Nitrogen Dioxide Toxicity

Practice Essentials

Nitrogen dioxide (NO₂) is a reddish-brown gas that has a sharp, harsh odor at higher concentrations, but may be clear and odorless at lower, but still harmful, concentrations. NO₂ is one of several pollutants formed as a byproduct of burning fuel or combustion. Common sources include cars, trucks, buses, power plants, and diesel-powered heavy engines, but smaller significant sources also include kerosene burners, gas space heaters, and tobacco smoke.^[1]

Thus, common occupations at risk for NO₂ toxicity include arc welders, firefighters, military and aerospace personnel, traffic personnel, and those working with explosives.^[2] In addition, individuals who spend significant amounts of time near major roadways or in traffic may be at considerably increased risk of long-term exposure.^[3]

Finally, NO₂ can also form from noncombustion sources. When farm silos are filled with fresh organic material (eg, corn, other grains), anaerobic fermentation of the crops results in NO₂ production. Within a few hours, high levels of NO₂ develop on top of the silage. This may also occur with silage bags, but this risk is lower given natural outdoor ventilation. In either case, farmers who enter silos, work with silage bags, or remain near open silo hatches during the first 10 days after filling may experience NO₂ toxicity in a phenomenon known as silo filler’s disease.

Signs and symptoms

The diagnosis of NO₂ toxicity largely depends on the history of exposure. If possible, inquire about exposure and occupation. Welders, firefighters, military and aerospace personnel, individuals working with explosives, traffic personnel, and farmers generally have higher risk of short-term exposure than those in other occupations. Additionally, individuals living in particular urban areas or near congested highways may have increased risk of long-term low-level exposure.

NO₂ is a mucous membrane irritant commonly associated with other toxic products of combustion. Symptoms most commonly range from mild cough and mucous membrane irritation to severe exacerbations of underlying pulmonary diseases like COPD or asthma and, in extreme cases, death. Suspect methemoglobinemia in patients exposed to NO₂ who exhibit cyanosis or dyspnea. The initial absence of significant symptoms does not exclude a subsequent development of serious disease.

Common symptoms are as follows:

• New or worsening cough and/or wheezing (most common)
• Eye, nose or throat irritation
• Light-headedness or headache
• Dyspnea (shortness of breath)
• Chest tightness
• Choking
• Chest pain
• Diaphoresis (sweating)

In addition, the following signs and symptoms may appear acutely or persist for days to weeks, and may indicate severe or worsening disease:

• Severe shortness of breath
• Turning blue in the lips, fingers, or toes
• Rapid breathing
• Rapid heart rate
• Fever
• More frequent use of inhalers

See Clinical Presentation for more detail.

Diagnosis

No laboratory studies that are specific to the diagnosis of NO₂ -induced illness have been reported. However, the following blood studies can be helpful in excluding other causes of the symptoms:

• Arterial blood gas (ABG) levels
• Lactate level
• Methemoglobin (MHb) level
• Complete blood cell count (CBC) with peripheral smear
• Glucose levels

Other studies are as follows:

• ECG can rule out cardiac events
• Chest radiography findings range from normal to noncardiogenic pulmonary edema to that of soft reticulonodular infiltrates (see the image below)

  View Image

  Noncardiogenic pulmonary edema following exposure to nitrogen dioxide. Courtesy of Dr. Ann Leung, Department of Radiology, Stanford University Hospita....

   

  

   
• Pulmonary function tests (PFTs) should be performed as soon as possible, to establish a baseline

See Workup for more detail.

Management

Treatment varies with the severity of symptoms, as follows:

• If no initial symptoms are present, observe the patient for at least 12 hours for hypoxemia
• Hospitalize the patient for 12-24 hours for observation or longer if gas exchange is compromised
• Administer oxygen to hypoxemic patients
• Consider high-dose steroids for patients with pulmonary manifestations
• Intubation and mechanical ventilation may be necessary if gas exchange is severely impaired
• Administer volume expanders cautiously
• Transfer to a tertiary care center for further diagnostic evaluation and ventilator support may be necessary
• Bronchiolitis obliterans, which may develop 2-6 weeks after NO₂ exposure, may require 6-12 months of corticosteroid therapy
• Inhaled sympathomimetics (eg, albuterol), anticholinergics (eg, ipratropium bromide), and steroids (eg, fluticasone propionate) may be indicated if the patient develops symptoms of reactive airway disease

See Treatment and Medication for more detail.

