A 14-year-old girl was brought to the ED by emergency medical services for dyspnea accompanied by her mother.
The patient reported that the dyspnea started suddenly that morning while she was on her way to school, and persisted throughout the day. She also reported generalized weakness and near syncope, stating she had collapsed twice earlier in the day due to the weakness. She denied fever, cough, nasal congestion, or sore throat but stated that she vomited once that morning. She denied any other abdominal complaints. Along with dizziness, she reported having a headache but denied any numbness or tingling.
Her mother noted a blue color around her daughter's lips when she arrived home from school and consequently took her to a local urgent care clinic, where she was found to be hypoxic and placed on supplemental oxygen. She was transported to the hospital for further evaluation.
The patient arrived in the ED in stable condition but appeared pale. She was an otherwise healthy female who took ibuprofen on occasion but no other medications. She had no previous hospitalizations and her only surgery was a tonsillectomy and adenoidectomy 7 years ago. She was adopted and was unaware of any birth complications or family history of medical problems. She reported being up-to-date on all vaccinations. The patient did not initially disclose a history of depression, but after healed lacerations were noted to her wrists she reported attempting suicide 5 weeks ago. However, she denied depression or suicidal ideations at this time. She denied ingesting any medications that day. The patient denied smoking, alcohol use, or illicit drug use.
The patient's vital signs were BP, 112/71 mm Hg; heart rate, 98 beats/minute; respirations, 26; oral temperature, 36.7° C (98.1° F); and SpO2, 90% on 4 L/min of supplemental oxygen by nasal cannula. Her mood and affect were appropriate and although she was tachypneic, she was able to speak in sentences, had no stridor, and was not in distress. Her head appeared atraumatic and normocephalic, external ocular movements were intact, and pupils were equal, round, and reactive to light. Her mucus membranes were pink and moist and her neck was supple and nontender without lymphadenopathy. She had normal capillary refill and regular rate and rhythm were noted on cardiac auscultation. Her breath sounds were normal without wheezes. Her abdomen was soft and nontender. She appeared pale but her skin was warm, dry, and intact without rashes. The patient had no cyanosis on examination in the ED.
While in the ED, the patient's SpO2 continued to decline, so she was switched to a non-rebreather mask with oxygen at 15 L/minute. Venous blood gases showed a pH of 7.41, PaCO2 of 41 cm H2O, PaO2 of 30 cm H2O (low normal range, 35 to 40 cm H2O), and serum bicarbonate of 25 mEq/L. The complete blood cell count, comprehensive metabolic panel, and urine drug screen were all within normal limits. Her ECG showed normal sinus rhythm. An anteroposterior (AP) view of the chest displayed a cardiac silhouette of normal size and shape with no acute pleuroparenchymal process identified. A d-dimer and contrast-enhanced helical CT pulmonary angiogram were performed to rule out a pulmonary embolism; both results were negative. While the patient was undergoing radiologic examinations, the nurse reported that the blood drawn for laboratory testing was dark in color. Once the blood was recognized as having a chocolate-brown appearance, methemoglobin levels were checked and found to be 26.5% (normal range, zero to 1.5%). The patient was diagnosed with methemoglobinemia.
One dose of methylene blue 2 mg/kg was administered IV over 10 minutes, followed by a 500-mL bolus of 0.9% sodium chloride solution. During administration of methylene blue, the patient's SpO2 dropped as low as 45% but she remained conscious and alert throughout. After the completion of treatment, her SpO2 improved, she was weaned from supplemental oxygen, and maintained an SpO2 greater than 95% on room air.
The patient was admitted to the pediatric ICU for monitoring and further observation. Follow-up tests showed that her methemoglobin value had decreased to 2%. The adoptive parent was questioned about the possibility of the patient having a glucose-6-phosphate dehydrogenase (G6PD) deficiency, due to concerns with methylene blue and the risk of hemolysis, but her status was unknown. Further testing with G6PD deficiency screening was negative. Her vital signs remained within normal limits, and she was asymptomatic the remainder of her hospital stay. The patient was questioned about common causes of methemoglobinemia but no specific cause was identified. She was discharged home with a list of medications, foods, and toxins that could cause acquired methemoglobinemia and advised to avoid contact with these substances.
Normally, less than 2% of the hemoglobin in the body is in the form of methemoglobin. Methemoglobinemia occurs when the levels exceed 2%, and can cause tissue hypoxia and death.1 Each hemoglobin molecule consists of four iron atoms that can each bind a molecule of oxygen. Methemoglobin occurs when hemoglobin is oxidized from the ferrous to ferric state, rendering the iron in heme unable to bind to oxygen and resulting in tissue hypoxia.2 Under normal physiologic conditions, red blood cells produce low levels of methemoglobin, which the body converts back to hemoglobin, and on average 99% of hemoglobin remains in the ferrous state.
