In addition to today’s resource, consider reviewing:
Glucose-6-Phosphate Dehydrogenase Deficiency from StatPearls. Gary K. Mak; Manan Shah. Last Update: November 30, 2025.
Today, I review methemoglobinemia. Here is the resource:
Methemoglobinemia from StatPearls.
Richard J. Chen; Thomas M. Nappe. Last Update: December 14, 2025.
Methemoglobinemia is a potentially life-threatening condition characterized by impaired oxygen delivery due to oxidation of hemoglobin iron from the ferrous (Fe2+) to the ferric (Fe3+) state. Ferric hemoglobin is incapable of binding oxygen, resulting in functional anemia and tissue hypoxia. The condition may be congenital or acquired. Congenital forms involve cytochrome b5 reductase deficiency or hemoglobin structural variants. Acquired methemoglobinemia typically arises after exposure to oxidizing agents, including topical anesthetics, nitrates and nitrites, dapsone, and industrial chemicals, such as aniline dyes. Infants, individuals with enzymatic deficiencies, and patients with comorbid oxidative stress face an elevated risk of severe illness.
Clinical manifestations include cyanosis unresponsive to oxygen therapy, headache, fatigue, dyspnea, and, at higher methemoglobin levels, arrhythmias, seizures, or coma. Diagnosis relies on co-oximetry*, with pulse oximetry often revealing saturation near 85% despite adequate oxygenation. Treatment focuses on immediate removal of the offending source and prompt administration of methylene blue when symptomatic or significantly elevated levels are present. Alternatives include high-dose ascorbic acid and exchange transfusion in specific populations. Rapid management prevents hypoxic injury, ensuring favorable outcomes.
*Link is to Google search: What is co-oximetry?
*Link is to CO-Oximetry, from AAMRI, Jan/Feb 2012 by Jared S. Ruckman.
Resuming Methemoglobinemia from StatPearls.
Richard J. Chen; Thomas M. Nappe. Last Update: December 14, 2025:
Etiology
Methemoglobin is present at low levels in the general population and typically does not produce clinical symptoms. Endogenous enzymatic mechanisms reduce methemoglobin iron back to its Fe2+ state. The normal half-life of methemoglobin ranges from 1 to 3 hours, but this interval is prolonged with ongoing oxidative stress.[1][2]
Methemoglobinemia may result from congenital or acquired processes.
Acquired methemoglobinemia is significantly more common and results from exposure to substances that oxidize hemoglobin. Oxidation may occur via direct or indirect processes. This exposure produces methemoglobin in quantities that exceed the body’s capacity to reduce the iron within hemoglobin back to the Fe2+ state. Acquired methemoglobinemia may arise from exposure to direct oxidizing agents (eg, benzocaine, prilocaine), indirect oxidants (eg, nitrates), or substances requiring metabolic activation (eg, aniline, dapsone).[8] Classic examples include patient exposure to benzocaine during endoscopy and infant exposure to nitrites in well water. Recreational use of “poppers” has recently emerged as a common source. Xenobiotics* associated with methemoglobinemia include, but are not limited to, the following:
*Xenobiotics: Link to a Google search on the term for quick review.
Additional acquired triggers include dietary nitrates, noncolorant industrial chemicals, and environmental toxins. Early recognition of unexplained cyanosis, persistent hypoxia, or sudden-onset symptoms should prompt evaluation for methemoglobinemia.
History and Physical
Methemoglobinemia should be considered in patients with dyspnea or cyanosis and hypoxemia refractory to supplemental oxygen, particularly following exposure to a known oxidative agent. Presentation can range from minimally symptomatic to severe. Clinical manifestations occur along a spectrum and include cyanosis, pallor, fatigue, weakness, headache, central nervous system depression, metabolic acidosis, seizures, dysrhythmias, coma, and death. Symptom severity is multifactorial, depending on the percentage of methemoglobin in the circulation, the rate of accumulation, intrinsic clearance capacity, and the patient’s underlying health status. Duration and magnitude of exposure to an oxidizing agent may further influence severity.
Evaluation
Methemoglobinemia is a clinical diagnosis based on history and presenting signs, including hypoxemia refractory to supplemental oxygen and the characteristic presence of chocolate-colored blood. Diagnosis is confirmed by arterial or venous blood gas with co-oximetry, which speciates hemoglobin to determine methemoglobin concentration and percentage. Conventional pulse oximeters, which measure peripheral capillary oxygen saturation (SpO2), cannot be used to assess methemoglobinemia severity, as explained below.
Refractory hypoxemia is a significant diagnostic clue. This condition is generally evident on SpO2 measurement based on wavelength detection, but not when calculated from blood gas analysis using the partial pressure of oxygen in the blood (SaO2).