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Background

Harmful effects of nitrogen dioxide (NO₂) often occur from either high-level short-term or low-level long-term exposures. In an era founded largely on the success and availability of fossil fuels, the realization of the harmful effects of fossil fuel byproducts has become an increasing public health concern. Clean air is recognized as a basic requirement for human health and well-being, alongside access to clean water and sanitation.^[4] NO₂ in particular is among the most commonly recognized components of air pollution. NO₂ and the other pollutants it consorts with are increasingly associated with worsening lung function, increased risk of ischemic heart disease and stroke, increased rates of hospital admissions, and even increased rates of mortality.^{[5, 6, 3]}

Registry numbers for NO₂ include the following:

• American Chemical Society's Chemical Abstract Service (CAS): CAS #10102-44-0
• United Nations/Department of Transportation: UN#1067
• National Institute of Occupational Safety and Health (NIOSH) Registry of Toxic Effects of Chemical Substances (RTECS): QW 9800000

NO₂ is poorly soluble in water. As a result, when inhaled, it easily bypasses the moist oral mucosa and upper airways and penetrates deep into the lower respiratory tract. Toxicity depends largely on the concentration and duration of exposure, as well as an individual’s baseline pulmonary function. Elderly individuals or individuals with COPD or asthma are at much higher risk of adverse events, are more susceptible to developing infections, and may experience more severe symptoms than healthy individuals with normal pulmonary function.

Currently, the WHO recommends limiting exposures to less than 40 µg/m³ (approximately 20 parts per billion [ppb]) annual average for long-term exposures and less than 200 µg/m³  (approximately 100 ppb) per hour for short-term exposure. These values are based on using NO₂ as a general marker for the complex mixture of pollutants generated by combustion. The recommended values were also based on values shown to have direct effects on the pulmonary function of asthmatic people.^[4]

In the United States, current Environmental Protection Agency (EPA) standards are set at less than 100 ppb for 1-hour exposures and less than 53 ppb annual average for long-term exposure.^[7] States such as California may have more stringent state regulations. Specific regions, including the Northeast corridor, Chicago, and Los Angeles have historically high levels of NO₂.^[8] See the EPA’s Nitrogen Dioxide Trends for specific NO₂ level trends in a particular national region.^[9] Also see the graph below.

View Image

Nitrogen dioxide air quality from 1980 to 2012. Courtesy of the Air Quality Analysis Group, US Environmental Protection Agency (EPA).

Some studies suggest that chronic exposure to NO₂ may predispose individuals to the development of chronic lung diseases, including infection and COPD, and particularly asthma in children. In a study of 728 children with active asthma, children in households with gas stoves (which increase the levels of NO₂) had an increased likelihood of wheezing, shortness of breath, and chest tightness.^[10]

More recent literature on NO₂ focuses on its association with nitrous acid (HONO), a molecule that can be formed as a primary product of gas combustion or by the reaction of NO₂ with surface water.^{[11, 12, 13, 14]} Although early data are inconclusive, some studies suggest that HONO may contribute to the adverse health outcomes previously attributed to NO₂.

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Pathophysiology

In the lung, nitrogen dioxide (NO₂) hydrolyzes to nitrous acid (HNO₂) and nitric acid (HNO₃), which can then cause chemical pneumonitis and pulmonary edema. Because NO₂ is poorly water soluble, it hydrolyzes more slowly than other water-soluble gases, resulting in deep lung injury in the bronchioles and alveoli. Type I pneumocytes and ciliated airway cells are primarily affected, but damage also occurs from free radical generation, which results in protein oxidation, lipid peroxidation, and cell membrane damage. A proposed pathway involves oxidation of mitochondrial cytochrome c,^[15] which can result in electron transport chain decoupling and cellular apoptosis.

The chemical irritation of the alveoli and bronchioles results in rapid destruction of the epithelial cells and breakdown of the pulmonary capillary bed. The subsequent release of fluid results in pulmonary edema.

