AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Nitrogen dioxide (NO₂) is a brownish gas that is produced primarily as a byproduct of high-temperature combustion.

• The American Chemical Society's Chemical Abstract Service (CAS) registry number for NO₂ is CAS #10102-44-0.
• The United Nations/Department of Transportation number for NO₂ is UN#1067.
• The National Institute of Occupational Safety and Health (NIOSH) Registry of Toxic Effects of Chemical Substances (RTECS) identifier for NO₂ is QW 9800000.

Workers are exposed to combustion-produced NO₂ in various occupations, including arc welders, firefighters, military and aerospace personnel, and those working with explosives. Nitric oxide (NO), NO₂ and other oxides of nitrogen are formed from nitrogen and oxygen during high-temperature combustion. NO is oxidized to NO₂, a precursor of ozone (O₃). NO, NO₂, and nitrogen tetroxide (N₂O₄) almost always occur together; hence, the terms oxides of nitrogen and nitrogen oxides are used in literature to refer to these molecules. The term NOX is used most often in air pollution literature in reference to the oxides of nitrogen.

NO₂ toxicity is also observed in environments where NO₂ is formed from noncombustion sources. These include silo fillers, where nitrogen oxides are a byproduct of anaerobic fermentation of crops, and indoor ice skating rinks, where the gas is generated by the propane-driven ice cleaning machine, the Zamboni. In addition, NO₂ from automobile exhaust smokestack emissions are thought to be a major contributor to the toxic effects of air pollution.

NO₂ is a deep lung irritant that can produce pulmonary edema and fatality if inhaled at high concentrations. The effects of NO₂ depend on the level and duration of exposure. Exposure to moderate NO₂ levels (50 ppm) may produce cough, hemoptysis, dyspnea, and chest pain. Exposure to higher concentrations of NO₂ (>100 ppm) can produce pulmonary edema that may be fatal or may lead to bronchiolitis obliterans. Some studies suggest that chronic exposure to NO₂ may predispose individuals to the development of chronic lung diseases, including infection and chronic obstructive pulmonary diseases.

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.^{1, 2, 3, 4} Although early data are inconclusive, some studies suggest HONO may contribute to the adverse health outcomes previously attributed to NO₂. The theoretical health risks of HONO include damage to the mucous membranes and lungs by direct contact with the acid, creation of the carcinogenic nitrosamines secondary to HONO combination with amines, and oxygen free radical production through HONO photolysis in air. However, further studies are needed to examine the differential effects of NO₂ and HONO.

Pathophysiology

The primary locus of NO₂ toxicity is the lung. Exposure to NO₂ induces pulmonary injury in a number of ways. NO₂ is converted to NO, HNO₃ (nitric acid), and HNO₂ (nitrous acid) in the distal airways, where it exerts direct toxic effects on type I pneumocytes and ciliated airway cells. NO₂ initiates free radical generation in the terminal bronchioles, resulting in protein oxidation, lipid peroxidation, and subsequent cell membrane damage. NO₂ also alters macrophage and immune function, causing impaired resistance to infection.

Methemoglobinemia may also be induced with the inhalation of NO₂ because NO is absorbed through the lungs and binds to hemoglobin, forming nitrosyl hemoglobin. NO has an affinity for hemoglobin that is several thousand times greater than that of carbon monoxide. This complex is readily oxidized to methemoglobin. Methemoglobinemia serves to compound the preexisting hypoxemia by causing a leftward shift of the oxygen-hemoglobin dissociation curve and further impairing tissue oxygenation. NO is synthesized endogenously from L-arginine by numerous cell types and has multiple physiologic roles.

Frequency

United States

Limited data in the United States and worldwide concerning the true prevalence of NO₂ exposure and its contribution to morbidity and mortality are available. The multiple gases and particulates that comprise pollution and the spontaneous conversion of NO₂ to other oxides make epidemiological studies difficult.

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.

Race

No epidemiologic studies have indicated that predilection to exposure or to the manifestations of exposure is attributable to race.