Methemoglobinemia can be inherited or acquired. The case patient demonstrated acquired methemoglobinemia, which can occur when a patient is exposed to certain oxidizing agents.3 These agents include pesticides, fertilizers, nitrates, nitrites, topical anesthetics (benzocaine, lidocaine, and prilocaine), dapsone, primaquine, and aniline dyes (found in shoe polish, varnish, paint, and ink).4 Contaminated well water can have high levels of nitrates and nitrites, so the Environmental Protection Agency recommends annual testing for these substances.5 Less frequently, sickle cell crisis, sepsis, and gastrointestinal infections in children and infants can cause an acquired form of methemoglobinemia.1
The severity of clinical symptoms is directly related to the percentage of methemoglobin in the blood. At levels less than 15%, patients usually are asymptomatic and may have a grayish pigmentation of the skin. When levels exceed 15%, the patient will develop central cyanosis and a brown coloration of the blood. At levels of 20% to 50%, the patient may present with headache, dizziness, tachycardia, nausea, vomiting, syncope, dyspnea, and weakness. Levels at or greater than 50% can result in seizures, coma, and respiratory or cardiovascular failure caused by insufficient tissue oxygenation. Methemoglobin levels greater than 70% are generally fatal.1,4
Consider methemoglobinemia in all patients with cyanosis and low oxygen saturation after more common cardiovascular and pulmonary conditions are excluded. The patient will experience hypoxia refractory to treatment with 100% oxygen.1 A characteristic sign of methemoglobinemia is chocolate-colored arterial blood.6 Routine blood gas analysis cannot diagnose methemoglobinemia. The gold standard for diagnosis is an arterial blood gas analysis with co-oximetry. Co-oximetry measures the different concentrations of hemoglobin (oxyhemoglobin, deoxyhemobglobin, sulfhemoglobin, methemoglobin, and carboxyhemoglobin) using the absorption of light through the blood, which produces unique wavelengths.2,6 In co-oximetry, methylene blue, can be interpreted as methemoglobin due to their similar absorbance wavelengths. Because this can overestimate the concentration of methemoglobin, co-oximetry should be performed before patients are treated with methylene blue.1
Pulse oximetry is unreliable in patients with methemoglobinemia and during treatment with methylene blue, as it may appear falsely high or falsely low SpO2 depending on the methemoglobin level.4,7,8
As soon as the patient is diagnosed with methemoglobinemia, address airway patency and hemodynamic support. Limit further absorption of the toxic agent through decontamination, which may include gastric lavage for oral ingestions.4 Treatment of methemoglobinemia should be based on the severity of symptoms at presentation. Patients who are asymptomatic without acute respiratory distress can be closely monitored with supportive care including high-flow oxygen.1 Symptomatic patients with methemoglobin levels above 20% and asymptomatic patients with methemoglobin level above 30% should be treated with methylene blue. The recommended dose is 1 to 2 mg/kg administered IV over 5 to 30 minutes.9 Patients with comorbidities, tissue hypoxia, or central nervous system depression may need to be treated at lower methemoglobin concentrations. Additional doses of up to 1 mg/kg may be given if the methemoglobin level remains above 30% or if the patient is still symptomatic but total dose should not exceed 7 mg/kg.1,9
The most common adverse reactions to methylene blue are pain in the extremity, dysgeusia, feeling hot, dizziness, sweating, nausea, and headache.9 About 40% of the methylene blue is excreted by the kidneys, which results in a blue-green discoloration to the urine.4 Patients with renal impairment should be monitored closely due to the risk of toxicities or drug interactions. Methylene blue is contraindicated in patients with G6PD deficiency because the drug may be ineffective and can cause hemolytic anemia.9
When methylene blue fails, is unavailable, or is contraindicated, high-dose ascorbic acid may be an alternative.10 Other alternatives include continued ventilation and hemodynamic support.4 Hyperbaric oxygen can be administered to increase the amount of oxygen in the plasma and reduce the amount of carbon dioxide needed for metabolic function. Hemodialysis may be used to remove the absorbed toxin.1
Methemoglobinemia is a rare and potentially life-threatening medical emergency. It can be acquired from a variety of chemicals, medications, and drugs and can be overlooked when evaluating someone with dyspnea. Common presenting features include acute onset of generalized weakness, headache, dizziness, nausea, syncope, vomiting, tachycardia, and central cyanosis. Rapid clinical recognition and treatment are vital to optimal patient outcomes.