Nitrogen oxides can alter immune function and macrophage activity, leading to an impaired resistance to infection. Viral illnesses such as influenza are commonly associated infections. Significant exposure can also result in methemoglobinemia. NO₂ binds to hemoglobin with great affinity, forming nitrosyl hemoglobin, which is readily oxidized to methemoglobin. Methemoglobin results in a leftward shift of the oxygen disassociation curve, which impairs the oxygen delivery and compounds the already present hypoxia.

In untreated cases, fibrous granulation tissue may develop within small airways and alveolar ducts, resulting in bronchiolitis obliterans. As its name suggests, bronchiolitis obliterans refers to an inflammatory process that results in the progressive partial or complete obliteration of the small airways. This results in obstructive lung disease. (See Constrictive Bronchiolitis Obliterans: The Fibrotic Airway Disorder.)

Briefly, bronchiolitis obliterans is classified in two subtypes: proliferative and constrictive. Proliferative bronchiolitis is more common and is characterized by the development of steroid-reversible intraluminal polyps that obstruct the small airways. By contrast, constrictive bronchiolitis is a more diffuse and chronic process characterized by concentric thickening and destruction of bronchioli. While fumes containing sulfur or ammonia have been associated with constrictive bronchiolitis, proliferative bronchiolitis is more common with nitrogen dioxide toxicity.

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Etiology

Occupational risk for nitrogen dioxide (NO₂) exposure is high for the following workers:

• Farmers, particularly those who work near silos
• Firefighters
• Arc welders
• Military personnel, particularly those working with explosives or in regions with poor air-quality control
• Aerospace workers (missile fuel)
• Traffic officers, particularly those standing at high-volume intersections
• Miners

In addition, workers in any occupation that involves the production, transportation, or use of nitric acid are at risk. Gas- and kerosene-fired household appliances and motor vehicle exhaust all pose significant risk of exposure. For example, there are multiple reports of nitrogen dioxide exposure occurring in ice skating rinks secondary to poor ventilation and exhaust from ice resurfacing machines^[16] and exposures in mines where poor ventilation results in exposure to fumes from diesel engine equipment or explosives.

Silo filler’s disease

Silos filled with freshly cut corn, oats, grass, alfalfa, or other plant material generates oxides of nitrogen within hours. Maximum concentrations of NO₂ are reached within 1-2 days, and then the levels begin to fall after 10-14 days. In well-sealed silos, NO₂ can be present for weeks. Silage that is heavily fertilized, has experienced drought, or is derived from immature plants produces much higher concentrations of nitrogen oxides within the silo. The same phenomenon occurs with silage bags, but because of better natural ventilation, the hazard is lower.

During storage, NO₂, which is 1.5 times heavier than air, can remain in deep depressions of the silage material. Exposure can develop while attempting to level the silage without proper ventilation or breathing apparatus. One documented case occurred in an individual who traversed the ladder at the opening of a silo. The heavier-than-air NO₂ flowed down the side of the silo, exposing the worker to toxic levels of gas.

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Epidemiology

In the United States, manufactured sources of nitrogen oxides primarily from burned fuels exceed 19.4 million metric tons. The US Environmental Protection Agency (EPA) has regulations for monitoring nitrogen dioxide (NO₂) concentrations and has historically found outdoor ambient air concentrations highest in large urban regions such as the New York metropolitan area, Chicago, and Los Angeles.^[8]

The World Health Organization (WHO) estimated that ambient (outdoor air pollution) in both cities and rural areas caused 3 million premature deaths worldwide in 2012. Approximately 88% of those premature deaths occurred in low- and middle-income countries, especially in the Western Pacific and South-East Asia regions.^[17] In the United States, the EPA estimates that 16% of US housing units are located within 100 yards of a major highway, railroad, or airport. This translates to roughly 48 million people at increased risk of exposure. In addition, this population likely includes an increased proportion of lower-income individuals and minorities.^[3]

Individuals at increased risk of adverse effects include those with underlying asthma or COPD, those with other pulmonary diseases with poor pulmonary function (eg, interstitial lung disease, pulmonary fibrosis, pulmonary hypertension), and those with existing cardiovascular disease and low oxygen reserve. Elderly persons and children are also at increased risk of respiratory infections or asthma exacerbations, respectively.

