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Symptoms: Fatigue and Lightheadedness

Vo, Timothy MD; Iwanicki, Janetta MD

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doi: 10.1097/01.EEM.0000484524.23892.f5

    A 64-year-old woman presented to the ED for evaluation of low oxygen levels. She has a history of cutaneous T-cell lymphoma for which she received a bone marrow transplant four years earlier. She developed graft-versus-host disease after the bone marrow transplant, and has been immunosuppressed with tacrolimus and prednisone. She is taking dapsone for Pneumocystis jiroveci pneumonia prophylaxis. She has a history of chronically low oxygen saturations since her transplant, and is on two liters of oxygen by nasal cannula at baseline.

    She reports that her home oximeter has been measuring 84-86 percent for the past week. She has tried increasing her supplemental oxygen to four liters without any change in her oximetry. She reports fatigue and lightheadedness, but denies cough, fevers, chills, chest pain, or increased dyspnea. Her chest x-ray and ECG were unremarkable. When her blood was drawn, a drop of it on the sheet was noted to be a different color from expected.

    What is the cause of her low oxygen saturation? What treatment did she receive?

    Find the diagnosis and case discussion on p. 20.

    Diagnosis: Methemoglobinemia

    Hemoglobin is a tetrameric protein composed of four globular protein subunits. Each subunit contains its own iron-containing heme group, the moiety that binds oxygen. Normally, the iron within the heme group is in the reduced ferrous (2+) state. It is able to associate with oxygen in the 2+ state, binding it and transporting it to tissues, where relative hypoxia within the peripheral tissues allows the oxygen to dissociate freely where it is needed. (Ann Emerg Med 1999;34[5]:646.)

    The heme iron atom loses its ability to bind to oxygen when it is oxidized to the ferric (3+) state. (J Cardiothorac Vasc Anesth 2014;28[4]:1043.) This form of hemoglobin, containing ferric 3+ iron, is termed methemoglobin. Should one subunit be oxidized to ferric iron, the oxygen affinity of the remaining ferrous iron-containing subunits is left-shifted, or increased such that they are unable to dissociate from their bound oxygen in the peripheral tissues. Methemoglobinemia therefore induces a state of functional anemia.

    Hemoglobin oxidizes to methemoglobin at a basal rate of 0.5 percent to 3 percent per day in physiologic conditions. Methemoglobin reductase, a two-enzyme NADH-dependent complex, converts the ferric 3+ iron to ferrous 2+ iron, turning methemoglobin back into hemoglobin. (Ann Emerg Med 1999;34[5]:646.) In the steady state that develops, approximately one percent of a person's hemoglobin is in the form of methemoglobin at baseline.

    Some congenital forms of methemoglobinemia exist, such as cytochrome b5 reductase deficiency, pyruvate kinase deficiency, and hemoglobin M disease, but most cases of methemoglobinemia are acquired through exposure to exogenous oxidizing agents. (J Cardiothorac Vasc Anesth 2014;28[4]:1043.) Most commonly, these oxidizing agents are medications, taken in overdose or normal therapeutic doses. Common culprits include topical anesthetics like inhaled benzocaine or lidocaine, inhaled nitric oxide, nitroglycerin and nitroprusside, quinones, sulfonamides, and as in the above case, dapsone. (Anesth Prog 2007;54[3]:115.)

    Compounds used in industrial applications, such as nitrites and nitrates, arsine, and aromatic amines, have also been shown to induce methemoglobinemia. Most identified cases occur from topical and sprayed anesthetics, commonly employed during bronchoscopies and dental procedures. (Local Reg Anesth 2011;4:25.)

    Patients are generally asymptomatic at levels less than 10 percent of total hemoglobin. Cyanosis becomes apparent between 10-20 percent of total hemoglobin. Symptoms of lightheadedness, tachycardia, anxiety, and fatigue may appear as the methemoglobin concentration continues to rise between 20-50 percent of total hemoglobin. Coma, seizure, arrhythmias, and acidosis may occur at levels between 50-70 percent of total hemoglobin, and cardiopulmonary collapse and eventually death will occur as levels rise above 70 percent. (J Cardiothorac Vasc Anesth 2014;28[4]:1043.)

    Standard pulse oximeters will generally read approximately 85 percent in the presence of methemoglobin. These pulse oximeters measure light absorption at wave lengths of 660 nm and 940 nm, and convert the ratio into a calculated percent saturation based on an algorithm that accounts only for oxyhemoglobin and deoxyhemoglobin. (Anesth Prog 2007;54[3]:115.) Methemoglobin absorbs these two wave lengths in a ratio that is roughly 1:1, which is interpreted by pulse oximeter conversion algorithms as approximately 85 percent. (Anesthesiology 1989;70[1]:112.) A saturation gap may be observed, or you may see a discrepancy between the saturation on an arterial blood gas and that of the pulse oximeter. Blood with a significant proportion of methemoglobin typically has a chocolate brown appearance to it, as seen in the image.

    Treatment for methemoglobinemia begins with supportive care and stopping the offending agent. The definitive treatment of methemoglobinemia is reducing the ferric 3+ iron into ferrous 2+ iron. Methylene blue, the antidote for methemoglobinemia, reduces methemoglobin back to hemoglobin by acting as a co-factor for NADPH-methemoglobin reductase. (Ann Pharmacother 1998;32[5]:549.) The initial dose is 1-2 mg/kg intravenously, which may be repeated after an hour. Paradoxically, doses greater than 15 mg/kg may cause oxidation of ferric 2+ iron into ferrous 3+ iron and induce methemoglobinemia. The dark blue color of the methylene blue will typically cause the pulse oximeter to read extremely low for a few minutes after administration.

    This patient was diagnosed with methemoglobinemia, secondary to the dapsone that she was taking for P. jiroveci pneumonia prophylaxis. Her methemoglobin level was 9.6 percent of her total hemoglobin, and she was mildly symptomatic. She was taken off dapsone and placed on trimethoprim/sulfamethoxazole for P. jiroveci pneumonia prophylaxis. She did not require methylene blue. She was noted to no longer require supplemental oxygen, with a pulse oximetry measurement of 96 percent on room air a month later in the bone marrow transplant clinic. She reported increased energy and increased exercise tolerance, walking a mile per day and working with physical therapy twice per week.

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