Continuing Education Activity

Nitrogen dioxide and other oxides of nitrogen are found in a variety of occupational settings. This activity reviews the evaluation, treatment, and management of nitrogen dioxide toxicity. This article also explains the role of healthcare professionals in evaluating and treating patients with exposure to oxides of nitrogen and its resultant toxicity in an emergency setting, as well as providing recommendations for patients with long-term sequelae of nitrogen dioxide toxicity.

Objectives:

• Describe the pathophysiology of nitrogen dioxide toxicity and its potential sources of exposure.
• Identify patients that have suffered exposure to nitrogen dioxide and summarize potential symptoms and treatment patterns.
• Review the appropriate observation time and rationale for patients with significant exposures to nitrogen dioxide.
• Summarize interprofessional management of patients with nitrogen dioxide toxicity to improve patient outcomes.

Introduction

Nitrogen is a colorless, tasteless, and odorless gas that comprises up to 78% volume by air. It usually is an inert diatomic gas that has no direct physiologic toxicity. Nitrogen oxides (nitric oxide and nitrogen dioxides) are gases that can be released from nitrous or nitric acid as a byproduct of the reaction between nitric acid and organic materials, burning of nitrocellulose, as a byproduct of detonations, and as a breakdown of rocket fuel.[1][2] A person may also become exposed to nitrogen oxides from electric arc welding, electroplating, and engraving. Nitrogen oxides are found in engine exhaust and are also produced when filling silos with grain with a high nitrite content. Nitric oxide reacts with oxygen to form nitrogen dioxide.[3]

Etiology

Oxides of nitrogen can be produced by ice resurfacing machines (so-called "Zamboni machines") during the combustion of their fuel source, propane. It can be significant exposure for an indoor ice-skating rink with poor ventilation. In 1987, 116 people attending an ice hockey game in Minnesota reported various symptoms from cough to hemoptysis due to significant nitrogen dioxide exposure. The classic example of nitrogen dioxide toxicity is known as “silo filler’s disease.” Silo filler's disease occurs when a patient inhales nitrogen dioxide that forms during the decomposition of silage.[4][5] Patients may experience various symptoms depending on the duration of exposure and the concentration of nitrogen dioxide. If a patient has a significant exposure initially, they may present with shortness of breath, cough, or even symptoms consistent with acute respiratory distress syndrome (ARDS). However, symptoms of nitrogen dioxide toxicity may occur remotely from the work site due to its delayed presentation.[1][5]

Epidemiology

Inhalation of numerous gases, aerosols, fumes, or dust may cause lung injury, asphyxiation, or systemic effects. The use of industrial chemicals that could be sources of toxicity is on the rise. The National Occupational Exposure Survey (NOES) estimates that more than one million U.S. workers to be at risk for pulmonary irritants each year.[6] Employees with occupations that expose them to nitrogen oxides are most commonly at risk for toxicity.  They may be unaware of ongoing exposures. Longer exposures allow a higher concentration of nitrogen oxides to reach the lower airways, leading to delayed lower respiratory tract injury.

Silo filler's disease is an occupational disease that occurs due to the inhalation of nitrogen oxides. Nitrogen oxides form when filling agricultural grain silos with organic matter, typically corn or other grains. The most significant risk of overexposure occurs within the first month after the silos are filled. Oxides of nitrogen are heavier than air and gather on top of the silage. Exposure occurs when a worker enters a silo or opens the hatch without proper respiratory protection. It is worth noting that silo filler's disease is an entirely preventable illness with proper workplace controls and personal protective equipment. As such, a case of silo filler's disease may require reporting to local public health authorities in some jurisdictions.[6]