Time-series studies on ozone (formed by the oxidation of NO₂ in ambient air) reported by the WHO suggested a 1-2% increase in attributable daily deaths when ozone concentrations exceeded 100 µg/mL (approximately 47.3 ppb). Levels above 160 µg/mL (approximately 75.7 ppb) were associated with an estimated 3-5% increase in daily mortality, even in purportedly healthy individuals. Levels above 240 µg/mL (approximately 114 ppb) were associated with a 5-9% increase. All numbers of daily mortality are relative to background levels of ozone at 70 µg/mL (33.1 ppb).

Silo filler's disease is prevalent during the harvest months of September and October. An estimated annual incidence of 5 cases per 100,000 silo-associated farm workers per year was reported in New York.^{[18, 19]} Silo filler's disease is likely significantly underreported.

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Prognosis

Overall, the long-term prognosis is good for patients who survive the initial exposure to nitrogen dioxide (NO₂). Some cases of NO₂ toxicity resolve with no persistent or delayed symptoms. The long-term prognosis for an individual patient can be determined by conducting follow-up pulmonary function tests.

In patients with lung damage from NO₂, improvement in pulmonary function may take weeks or months. Permanent mild dysfunction, likely due to bronchiolitis obliterans, may occur. This manifests as the following:

• Mild hyperinflation
• Abnormal flow at 50% or 75% of vital capacity (V_max50, V_max75)
• Reduction in forced expiratory flow from 25-75% of vital capacity (FEF_25-75)
• Increased respiratory resistance
• Airway obstruction

The lungs clear quickly with steroid treatment, and the chest radiograph may reveal no evidence of residual lung damage. Deconditioning can be treated with a pulmonary rehabilitation program.

Complications

Complications include secondary infection and bronchiolitis obliterans. Infection (eg, pneumonia) is possible because of the mucosal injury caused by pulmonary edema and the inhibition of immune function by NO₂. Bronchiolitis obliterans consists of fibrous granulation tissue that develops within small airways and alveolar ducts. It occurs weeks or months after the initial incident.

Mortality/morbidity

NO₂ poisoning may result in mortality or short-term and long-term morbidity. Manifestations of NO₂ toxicity are related to the concentration inhaled, duration of exposure, and time since exposure.

Illness from acute exposure is usually mild and self-limiting; however, some exposure results in pulmonary edema, bronchiolitis obliterans, or rapid asphyxiation. In one study, approximately one third of people with severe exposures died. Death can result from bronchiolar spasm, laryngeal spasm, reflex respiratory arrest, or asphyxia. If sufficiently high, NO₂ can displace oxygen and cause fatal asphyxiation. High concentrations can render a person helpless within 2-3 minutes.

A meta-analysis found consistent evidence of a relationship between NO₂, as a proxy for exposure to air pollution from traffic, with lung cancer. The study estimated that a 10-μg/m³ increase in exposure to NO₂ was associated with a 4% change in lung cancer rates.^[20]

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Patient Education

In general, patients should be taught to recognize the signs and symptoms of worsening pulmonary or cardiovascular function.

Educate farm workers at risk for exposure and development of silo filler's disease. Offer the following preventive advice:

• Stay out of silos during the 2-week danger period after the initial filling
• Close all doors before putting in the silage
• Go up the outside ladder to the level of silage
• If the silo is not completely full, remove the doors that lead down to the silage
• Enter the silo only with a complete oxygen support system (ie, air supply, self-contained breathing apparatus)
• Ventilate the silo by opening the cover flaps and running the silo blower for 24-48 hours before entering
• Never enter the silo alone or without a lifeline for rescue during the danger period.
• If it is necessary to enter a silo during filling, enter immediately after the last load

Advise patients who have had a significant exposure to nitrogen dioxide (NO₂) to avoid other pulmonary toxins. They should wear appropriate personal protective equipment in the workplace.

Advise patients that delayed symptoms, including life-threatening pulmonary edema and dyspnea caused by bronchiolitis obliterans, may result. Therefore, patients should be followed for a minimum of 2-3 months after exposure to monitor possible development of bronchiolitis obliterans.

