Case Presentation: An 89-year-old woman was admitted with abdominal discomfort plus five days of dysuria and urinary frequency. Previously, the patient had seen a urologist for chronic dysuria and was prescribed an estrogen cream for vaginal atrophy. She admitted to non-adherence with the treatment, instead trying an over-the-counter medication whose name she did not initially remember.
On admission, her vital signs were remarkable for oxygen saturation of 88%, unresponsive to oxygen supplementation. Other notable clinical findings were yellow pigmented skin, right upper quadrant and suprapubic tenderness, anemia with hemoglobin 8 g/dL, serum creatinine 2.2 mg/dL, unremarkable liver function testing and ultrasound imaging, and a urinalysis consistent with a urinary tract infection. Her chest X-ray was unremarkable and an arterial blood gas (ABG) obtained off of oxygen demonstrated normal partial pressure of oxygen (PaO2). Given the discrepancy between oxygen saturation on pulse oximetry and PaO2, methemoglobinemia was suspected. Co-oximetry revealed oxyhemoglobin 70% and methemoglobin >21%.
The patient denied recent benzocaine, nitrates, or dapsone use, but eventually recalled the name of the medication she took for dysuria – phenazopyridine – which she had taken 200 mg three times daily for several weeks prior to admission. Intravenous methylene blue was administered, ceftriaxone was given for her urinary tract infection, and supportive care was provided until her clinical status returned to baseline. Prior to discharge, the patient was educated about the risks of extended phenazopyridine use.
Discussion: Methemoglobinemia, a condition whereby functional anemia and tissue hypoxia are precipitated by acutely elevated concentrations of methemoglobin, is often iatrogenic, caused by oxidizing agents such as topical anesthetics or dapsone. Non-specific symptoms (e.g. lightheadedness and dyspnea) plus laboratory findings such as anemia and acute kidney injury (AKI) can be mistaken for a number of ailments, highlighting the importance of thorough medication reviews and having a high index of suspicion for methemoglobinemia when there is a recent history of medications such as those mentioned above as well as nitrates, phenytoin, or antimalarials.
The pathophysiology of acute respiratory distress in methemoglobinemia relates to the reduced erythrocyte oxygen-carrying capacity of functionally impaired hemoglobin. The skin discoloration, hemolytic anemia, and AKI described above have also been associated with phenazopyridine toxicity. The pathophysiology of AKI is still being investigated but may be multifactorial, including renal tubular epithelial cell injury, heme pigment-induced nephropathy from hemolytic anemia, and hypoxic injury from methemoglobinemia itself.
Conclusions: Iatrogenic methemolglobinemia presents with non-specific symptoms such as headache, dizziness, dyspnea, fatigue, or mental status changes. When a patient exhibits hypoxia unresponsive to supplemental oxygen, chocolate-brown hued arterial blood, and a discrepancy between pulse oximetry and ABG, methemoglobinemia should be at the top of one’s differential. History-taking should include a thorough review of medications (including over-the-counter agents) and chemical exposures. Diagnosis is confirmed with co-oximetry. Treatment depends on the degree of symptoms and/or methemoglobinemia, with methylene blue and supplemental oxygen used in cases where methemoglobin level is greater than 20%.