Pathophysiology

Nitrogen oxides are irritant gases with low water solubility. In contrast, highly water-soluble gases generally deposit in the upper airways causing relatively quick onset upper airway and mucous membrane irritation. This situation typically prompts exposed individuals to remove themselves from the exposure early on. Gases with lower water solubility, such as oxides of nitrogen, do not produce this early mucous membrane irritation. Thus, without this effective warning, patients may receive a larger cumulative inhaled dose of nitrogen dioxide, and the gas may travel deeper into the respiratory tract.[6] It is because of this low water solubility of nitrogen oxides that delayed-onset pulmonary effects occur. Nitrogen dioxide and other oxides of nitrogen damage lung tissue through the ultimate generation of reactive nitrogen-derived free radicals. Furthermore, upon contact with water, oxides of nitrogen produce nitric acid, following irritating or damaging lung tissue.[7] Nitrogen oxide is low water-soluble gas and is, therefore, able to penetrate the distal bronchioles and adjacent alveoli. Nitrogen dioxide is thought to cause a direct injury to the alveolar epithelial cells via the generation of toxic free radicals, which may lead to diffuse alveolar injury damage.[2] With increasing concentration exposures, there is an increased risk of pulmonary edema. Toxic pneumonitis and bronchiolitis can develop at exposure levels of 25 to 100 ppm. Exposures greater than 150 ppm are usually fatal due to bronchiolitis obliterans, chemical pneumonitis, and pulmonary edema.[6]

Agents that penetrate the distal airways can lead to persistent, chronic injuries such as bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP). BO is defined by narrowing and obstruction of the distal airways.  Patients with BO may present with shortness of breath, cough, fever, and malaise. On a chest radiograph, one may see hyperinflation of the lungs. Pathology reveals granulation tissue, small airway lumens, and bronchiolar obliteration. BO may be delayed in onset. BOOP usually responds well to systemic corticosteroids. Pulmonary function testing usually reveals a restrictive pattern.[8] Lee et al. describe a patient with clinical, radiological, and pathological features of BOOP, likely a delayed consequence of inhaling nitrogen dioxide fumes after a fire.[9] 

The degree of lung injury is affected by multiple factors. Patients that are elderly or very young have a history of allergic or nonallergic bronchospastic response, history of smoking, those with underlying lung debilitating illness, particularly underlying reactive airway disease or lung disease that impairs host defense mechanisms typically have a worse course.[6]

History and Physical

Given its low water solubility, a patient may have prolonged exposure to nitrogen dioxide with little or no warning symptoms.  Some early warning symptoms may include a mild cough or nausea. Exposure to very high concentrations may result in upper respiratory symptoms, including burning eyes, sore throat, or cough.[7] Chemical pneumonitis may develop up to 24 hours after exposure, manifesting as progressive hypoxemia and pulmonary edema. Some cases may develop into bronchiolitis obliterans days after exposure.[3] Patients may present with symptoms consistent with acute respiratory distress syndrome (ARDS), sepsis, or acute heart failure. Thus, a thorough history of exposure is a necessity. 

Nitrogen dioxide toxicity can be described as a triphasic illness. The initial presentation may consist of cough, wheezing, dyspnea, central chest pain, fever, sweating, and weakness. The physical exam at this stage may reveal wheezing and crackles. A patient’s chest X-ray may be normal or show pulmonary edema. In the second phase, the patient may be relatively asymptomatic. The third phase develops 2 to 8 weeks later when a patient may develop bronchiolitis obliterans. A patient may experience fever, chills, wheezing, cough, dyspnea, chest pain. In this stage, the chest x-ray can be normal or show small, diffuse nodules.[3][2]

Evaluation

Nitrogen dioxide-exposed patients should receive regular monitoring of vital signs and mental status. Continuous invasive monitoring of oxygen saturation and end-tidal carbon dioxide are recommendations to monitor respiratory status. The diagnosis of nitrogen dioxide toxicity will be based on a history of exposure as no specific laboratory, or radiographic findings exist to confirm oxides of nitrogen exposure. Inquiries into the specific occupational or industrial environments where a patient works may provide clues. Adjunctive testing in the emergency setting will likely include arterial blood gas and chest radiography. After recovery from the acute toxicity, pulmonary function testing may be indicated to assess for residual degradation of pulmonary function.[6]