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History

New-onset asthma or chronic obstructive pulmonary disease (COPD) in an otherwise previously healthy nonsmoker should immediately raise suspicion for potential nitrogen dioxide (NO₂) or other toxic gaseous exposure. One should first rule out common infectious etiologies for symptoms. Recent sick contacts, flulike or viral symptoms, any history of exposure to pulmonary mycoses, and other factors should all be considered prior to a diagnosis of NO₂ toxicity.

A thorough social history is then essential to identifying potential NO₂ exposures. Inquire about occupation. Welders, firefighters, military and aerospace personnel, traffic personnel, individuals working with explosives, and farmers generally have higher risk of exposure than those in other occupations. Additionally, those working with poor air ventilation are at much higher risk. Inquire about living situations. Individuals living in large urban centers or near congested roadways, highways, or airports are at increased risk of long-term exposure. Inquire about household burners, smoking history, and second-hand smoke exposure.

Attempt to establish the duration of exposure. Short-term and low-dose NO₂ exposures are generally less pathogenic.^[21] Timing of potential exposures may also be important with respect to seasonal and diurnal variations in air quality.^{[22, 23]} Silo filler’s disease is prevalent primarily during harvest seasons.

In acute exposure, symptoms may range from mild cough to mucous membrane irritation to sudden fatality. Suspect methemoglobinemia in patients exposed to NO₂ who exhibit cyanosis or dyspnea. The initial absence of significant symptoms does not exclude a subsequent development of serious disease. If a patient presents immediately postexposure, the full injury may not be appreciated; effects may occur up to 24 hours after the event.

Acute symptoms

Common signs and symptoms are as follows:

• Cough
• Light-headedness
• Dyspnea
• Chest tightness
• Choking
• Diaphoresis
• Loss of consciousness (at very high concentrations or in very susceptible individuals)

Coughing is the most common manifestation; however, it may not occur in all patients. Wheezing, chest pain, weakness, throat and ocular irritation, and nausea are less common with pure NO₂ exposure. NO₂ is not as soluble as other gases (eg, chlorine); consequently, mucous membrane irritation is not common. However, NO₂ may often be found in association with other harmful gases that do produce these effects, so NO₂ toxicity cannot be excluded.

Following a delay of 2-48 hours, patients exposed to NO₂ may develop the following signs and symptoms:

• Dyspnea
• Cough
• Chest pain
• Clinical manifestations of noncardiogenic pulmonary edema

Subacute signs and symptoms

The following may develop 2-6 weeks after initial exposure:

• Bronchiolitis obliterans, manifested as fever, cough, and dyspnea
• Diffuse reticulonodular or miliary pattern on chest radiography

Chronic, persistent, or delayed manifestations

These cases may resemble asthma or COPD exacerbations. Signs and symptoms may appear days or even weeks after both short- and long-term exposures. They include the following:

• Dyspnea
• Cough
• Chest pain
• Rapid breathing
• Chest tightness
• Headache
• Fever
• Insomnia
• Wheezing
• Chills
• Light-headedness
• Myalgias
• Nausea
• Hemoptysis
• Palpitations
• Blue lips
• Weakness
• Fatigue

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Physical Examination

Initial physical findings are generally mild but, depending on the severity of exposure, may progress quickly to life-threatening respiratory distress. Findings may be difficult to distinguish from severe asthma or COPD exacerbations. Pulmonary signs are the most common manifestation of nitrogen dioxide (NO₂) toxicity and include the following:

• Tachypnea
• Wheezing
• Rales
• Rhonchi
• Decreased breath sounds
• Stridor
• Tripod breathing or use of accessory muscles

Other signs include the following:

• Tachycardia
• Irritation or erythema of mucous membranes
• Conjunctival injection
• Decreased strength
• Skin burns, in cases of liquid N₂O₄ exposure
• Cyanosis, particularly of lips or distal extremities

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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:

• Arterial blood gas (ABG) or venous blood gas (VBG) levels
• Lactate level
• Methemoglobin (MHb) level

To help rule out infectious etiologies, request the following:

• Sputum culture and Gram stain
• Respiratory virus polymerase chain reaction (PCR) panel
• Urine Legionella
• Coccidioides immunoglobulin G and immunoglobulin M
• Histoplasma enzyme immunoassay
• Cryptococcal antigen

Other tests to possibly consider include the following:

• Glucose levels
• Complete blood cell (CBC) count

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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.

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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.

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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 Hospita....

