The development of methemoglobinemia requires rapid recognition, confirmation, and treatment. This case study describes the development, diagnosis, and management of a 63-year-old male scheduled for a laparoscopic cholecystectomy with an intraoperative cholangiogram who developed methemoglobinemia after benzocaine was given for intubation.

Objectives—Upon completion of this activity, the learner will be able to: (1) define methemoglobinemia; (2) identify at least 3 causes of methemoglobinemia; (3) describe the signs and symptoms of methemoglobinemia; (4) discuss the primary treatment options for methemoglobinemia.

THE DEVELOPMENT OF methemoglobinemia after the use of a local anesthetic for intubation is a life-threatening situation. Methemoglobinemia impairs the ability of the hemoglobin to transport oxygen and carbon dioxide, resulting in tissue hypoxemia. The development of methemoglobinemia requires rapid recognition, confirmation, and treatment to anticipate potential problems and avoid negative outcomes. This case study describes the assessment and management of methemoglobinemia in the PACU.

The preoperative labs included a complete blood count, electrolytes, blood uremic nitrogen (BUN), creatinine, pro time, and partial thromboplastin time (PTT) (Table 1). In addition, the patient was typed and cross-matched for two units of packed red blood cells.

Physical assessment revealed limited mouth and neck motion, and the patient also reported encountering difficulty with airway maintenance with prior surgeries. The anesthesia plan, therefore, included an awake, fiberoptic intubation and general anesthesia. The anesthesiologist reviewed and discussed this plan with the patient and he consented.

The preoperative phase was uneventful. The patient was prepped in the usual manner, and bilateral sequential compression sleeves were applied. Preop medications included famotidine 20 mg intravenous (IV), glycopyrrolate 0.2 mg IV, and midazolam 2 mg IV. In addition, the patient received lidocaine treatment via an aerosol nebulizer prior to surgery to numb the upper airways.

The patient was given albuterol 8 puffs through the anesthesia circuit; however, the oxygen saturation level showed no signs of improvement after the treatment and increase in FiO₂. As the oxygen saturation level continued to drop into the 90 to 92% range, the focus turned to ruling out other potential causes. An intraoperative chest x-ray was performed, and the results were within normal limits and the ET placement was reconfirmed. Arterial blood gases (ABGs) were drawn and except for a very slight drop in pH and HCO₃, the results fell within the normal range (Table 2). Because co-oximetry blood gas analysis was not requested, no carboxyhemoglobin or methemoglobin levels were recorded.

In an effort to rule out other potential causes, the patient was given furosemide 10 mg IV to address any volume overload issues. Midazolam 2 mg and morphine sulfate 10 mg IV were also given to ensure adequate sedation. The surgical procedure was completed, and the patient was transferred to the PACU in guarded condition.

In PACU the anesthesiologist ordered a second albuterol treatment with no improvement noted. The patient’s condition continued to be precarious without any visible clues or causes for the hypoxemia and cyanosis. Deciding that close monitoring and frequent lab work would be necessary; the anesthesiologist inserted a left radial arterial line. Upon insertion, the anesthesiologist noticed that the blood was a dark brown color. ABGs were drawn and a co-oximetry analysis requested; the results showed an elevated pO₂ (564.5 mm Hg) and methemoglobin levels (29.0%, normal range is 0 to 1.5%) (Table 2).

A diagnosis of methemoglobinemia was made on the basis of the signs and symptoms of the patient, cyanosis not responding to oxygen therapy, and the elevated methemoglobin level. The patient had also received two drugs (lidocaine and benzocaine), implicated in causing methemoglobinemia. Methylene blue 1 mg/kg in 50 mL of 0.9 normal saline was given intravenous piggyback over 5 minutes. Initially, the patient’s O₂ saturation dropped to 85% with a slight decrease in blood pressure. Oxygen saturation and blood pressure then returned to normal limits within minutes. Forty minutes after the start of the methylene blue infusion, the O₂ saturation remained at 97%, and there was a noticeable decrease in cyanosis. The patient was more responsive, following commands, and he indicated that he was having pain. Follow-up ABGs were drawn 50 minutes after the infusion; the results indicated a dramatic drop in MHb level (Table 2).

