Toxicology Case Files from the Utah Poison Control Center
Take Home Points
- Methemoglobinemia (MetHb) occurs when heme iron is oxidized to the Fe3+ state and is unable to bind and deliver oxygen to tissues
- Classic findings include cyanosis, chocolate brown blood at phlebotomy, and a falsely low pulse oximetry reading of 85%
- Treatment is with methylene blue 1 mg/kg IV over 5 minutes
- Common drug-induced causes include benzocaine, phenazopyridine, and dapsone. Suicide attempts have increased in recent years with ingestion of sodium nitrite used for meat curing
Sodium Nitrite Suicide Attempt
A 23-year-old male ingested an unknown amount of sodium nitrite purchased online in a suicide attempt. He immediately called 911 and was transported by EMS to a local emergency department. En route, he developed dyspnea, chest pain, confusion, cyanosis, and suffered cardiac arrest.
He received standard advanced cardiac life support for a PEA arrest with multiple rounds of CPR and epinephrine. He also received 2 doses of methylene blue 1 mg/kg IV. Levels of methemoglobin were too high to measure during the code.
He had return of spontaneous circulation after about 40 minutes of downtime. He was admitted to the ICU, intubated without sedation, and started on a low-dose epinephrine infusion for hypotension.
Post-arrest, a blood gas was eventually able to be interpreted by the analyzer, and MetHb resulted at 13%.
A non-contrast head CT showed signs of anoxic brain injury on admission. A few hours later, in the ICU, his condition deteriorated with evidence of cerebral edema and herniation. Care was withdrawn. Nitrites were confirmed in his blood at autopsy.
Methemoglobinemia & Nitrites
Hemoglobin transports oxygen with heme Fe2+ binding O2. Oxidation of the heme iron from the ferrous to the ferric (Fe3+) state renders heme unable to transport oxygen. Additionally, the remaining normal heme iron develops an increased affinity for oxygen, further decreasing tissue oxygen delivery.
This phenomenon may spontaneously occur when oxygen dissociates from iron under normal physiologic conditions. Endogenous mechanisms are sufficient to reduce the low level of methemoglobin back to hemoglobin. When an excess of MetHb is produced, endogenous mechanisms cannot rapidly reduce MetHb to hemoglobin.
Drug-induced MetHb is the most common cause of MetHb, though rare congenital forms do occur.
Though the list of methemoglobin inducers is extensive (Wright 1999), the most common drugs implicated are benzocaine, phenazopyridine, and dapsone. For this reason, benzocaine has been removed from child teething medications, and hospitals preferentially use single-dose benzocaine formulations instead of aerosol sprays. Phenazopyridine should only be used for 3 days due to the risk of MetHb. Patients receiving dapsone, often for dermatological conditions, may develop MetHb. Usually, they do not have high levels of MetHb, but they may remain symptomatic for some time, given the extended half-life of dapsone.
Beginning in 2017, an increase in suicide attempts with sodium nitrite occurred in the US and other countries following promotion of the method on pro-suicide websites (McCann 2021, Stephenson 2022). Patients may obtain large quantities of pure sodium nitrite for meat curing from typical retail outlets.
Signs & Symptoms
Methemoglobinemia causes visible cyanosis at concentrations far less than deoxyhemoglobin. Patients may appear profoundly pale, gray, or cyanotic out of proportion to their level of respiratory distress.
Blood with a significant amount of MetHb appears chocolate brown during venipuncture.
Patients may experience signs and symptoms consistent with the level of decreased tissue oxygen delivery ranging from no symptoms in mild cases to dizziness, dyspnea, fatigue, and chest pain in moderate cases to coma, seizures, hypotension, and cardiac arrest in severe cases.
Pulse oximeters utilize two wavelengths of light to distinguish oxyhemoglobin and deoxyhemoglobin and estimate hemoglobin oxygen saturation. MetHb absorbs light differently at these wavelengths, and pulse oximeter readings become unreliable. Though classically described as staying fixed at 85%, in real-world practice, the exact deviation is unpredictable. Notably, supplemental oxygen will not improve the pulse oximeter reading, lung sounds are usually clear, and a chest x-ray should be normal.
A blood gas (venous is sufficient) can accurately determine the exact amounts of the various hemoglobin species (oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, methemoglobin) by co-oximetry utilizing a separate wavelength for each.
Any phenomenon that leads to increased oxidation of heme iron may also oxidize red blood cells leading to hemolysis. Routine workup for hemolysis (peripheral smear, LDH, haptoglobin) should be performed in severe cases, chronic cases (e.g., dapsone), or in patients with a low hemoglobin concentration.
Other workup usually occurs simultaneously while investigating the patient’s symptoms and before the diagnosis is recognized. Additional testing should be patient-specific (e.g., EKG and troponin for chest pain associated with MetHb).
An electron donor, methylene blue, can be used to reduce methemoglobin via NADPH MetHb reductase, rapidly restoring the heme iron to the ferrous (Fe2+) state.
Indications for methylene blue include moderate to severe signs and symptoms of MetHb or those with a MetHb >25-30%. Typical dosing is 1 mg/kg IV over 5 minutes. Maximal effects occur within about 30 minutes. A single dose is sufficient in most cases of moderate MetHb.
In severe cases such as this, transfusion of normal red blood cells containing normal hemoglobin could be considered. This is largely unstudied, and presumably, the hemoglobin in the transfused blood would also become rapidly oxidized.
Extracorporeal membrane oxygenation might seem like a useful option; however, the primary problem is not oxygenation or cardiogenic shock, but rather the inability to deliver sufficient oxygen to tissues.
Theoretically, hyperbaric oxygen therapy could provide supraphysiologic amounts of dissolved oxygen in blood, obviating the need for hemoglobin to carry oxygen. However, such unstable, severely poisoned patients could not be transported to, nor placed in a hyperbaric chamber.
Despite a witnessed arrest with prompt ACLS and high-quality CPR, this patient suffered devastating hypoxic injury as very little oxygen was delivered to tissues. Even though the duration of MetHb was ultimately short, with improvement with methylene blue, the dyshemoglobinemia could not be corrected quickly enough.
- McCann SD, Tweet MS, Wahl MS. Rising incidence and high mortality in intentional sodium nitrite exposures reported to US poison centers. Clinical toxicology. 2021 Dec 2;59(12):1264-9.
- Stephenson L, Wills S, van den Heuvel C, Humphries M, Byard RW. Increasing use of sodium nitrite in suicides—an emerging trend. Forensic Science, Medicine and Pathology. 2022 Sep;18(3):311-8.
- Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Annals of emergency medicine. 1999 Nov 1;34(5):646-56.
Author: Michael Moss, MD, FAACT, Medical Director, Utah Poison Control Center