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Computed Tomography

High-resolution computed tomography (CT) presentations vary from patchy subpleural ground glass opacities to a diffuse hyperlucency.

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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.

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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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Approach Considerations

If no initial symptoms are present, observe the patient for at least 12 hours for hypoxemia. Hospitalize the patient for 12-24 hours or longer for observation if gas exchange is compromised. Noncardiogenic pulmonary edema can take up to 48 hours to develop. Educate the patient on the possible symptoms and instruct the patient to return if symptoms develop.

Administer oxygen for hypoxemia. Intubation and mechanical ventilation may be necessary if gas exchange is severely impaired. Treat secondary infection, if present.

Administer volume expanders cautiously. The patient may require invasive monitoring because excessive administration of volume expanders can cause hydrostatic pulmonary edema. Nitrogen dioxide (NO₂) forms nitric oxide, causing vasodilation and an apparent volume depletion.^[24]

Transferring the patient to a tertiary care center for further diagnostic evaluation and ventilatory support may be necessary.

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Prehospital and Emergency Department Care

Rescuers must remove the patient from the source of exposure without endangering themselves. Wearing a self-contained breathing apparatus (SCBA) may be indicated. The patient should then receive supplemental oxygen, and, if needed, airway management and ventilatory support.

The primary emergency department (ED) treatment of NO₂-induced respiratory illness is supportive therapy directed at correction of hypoxemia, ventilatory failure, and secondary infection. Endotracheal intubation and mechanical ventilation may be required, depending on the degree of respiratory distress and hypoxemia. High-dose corticosteroids are suggested in the treatment of pulmonary manifestations, but data on their prophylactic use after nitrogen dioxide (NO₂) exposure are anecdotal.

Monitor continuous pulse oximetry. Pulse oximetry results may be misleading in the presence of methemoglobinemia, however.

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Inpatient Care

Patients who have been exposed to nitrogen dioxide (NO₂) should be admitted for at least 24 hours if they have any of the following:

• Dyspnea
• Altered mental status
• Hypoxemia
• A widened alveolar-arterial oxygen gradient

In patients who are critically ill, placement of a pulmonary artery catheter for monitoring of mixed venous oxygenation and pulmonary vascular resistance may assist in the management of oxygenation requirements, fluids, acute respiratory distress syndrome (ARDS), and physiologic variables.

Evidence of significant methemoglobinemia should prompt treatment with methylene blue (see Medication). Clinical improvement and resolution of hypoxemia and methemoglobinemia are helpful endpoints for discharge. Advise the patient to avoid exercise for 1-2 days after exposure.

In prolonged cases of toxicity with evidence of proliferative bronchiolitis obliterans, patients may be responsive to steroid therapy. Resolution of symptoms generally occurs slowly over a period of several months. Few data suggest that prophylactic steroids will prevent development of bronchiolitis obliterans. As mentioned above, constrictive bronchiolitis is not as responsive to steroid therapy.

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Deterrence/Prevention

Working environments should be evaluated for elevated nitrogen dioxide (NO₂) levels and proper ventilation and protective gear, such as SCBA, should be used. American Conference of Governmental Industrial Hygienists threshold limit values (ACGIH-TLV) for NO₂ are as follows:

• Time-weighted average (TWA): 3 ppm
• Short-term exposure limit (STEL): 5 ppm

National Institute of Occupational Safety and Health (NIOSH) values are as follows:

• Recommended exposure limit (REL): 1 ppm
• STEL (immediately dangerous to life or health): 20 ppm

National Fire Protection Association (NFPA) hazard ratings are as follows:

• Health (Blue) - 3
• Flammability (Red) - 0
• Reactivity (Yellow) - 0

Other workplace safety measures are as follows:

• Labels required: Poison gas, oxidizer, corrosive
• Respiratory equipment recommendations: Positive-pressure SCBA (according to North American Emergency Response Guide [NAERG] 124)
• Protective clothing: Chemically protective clothing, as recommended by the manufacturer (according to NAERG 124)

Exposure to air pollution and nitrogen dioxide in particular is increasingly recognized as a significant factor in the development of asthma, COPD and pulmonary disease.^[25] Some studies suggest the potential for antibiotics or anti-oxidants such as vitamin C or vitamin E to prevent or mitigate the progression of disease.^{[26, 27]} This remains an area in need of ongoing research.