Traditional dual-wavelength pulse oximetry yields inaccurate readings in methemoglobinemia because these devices measure light absorbance at 2 wavelengths—660 and 940 nm. The ratio of absorbance allows differentiation between oxyhemoglobin and deoxyhemoglobin, with the expressed percentage, or SpO2, indicating the measured fraction of hemoglobin that is oxygenated. Methemoglobin absorbs strongly at both wavelengths, producing interference that causes inaccurate SpO2 readings. When methemoglobin levels approach 30% to 35%, the absorbance ratio (A660/A940) reaches 1.0, which corresponds to a SpO2 reading of 85%.[38]
Treatment / Management
Treatment of methemoglobinemia includes removal of the inciting agent and consideration of antidotal therapy with adjunctive interventions such as methylene blue (tetramethylthionine chloride). High-flow oxygen delivered via a nonrebreather mask increases tissue oxygen delivery and enhances the natural degradation of methemoglobin.
Methylene blue typically acts rapidly and effectively through the secondary pathway of methemoglobin reduction, in which NADPH-MetHb reductase reduces methylene blue to leukomethylene blue using NADPH generated from the G6PD-dependent hexose monophosphate shunt. Leukomethylene blue then serves as an electron donor to reduce methemoglobin to hemoglobin.
Methylene blue treatment is indicated for acquired methemoglobinemia when levels exceed 20% to 30% or the patient is symptomatic, even at lower levels. In cases of suspected severe methemoglobinemia, treatment should not be delayed pending confirmatory laboratory values. The recommended dose is 1 to 2 mg/kg (0.1 to 0.2 mL/kg of 1% solution) administered intravenously over 5 minutes. The dose may be repeated after 30 to 60 minutes if symptoms persist or methemoglobin levels remain above the treatment threshold.
Practitioners should be aware of the side-effect profile of methylene blue. Benign effects include green or blue discoloration of urine, for which patients should be forewarned. Significant adverse effects arise from methylene blue functioning as both an oxidizing agent and an inhibitor of monoamine oxidase A. As an oxidizing agent, methylene blue can precipitate methemoglobinemia or hemolysis when doses are high or reduction is inadequate. Meanwhile, concurrent administration with serotonergic agents may predispose patients to serotonin syndrome.[40]
Caution is warranted in neonates, who are highly sensitive to oxidizing agents. Methylene blue is classified as pregnancy category X by the U.S. Food and Drug Administration, indicating confirmed fetal abnormalities from in utero exposure. Risk-benefit evaluation is recommended when treating pregnant patients.[41][42]
Although methylene blue use in G6PD deficiency is controversial due to reduced NADPH levels, it is not contraindicated and should be administered cautiously. Many G6PD-deficient patients retain sufficient enzymatic activity to generate an adequate response, and thus, treatment should not be withheld. Hemolysis in individuals with G6PD deficiency has been observed at doses exceeding 5 mg/kg, more than twice the recommended dose.[43]
If methylene blue administration is ineffective after a 2nd dose, underlying conditions—such as, but not limited to, G6PD deficiency and NADPH-MetHb reductase deficiency—should be considered as potential causes of treatment refractoriness. Methemoglobinemia alone is not an indication to screen for these disorders.
Additional options when methylene blue is ineffective or contraindicated include ascorbic acid, exchange transfusion, and hyperbaric oxygen therapy (HBOT).[44] High-dose ascorbic acid (vitamin C), up to 10 g intravenously per dose, may be considered for treatment. However, this intervention is generally ineffective and is not standard of care. High-dose administration increases urinary oxalate excretion and may predispose patients with renal insufficiency to renal failure due to hyperoxaluria.[45]
Exchange transfusion treats methemoglobinemia by replacing the patient’s blood with donor blood free of methemoglobin. Case reports describe successful outcomes when methylene blue was ineffective or unavailable.[46][47] HBOT increases dissolved oxygen in the bloodstream, providing additional time for endogenous mechanisms to reduce methemoglobin.
Differential Diagnosis
Cyanosis may result from a variety of conditions that cause acute or chronic hypoxia. The differential diagnosis includes pulmonary, cardiac, hematologic, and toxicologic causes, such as the following
Bluish skin discoloration is a nonspecific finding that may result from a variety of conditions, including the following:
Differentiating between the potential causes of cyanosis and bluish skin discoloration involves integrating clinical history, physical examination, and relevant laboratory or imaging studies. This approach ensures timely recognition of critical conditions while avoiding unnecessary or inappropriate interventions.
Prognosis
Most patients with mild methemoglobinemia do not require treatment beyond discontinuation of the offending agent. Patients exhibiting signs of end-organ damage, such as cardiac ischemia, altered mental status, significant laboratory abnormalities, or persistent symptoms, may require treatment with methylene blue. Symptomatic patients, particularly those receiving methylene blue, should be considered for hospital admission.
Consultations
All cases of methemoglobinemia should be managed in consultation with a medical toxicologist. Coordination with such a specialist helps tailor management strategies to patient-specific risks and comorbidities.
Pearls and Other Issues
Key considerations in the management of methemoglobinemia include the following:
Patient education should focus on minimizing exposure to substances that increase methemoglobin and identifying early warning signs. Prompt medical attention is essential if symptoms develop, and treatment options should be discussed to ensure safe and effective care.
