Approach Considerations
No laboratory studies that are specific to the diagnosis of nitrogen dioxide (NO2)–induced illness have been reported. However, in addition to a thorough history, the following blood studies can be helpful in excluding other causes of the illness and should be ordered based on clinical suspicion or history:
To assess severity of disease, request the following:
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Arterial blood gas (ABG) or venous blood gas (VBG) levels
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Lactate level
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Methemoglobin (MHb) level
To help rule out infectious etiologies, request the following:
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Sputum culture and Gram stain
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Respiratory virus polymerase chain reaction (PCR) panel
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Urine Legionella
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Coccidioides immunoglobulin G and immunoglobulin M
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Histoplasma enzyme immunoassay
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Cryptococcal antigen
Other tests to possibly consider include the following:
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Glucose levels
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Complete blood cell (CBC) count
Blood Studies
Significant nitrogen dioxide (NO2) exposure usually results in hypoxemia. Initial blood gas levels establish the presence and severity of gas exchange impairment, and are extremely important in deciding whether to intubate. Some literature supports obtaining serial ABG levels during follow-up visits to ascertain whether bronchiolitis obliterans is developing. Metabolic acidosis can occur by dissolution of nitrous oxide in body fluids, resulting in tissue hypoxemia and subsequent lactic acid formation.
Measure MHb to evaluate cyanosis that does not respond to oxygen administration. MHb is an inactive oxidized form of hemoglobin that does not contribute to oxygen transport; levels greater than 10-15% result in cyanosis. MHb levels may be increased after exposure to NO2. Although levels as high as 71% have been reported following exposure to nitrous fumes, welders exposed to NO2 at 4-5 ppm (4000-5000 ppb) were noted to have MHb levels of 2-3%. Methylene blue administration can affect this test result.
On the CBC count, leukocytosis is often present in patients who have been exposed to NO2. Peripheral eosinophilia may suggest an alternative cause of pulmonary inflammation more consistent with allergic or reactive airway disease.
Measure glucose levels to assure that anxiety and restlessness are not caused by concomitant hypoglycemia. Exposure to NO2 does not cause a primary hypoglycemia.
Chest Radiography
Chest radiography findings may be normal. During acute injury, the chest radiograph shows ill-defined, alveolar opacities, which are characteristic of pulmonary edema or acute respiratory distress syndrome (ARDS). Subacute injury reveals patchy, bilateral confluent woolly air-opacities. The small opacities can be mistaken for miliary tuberculosis. See the images below.
Bronchiolitis obliterans following exposure to nitrogen dioxide. Courtesy of Dr. Ann Leung, Department of Radiology, Stanford University Hospital.
Noncardiogenic pulmonary edema following exposure to nitrogen dioxide. Courtesy of Dr. Ann Leung, Department of Radiology, Stanford University Hospital.
Computed Tomography
High-resolution computed tomography (CT) presentations vary from patchy subpleural ground glass opacities to a diffuse hyperlucency.
Pulmonary Function Testing
Pulmonary function tests (PFTs) should be performed as soon as possible to establish the extent of involvement. Repeat PFTs may be performed at regular intervals to chart progress and recovery. PFTs obtained late in the clinical course when bronchiolitis obliterans has developed may demonstrate presence of obstructive disease with prolonged forced expiratory volume at 1 second (FEV1).
Proliferative bronchiolitis is characterized by granulation tissue that primarily involves the bronchiolar lumen. It rarely involves alveolar spaces. In contrast, constrictive bronchiolitis involves collagenous scarring of the lumen with proliferation of underlying smooth muscle and occasional luminal erosions.
Histologic Findings
In patients who die quickly from nitrogen dioxide (NO2) toxicity, microscopic evaluation of lung tissue shows hemorrhagic edema and extensive damage of the respiratory epithelium. Complete shedding of the epithelium may occur in the small bronchi and bronchioles.
In patients who survive, small palpable nodules and hemorrhagic areas appear after several weeks. Generalized infiltration of the alveolar walls with lymphocytes (ie, numerous macrophages in alveolar spaces) occurs. Bronchiolitis obliterans occurs in various stages of organization and is responsible for the palpable nodules.
Proliferative bronchiolitis is characterized by granulation tissue that primarily involves the bronchiolar lumen. It rarely involves alveolar spaces. In contrast, constrictive bronchiolitis involves collagenous scarring of the lumen with proliferation of underlying smooth and occasional luminal erosions.
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Bronchiolitis obliterans following exposure to nitrogen dioxide. Courtesy of Dr. Ann Leung, Department of Radiology, Stanford University Hospital.
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Noncardiogenic pulmonary edema following exposure to nitrogen dioxide. Courtesy of Dr. Ann Leung, Department of Radiology, Stanford University Hospital.
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Nitrogen dioxide air quality from 1980 to 2012. Courtesy of the Air Quality Analysis Group, US Environmental Protection Agency (EPA).