Sex

Historically, males are afflicted with the pulmonary sequelae more frequently than females because of their increased numbers in the predisposed occupations. However, no difference in physiologic response appears to be attributable to sex.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The diagnosis of nitrogen dioxide (NO₂) toxicity largely depends on the history of exposure. Query patients on this history if possible.

• Inquire about exposure and occupation. Welders, firefighters, military and aerospace personnel, individuals working with explosives, and farmers generally have higher risk of exposure than those in other occupations.
• Try to establish duration of exposure.
• 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.
• Following a delay of 2-48 hours, patients exposed to NO₂ may develop the following symptoms:
• • Dyspnea
  • Cough
  • Chest pain
  • Clinical manifestations of noncardiogenic pulmonary edema
• 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

Physical

Initial physical findings are sometimes mild but may progress over the following 72 hours to life-threatening respiratory distress.

• Pulmonary symptoms are the most common manifestation of NO₂ toxicity.
• • Cough
  • Dyspnea
  • Chest tightness
  • Choking
  • Wheezing
  • Chest pain
  • Rales
  • Rhonchi
  • Decreased breath sounds
  • Stridor
• Other acute symptoms
• • Light-headedness
  • Loss of consciousness
  • Restlessness
  • Agitation
  • Confusion
  • Irritation of mucous membranes, including the eyes
  • Conjunctival infection
  • Weakness
  • Fatigue
  • Nausea
  • Abdominal pain
  • Skin burns, in cases of liquid N₂O₄ exposure
• Delayed symptoms
• • Tachypnea
  • Headache
  • Fever, chills
  • Insomnia
  • Myalgias
  • Hemoptysis
  • Palpitations
  • Cyanosis
  • Coma

Causes

• Occupational risk factors for NO₂ exposure are high among farmers, particularly those who work near silos, firefighters, arc welders, military personnel, and aerospace workers (missile fuel). Any occupation that involves the production, transportation, or use of nitric acid is at risk.
• Other significant sources of risk include ice arenas with ice resurfacing (Zamboni) machines. Gas-fired and kerosene-fired household appliances and motor vehicle exhaust all pose significant risk of exposure.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No laboratory studies that are specific to nitrogen dioxide (NO₂)–induced illness have been reported.
• Pulmonary function tests, if obtained late in the clinical course when bronchiolitis obliterans has developed, demonstrate presence of restrictive and obstructive disease.
• Following a significant exposure, ABG findings usually reveal hypoxemia.
• Methemoglobin levels may be increased after exposure to NO₂. Although methemoglobin levels as high as 71% have been reported following exposure to nitrous fumes, welders exposed to NO₂ at 4-5 ppm were noted to have methemoglobin levels of 2-3%.
• Obtain a CBC count with a peripheral smear and examine it for indications of hemolysis.
• Measure glucose levels to assure that anxiety and restlessness is not caused by concomitant hypoglycemia; however, exposure to NO₂ does not cause a primary hypoglycemia.

Imaging Studies

• Chest radiography findings range from normal to noncardiogenic pulmonary edema to that of soft reticulonodular infiltrates.

TREATMENT

Section 6 of 11  

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• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Prehospital Care

• Direct prehospital care towards stabilization of pulmonary function. These actions should include removal of the patient from the source of exposure, provision of supplemental oxygen, and, if needed, airway management and ventilatory support.
• Be aware of the risk of exposure when treating patients and wear a self-contained breathing apparatus (SCBA), when indicated.

Emergency Department Care

• The primary treatment of nitrous dioxide (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 clinical degree of respiratory distress and hypoxemia.
• High-dose corticosteroids are suggested in the treatment of pulmonary manifestations, but data on their prophylactic use after NO₂ exposure is anecdotal.
• Most authors agree that patients with bronchiolitis obliterans should be maintained on corticosteroids until their symptoms have resolved.

Consultations

• 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.
• Prolonged critical care management is often required for the pulmonary complications of those patients who require endotracheal intubation.

MEDICATION

Section 7 of 11  

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• References

High-dose corticosteroids are suggested in the treatment of pulmonary manifestations, but data on their prophylactic use after nitrous dioxide (NO₂) exposure are anecdotal.