The patient continued to show significant improvements and was soon extubated and placed on a non-rebreather mask without any signs of respiratory difficulty. Approximately 4 hours after PACU admission, the patient was transferred to a medical-surgical floor with oxygen at 2 L/min by nasal cannula, maintaining an O₂ saturation in the 98 to 100% range.

Hemoglobin is the functional component of the erythrocyte and is a conjugated protein that transports oxygen. A molecule of hemoglobin is composed of two pairs of polypeptide chains (globin) and four heme groups, each containing one atom of ferrous iron (Fe++). The heme groups are located near the surface of the molecule and reversibly bind with oxygen.1

Methemoglobinemia refers to the oxidation of ferrous iron (Fe++) to ferric iron (Fe+++) within the hemoglobin molecule.2–6 This oxidation process involves the extraction of electrons from a substrate (i.e., loss of an electron). This reaction prevents the hemoglobin from carrying oxygen and carbon dioxide, resulting in tissue hypoxemia, cyanosis, metabolic acidosis, and in severe cases, death.6 Methemoglobin is incapable of oxygen binding until an electron is regained, reducing the heme molecule back to its ferrous (Fe++) state. In addition, the oxidized heme increases the oxygen affinity of the remaining functional heme groups,7 shifting the oxyhemoglobin dissociation curve to the left.1,3,4 Therefore, cellular hypoxia is exaggerated by less efficient unloading of oxygen in the central organs and peripheral tissues.1

In erythrocytes, the ferrous iron of hemoglobin undergoes slow oxidation at a rate of about 3% per day, but there are several intracellular pathways that help to maintain intraerythrocytic MHb concentrations at less than 1%.7 The most important of these pathways is nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase, which allows NADH to donate an electron to cytochrome b5, which then nonenzymatically transfers the electron to methemoglobin, thereby reducing it to ferrous hemoglobin. The secondary and much slower pathway of methemoglobin reduction is through the direct transfer of electrons from ascorbic acid and glutathione.1 Protective mechanisms against oxidative stress include sulfation enzymes, ascorbic acid, and glutathione. These enzymes and peptides serve to detoxify oxidative exogenous chemicals and thereby indirectly prevent methemoglobinemia.6 Another enzyme that reduces MHb is reduced nicotinamide adenine dinucleotide phosphate (NADPH)-MHb reductase; however, this pathway plays a very minor role because it is physiologically dormant and is dependent on NADPH provided by the pentose phosphate pathway.1,7

Three conditions can cause the accumulation of methemoglobin to occur: acquired methemoglobinemia (when the rate of heme oxidation is increased), NADH-cytochrome b5 reductase deficiency (when methemoglobin reduction is limited by a lack in enzymatic activity), or hemoglobin M disorder (when a structural abnormality in the red cells stabilize hemoglobin in the oxidized state). Acquired methemoglobinemia is the most commonly implicated; in contrast, the latter two forms are rare hereditary disorders.1

Genetic methemoglobinemia is a rare disorder that is caused by a deficiency of enzymes NADH cytochrome-b5 reductase or cytochrome-b5 deficiency.6,7 The NADH-MHb reductase is responsible for 95% of the reduction of the ferric iron in MHb to a ferrous state in vivo.7 This autosomal recessive disorder is common among Native Americans of Alaskan or Inuit descent and results in unusual susceptibility to oxidant stress caused by drugs or toxins.7 These patients present at, or very shortly after, birth with cyanosis.5,6 Patients may appear cyanotic but are usually asymptomatic. Ascorbic acid treatment enhances the NADPH-Mhb reductase activity; however, this is often initiated only for cosmetic purposes.5,7

Hemoglobin M is an autosomal-dominant inherited disorder in which the hemoglobin molecule itself is abnormal.3,6 Although there are several variants, the abnormalities have the same result: iron is maintained in its ferric form.5,7 These hemoglobin variants are associated with cyanosis, which is present from birth.5,7 Methemoglobinemia due to hemoglobin M does not respond to ascorbic acid or methylene blue.5

Acquired methemoglobinemia results when the rate of formation of MHb exceeds the rate of reduction after exposure to certain substances. There are several causes including a number of pharmaceutical agents (Table 3). The most common causes are exposure to nitrates3,7,8 (nitroglycerine, nitroprusside, and silver nitrate), sulfonamides,3,8 phenacetin,3,5 antimalarials3,5 (chloroquine and primaquine), metoclopramide, dapsone,5,8 and local anesthetics5 (benzocaine,8 lidocaine, and prilocaine).3,7 In addition, toxic exposures to aniline dyes, inhaled nitrates, nitrobenzene, and certain herbicides can cause methemoglobinemia.3,7