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Consultations

Consult a pulmonary medicine or critical care specialist if the patient requires endotracheal intubation or hemodynamic monitoring. Consult with a regional poison control center or a local medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) to obtain additional information and patient care recommendations.

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Long-Term Monitoring

When a patient who has been placed on corticosteroid therapy acutely is discharged, prescribe corticosteroid taper for at least 8 weeks. Most authors agree that patients with bronchiolitis obliterans should be maintained on corticosteroids until their symptoms have resolved. A longer duration of therapy (ie, 6-12 months) may be indicated if symptoms of bronchiolitis obliterans persist or recur after initial steroid taper.

Inhaled sympathomimetics (eg, albuterol), anticholinergics (eg, ipratropium bromide), and steroids (eg, fluticasone propionate) may also be indicated if the patient develops symptoms of reactive airway disease. A typical asthma disease management plan can be used for these patients.

Conduct follow-up examinations at 1 week, 1 month, and 3 months after exposure, with serial pulmonary function testing and radiographs.

Multiple studies have shown an increased association between bacterial pneumonia, increased mortality, and inhalational exposures.^{[28, 29, 30]} At this time, however, the use of prophylactic antibiotics has not shown any long-term benefits in randomized controlled trials. Given the propensity for development of antibiotic resistance, long-term prophylactic antibiotics are not recommended.

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Medication Summary

Methylene blue is indicated for significant methemoglobinemia. However, note that methylene blue can cause serious central nervous system reactions in patients taking serotonergic psychiatric medications, which include numerous antidepressants and antipsychotic agents.^[31]

Other possible treatments may include antibiotics if infection becomes evident, and vasopressor drugs are required to correct normovolemic shock. High-dose corticosteroids are suggested in the treatment of pulmonary manifestations, but data on their use for prevention of bronchiolitis obliterans after nitrogen dioxide (NO₂) exposure are anecdotal.

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Methylene blue

• Dosing, Interactions, etc.

Clinical Context:  Methylene blue is the drug of choice for patients who are cyanotic from methemoglobinemia and symptomatic or whose methemoglobin level exceeds 30%. It is administered intravenously. It is available as 1% solution (10 mg/mL) in 10 mL ampules.

The US Food and Drug Administration (FDA) warns against the concurrent use of methylene blue with serotonergic psychiatric drugs, unless indicated for life-threatening or urgent conditions. Methylene blue may increase serotonin levels in the central nervous system as a result of monoamine oxidase–A (MAO-A) inhibition, increasing the risk of serotonin syndrome.

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Class Summary

Methylene blue (ie, tetramethyl thionine chloride) is the recommended antidote for methemoglobinemia. It is reduced to leukomethylene blue, which is then available to reduce methemoglobin to hemoglobin.

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Methylprednisolone (Solu-Medrol, Depo-Medrol, A-Methapred)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability, thus reducing the inflammatory response of bronchiolitis obliterans. Consider tapering if prolonged dosing (>14 d) is required. The dose can be tapered over 8 weeks, on the basis of clinical symptoms, radiographic findings, and spirometry results.

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Class Summary

These agents reduce the inflammatory response. Whether early administration can prevent development of noncardiogenic pulmonary edema is unknown. The decision to administer corticosteroids must be made on clinical grounds.

Corticosteroids are effective in treating bronchiolitis obliterans. Because not all patients with acute lung injury develop this condition, judge the risk factors and choose between prescribing the patient corticosteroids for prevention and monitoring the patient for clinical or radiographic evidence of bronchiolitis obliterans.

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Nitric oxide (INOmax)

• Dosing, Interactions, etc.

Clinical Context:  NO is produced endogenously from the action of the enzyme NO synthetase on arginine. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine monophosphate (cGMP), which then leads to vasodilation. When inhaled, NO decreases pulmonary vascular resistance and improves lung blood flow.

• References

Class Summary

One case report described a patient with ARDS secondary to silo filler’s disease who required nitric oxide (NO) therapy because of worsening oxygenation. Use of NO therapy requires great care because of the possibility of worsening pulmonary damage and methemoglobinemia, which are already present in patients with NO₂ toxicity.

• References