Drug Category: Corticosteroids

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.

Drug Category: Antidotes

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

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients presenting with hypoxemia, dyspnea, or an altered level of consciousness require observation in the hospital for a minimum of 24 hours.
• Determine discharge decisions based on clinical improvement and resolution of hypoxemia and methemoglobinemia.
• Patients initially asymptomatic following a known exposure should be observed for at least 8 hours for evidence of developing hypoxemia and respiratory failure. Noncardiogenic pulmonary edema may develop slowly over 48 hours after a significant exposure.

Further Outpatient Care

• Following a known exposure, perform complete pulmonary function tests and clinical evaluations in 3 weeks and again in 3 months.

In/Out Patient Meds

• Corticosteroids may need to be tapered over a long period (6-12 mo) if the development of toxic bronchiolitis obliterans is a serious concern.
• Inhaled sympathomimetics (eg, albuterol), anticholinergics (eg, ipratropium bromide), and steroids (eg, fluticasone propionate) may be indicated for those who develop a reactive airways dysfunction syndrome (RADS) postexposure.

Deterrence/Prevention

Working environments should be evaluated for elevated nitrous dioxide (NO₂) levels and proper ventilation and protective gear, such as SCBA, should be used.

Workplace standards are as follows:

• American Conference of Governmental Industrial Hygienists threshold limit values (ACGIH-TLV)
• • Time weighted average (TWA) - 3 ppm
  • Short-term exposure limit (STEL) - 5 ppm
• The National Institute of Occupational Safety and Health (NIOSH) values
• • Recommended exposure limit (REL) - 1 ppm 
  • STEL (immediately dangerous to life or health) - 20 ppm
• Labels required - Poison gas, oxidizer, corrosive
• National Fire Protection Association (NFPA) hazard ratings
• • Health (Blue) - 3
  • Flammability (Red) - 0
  • Reactivity (Yellow) - 0
• Respiratory 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)

Prognosis

• Overall, the long-term prognosis is good for patients who survive the initial exposure to NO₂.
• The long-term prognosis is determined by follow-up pulmonary function evaluation.

Patient Education

• Advise patients who have had a significant exposure to 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to consider the asymptomatic period and delayed onset of symptoms associated with nitrogen dioxide (NO₂) toxicity; discharging the patient from the emergency department too soon
• Failure to consider NO₂ toxicity in patients who present with dyspnea and have occupations with risk of exposure
• Failure to recognize early signs of significant respiratory distress and document either PO₂ or oxygen saturation via pulse oximetry
• Failure to have the patient monitored in a setting where respiratory support is immediately available

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Bronchiolitis obliterans following exposure to nitrogen dioxide. (Radiograph courtesy of Dr Ann Leung, Stanford University Hospital, Department of Radiology, Palo Alto, CA)
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Media type:  Radiograph

Media file 2:  Noncardiogenic pulmonary edema following exposure to nitrogen dioxide. (Radiograph courtesy of Dr Ann Leung, Stanford University Hospital, Department of Radiology, Palo Alto, CA)
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Media type:  Radiograph

Media file 3:  Chemical terrorism agents and syndromes: signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/chemical.html.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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15. Sagai M, Ichinose T. Lipid peroxidation and antioxidative protection mechanism in rat lungs upon acute and chronic exposure to nitrogen dioxide. Environ Health Perspect. Aug 1987;73:179-89. [Medline].
16. van Bree L, Rietjens I, Alink GM, et al. Biochemical and morphological changes in lung tissue and isolated lung cells of rats induced by short-term nitrogen dioxide exposure. Hum Exp Toxicol. Jul 2000;19(7):392-401. [Medline].
17. Veeramachaneni NK, Harken AH, Cairns CB. Clinical implications of hemoglobin as a nitric oxide carrier. Arch Surg. Apr 1999;134(4):434-7. [Medline].
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19. World Health Organization. Nitrogen oxides. In: Recommended Health-Based Occupation Exposure Limits for Respiratory Irritants. 1984:73-114.

Article Last Updated: Jun 10, 2008