Although topical anesthetics agents generally have a wide margin of safety, infrequently they may cause potentially life-threatening methemoglobinemia. Almost all topical anesthetic preparations have been associated with methemoglobinemia; however, benzocaine is the most commonly implicated agent.7 Physicians rarely consider the amount of benzocaine delivered, because they liberally spray this topical anesthetic into a patient’s oropharynx. The manufacture recommends a 1-second or less spraying time for normal topical anesthesia. Spray times in excess of 2 seconds are contraindicated. Benzocaine may be rapidly absorbed across mucosal membranes and into the central circulation, where it can lead to the development of methemoglobinemia.1

The Federal Drug Administration MEDWATCH database contains about 100 reports of methemoglobinemia related to the use of benzocaine. However, this is probably only a small fraction of actual cases experienced in the United States.9 Based on data reported from 1 institution, the incidence has been estimated to be 1 in 7,000 exposures.7 Cases have been reported after application to the pharyngeal mucosa (for endoscopy, bronchoscopy, and intubation), rectal mucosa (for rectal probe insertion, sigmoidoscopy, and colonscopy), vaginal mucosa (using antipruritic creams), skin, and after toxic ingestion.7

It is not clear why some individuals are more prone to developing methemoglobinemia than others.1 Predisposing factors include age (infants under 6 months of age and older patients with cardiac problems may be sensitive to even low MHg levels), the status of the area that is being sprayed (inflamed areas absorb more drug), concomitant use of other drugs that also have been implicated in causing methemoglobinemia, and the genetic makeup of the patient (due to altered hemoglobin, G6PD deficiency, or methemoglobin reductase enzyme deficiency).9 Septic patients are also more prone to methemoglobinemia because large amounts of nitric oxide are released in patients with sepsis, and the nitric oxide is converted to MHb and nitrate.5

More than half of the cases reported in the literature involved infants and the elderly.7 Infants are particularly susceptible because of a limited capacity for methemoglobin reduction during the first months of life. Enzymatic activity for methemoglobin reduction reaches adult levels by 6 months of age.1

The signs and symptoms commonly displayed in a methemoglobinemia crisis depend on the circulating level of MHb. Levels greater than 15% are associated with cyanosis, headache, lethargy, tachycardia, weakness, and dizziness. Dyspnea, acidosis, cardiac dysrhythmias, heart failure, seizures, and coma may occur at levels exceeding 45%.7 MHb levels above 70% are generally associated with high mortality. Clinical effects may appear earlier and be more severe in patients with underlying anemia or cardiopulmonary disorders.7

The diagnosis of methemoglobinemia should be suspected in patients with unexplained cyanosis,3 a decrease in oxygen saturation, and no demonstrable pulmonary or cardiac pathologic findings, including a normal chest radiograph.4 A diagnosis should also be suspected if a patient suddenly develops cyanosis after the application of a topical anesthetic agent.7 The administration of increased percentages of oxygen usually provide minimal or no change in arterial oxygen saturation.2,4 Administering supplemental oxygen raises the partial pressure of oxygen because of the dissolved component but adds little to either content or delivery to the cells.4

The key to the diagnosis of acquired methemoglobinemia is in the analysis of the arterial blood gas, using co-oximetry,1,2,7 which demonstrates a discrepancy between a low arterial oxyhemoglobin saturation (SaO₂) and a relatively high arterial oxygen partial pressure (PaO₂).1 A clinical clue may be in the observation that arterial blood has taken on the characteristic chocolate brownish coloration1,4,5,7,8 associated with methemoglobinemia.

