can be expected within 1 hour. The administration of methylene blue can be repeated if necessary in 30−60 minutes provided the total does not exceed a maximum dosage of 7 mg/kg. It should be noted that excessive administration of methylene blue may produce hemolysis because methylene blue can also act as an oxidant.^13,14 In addition, it is still controversial to use prophylactic methylene blue in a patient with congenital methemoglobinemia.^15,16 In our patient, the vital signs including heart rate and blood pressure did not deteriorate in spite of low SpO₂. Also, since the arterial blood gas analysis did not show metabolic acidosis, it may indicate that our patient was not in a hypoxic state. The use of methylene blue to decrease methemoglobin levels should be attempted only when increased methemoglobin leads to impaired oxygenation, because methylene blue can also act as an oxidant.¹⁶ If there is no significant resolution, patients should be suspected of having hemoglobin M disease, sulfhemoglobinemia, NADPH reductase deficiency, or G6PD deficiency.^15,17 In such conditions, methylene blue will not only fail to have the desired effect on methemoglobin level but also may produce hemolysis or increase the level of methemoglobin.¹⁵ Exchange transfusion should be considered in these patients.¹⁸

Methemoglobinemia commonly results from exposure to oxidizing agents because congenital methemoglobinemia is extremely rare. The methemoglobin level of this patient did not return to the normal range after 2 months, and physical examination still revealed mild cyanosis of the lips and nails. Congenital methemoglobinemia was diagnosed by our hematologist. Because of the stable hemodynamics and absence of metabolic acidosis, the patient’s oxygen-carrying capacity could be adequate. When the methemoglobin level is less than 20% and oxygenation is adequate, conservative treatment could suffice. However, the administration of 100% oxygen, correcting metabolic acidosis, prescribing methylene blue, and performing an exchange blood transfusion should be considered when the patient is symptomatic.

In conclusion, avoidance of exposure to oxidizing agents is important in patients with congenital methemoglobinemia because of their deficient enzymatic pathways and decreased oxygen-carrying capacity. Preoperative considerations for congenital methemoglobinemia include the supplementation of oxygen of higher concentration, examination of methemoglobin by CO-oximetry to determine whether the oxygenation is adequate, avoidance of the use of oxidizing drugs (such as lidocaine, benzocaine, prilocaine, nitroglycerin), and treatment with methylene blue if methemoglobinemia deteriorates severely. If the patient is not responsive, exchange transfusion should be considered. To deliver safe anesthesia in patients with congenital methemoglobinemia, it is imperative to recognize the nature of this rare disease, and to know how to correctly treat the patient who has sustained oxygen desaturation.