Standard blood gas analyzers measure the partial pressure of oxygen PO₂ and calculate an oxygen saturation from this value.3 However, this estimated SO₂ is inaccurate because the MHb level is assumed to be zero.7 A co-oximeter, however, is a simplified spectophotomer that measures light absorbency at 4 different wavelengths. These wavelengths correspond to specific absorbency characteristics of deoxyhemoglobin, oxyhemoglobin, carboxyhemoglobin, and hemoglobin.6 Methemoglobin is not stable in blood samples; therefore, co-oximetry measurements should be obtained promptly with the rest of the blood gas analysis.1

The presence of MHb in blood will turn the blood chocolaty brown, as opposed to the dark red-violet color of deoxygenated blood. A second test that may be used to differentiate deoxyhemoglobin from MHb is to place 1 to 2 drops of the patient’s blood on any white filter paper. The MHb blood does not change on exposure to air over time, whereas the dark red-violet deoxyhemoglobin blood will brighten up over time when exposed to air.6

Assessment of oxygenation by pulse oximetry is inaccurate in the presence of methemoglobinemia.7 Pulse oximetry (SpO₂) does not reliably reflect the degree of desaturation1,2,5 and, depending on the severity of the methemoglobinemia, can under- or overestimate the degree of oxygenation.7 Frequently, pulse oximetry will give a reading of about 85%, despite a much lower actual arterial oxyhemoglobin saturation.1

The primary treatment of choice for MHb is the administration of methylene blue; however, not all patients with methemoglobinemia need to be treated with methylene blue. In the absence of serious underlying illness, MHb levels less than 30% usually resolve spontaneously over 15 to 20 hours without serious consequences.7 Methylene blue is given at 1 to 2 mg/kg intravenously over 5 minutes.1,2–5,7 Cyanosis will usually resolve within minutes; however, if it fails to do so, a second dose of 1 to 2 mg/kg may be repeated1,7 in 1 hour.7 Further repeated dosing of methylene blue is contraindicated because it can lead to hemolysis and persistent cyanosis.1

Methylene blue accelerates the action of the NADPH-MHb reductase, which is the alternative pathway for MHb reduction.3,4 NADPH-dependent methemoglobin reductase (dehydrogenase) is normally inactive in vivo because it lacks an endogenous electron acceptor. However, this pathway can become activated if an exogenous electron acceptor such as methylene blue or riboflavin, is added.1 Methylene blue is an oxidant: its metabolic product leukomethylene blue is the reducing agent.5 The NADPH-dependent enzyme reduces methylene blue to leukomethylene blue, which rapidly donates an election nonenzymatically to methemoglobin, reducing the heme molecule.1

For methylene blue to be effective, the patient must have an intact pentose phosphate pathway to regenerate NADPH. Individuals with glucose-6-phosphate dehydrogenase deficiency lack this pathway and will not only fail to respond to methylene blue1,5,7 but are at risk for developing hemolysis as a result of its oxidant properties.1,5 Methylene blue is usually well tolerated, although reported side effects include nausea, vomiting, diarrhea, a burning sensation in mouth and abdomen, dyspnea, restlessness, and perspiration. Doses exceeding 15 mg/kg may actually cause methemoglobinemia by direct oxidation of hemoglobin to MHb.7 Some drugs, such as dapsone, benzocaine, and aniline, produce a rebound methemoglobinemia in which MHg levels increase 4 to 12 hours after successful methylene blue therapy.5

Dextrose should also be given because the major source of NADH in the red blood cells is the catabolism of sugar through glycolysis. Dextrose is also necessary to form NADPH through the hexose monophosphate shunt, which is necessary for methylene blue to be effective.5

There is no specific antidote for life-threatening methemoglobinemia refractory to methylene blue. Ascorbic acid works slowly and probably is of no benefit in acute situations.7 If methylene blue is unsuccessful, the patient could be managed with transfusions or exchange transfusions1,3–5,7 to replenish reduced hemoglobin.1 Another alternative treatment includes hyperbaric oxygen therapy.3,7 However, the efficiency of these alternative therapies have not been studied.7

Methemoglobinemia is a life-threatening emergency with signs and symptoms that mimic many other respiratory crises. Diagnosing methemoglobinemia involves ruling out other medical emergencies, which can mimic the signs and symptoms observed. Only through arterial blood gas analysis with the use of co-oximetry can methemoglobinemia be accurately diagnosed. The diagnosis process also involves recognizing any potential exposures to methemoglobinemia causative agents, such as those listed in Table 3, and being aware of any genetic deficiencies. Only through an astute assessment and diagnosis process can quick and accurate treatment for this life-threatening medical emergency be provided.