An arterial blood gas can represent if a patient is hypoxemic or has a low partial pressure of oxygen. Nitrogen dioxide directly oxidizes oxyhemoglobin to a methemoglobin-peroxide complex. A chest X-ray may demonstrate patchy opacities. Pulmonary function testing may determine if a restrictive lung pattern has developed, such as bronchiolitis obliterans.[2]

A diagnosis of methemoglobinemia should be a consideration in patients who are hypoxemic and cyanotic.[10] Methemoglobin is hemoglobin in an oxidized form, and many oxidizing chemicals and drugs can induce methemoglobinemia (MetHb), including nitrites and nitrates. This abnormal hemoglobin cannot carry oxygen and induces functional anemia. The diagnosis is suggested by "chocolate brown" blood, usually apparent when MetHb is greater than 15% and the presence of hypoxemia unresponsive to oxygen. An ABG will show a normal partial pressure of oxygen. Co-oximetry is the gold standard in the diagnosis of MetHb. Patients with levels under 15 are usually asymptomatic. Levels of 15% to 20% can cause cyanosis, and patients may be mildly symptomatic. Levels of 20% to 45% cause marked cyanosis, and patients are moderately symptomatic. Levels of 45 to 50% cause severe cyanosis and severe symptomatic patients and levels greater than 70% may be lethal. Treatment includes removal of the offending agent, aggressive supplemental oxygen, and treatment with the antidote methylene blue.[11][12]

Treatment / Management

Significant inhalational exposures to nitrogen dioxide, or other oxides of nitrogen, should be referred to an emergency department for evaluation. Consultation with the local poison control center is recommended by calling 1-800-222-1222 in the United States. 

The clinical evaluation of the nitrogen dioxide poisoned patient should focus first on primary supportive measures such as ensuring a patent airway, as well as supporting oxygenation, ventilation, and circulation as needed. Immediate removal from the source of exposure is paramount, but caution is necessary to prevent other rescue personnel from becoming additional casualties of nitrogen oxides. Upon removal from exposure, supplemental oxygen is generally recommended, but even simply moving to an area with fresh flowing air will be initially beneficial. External decontamination should not be necessary, and treating health care personnel need not be concerned with cross-contamination of nitrogen oxide to themselves or other patients. Even asymptomatic victims of nitrogen dioxide exposure require observation in a monitored setting for a minimum of 24 hours post-exposure due to the concern for delayed development of chemical pneumonitis.   

Treatment of chemical pneumonitis and/or noncardiogenic pulmonary edema is primarily supportive with supplemental oxygen, inhaled bronchodilators, inhaled corticosteroids, and/or mechanical ventilation as required. In acute lung injury, corticosteroids have not proven to be beneficial. However, corticosteroids may be indicated in patients with delayed lung injury, such as bronchiolitis obliterans.[6] In one case report, a patient with an acute nitrogen dioxide exposure from electroplating received intravenous methylprednisolone pulse therapy at 500 mg per day for three days early in the hospitalization with a reported dramatic improvement in respiratory status by day 5.[2][13]

Differential Diagnosis

The differential diagnosis for delayed onset pneumonitis following gaseous exposure includes oxides of nitrogen, chlorine gas, chloramine gas, ammonia, phosgene, sulfur oxides, hydrogen sulfide, cadmium, or metal fume fever (zinc oxide fumes), among others. Indeed, any irritating gas could produce this picture. Non-poisoned patients with severe pneumonia, sepsis, acute heart failure, or any form of acute respiratory distress syndrome (ARDS) might also present with symptoms similar to those caused by nitrogen dioxide exposure. Only a thorough history of occupational and/or environmental exposure will help determine the etiology of the illness.[2] 

• Acute respiratory distress syndrome
• Cardiogenic pulmonary edema
• Congestive heart failure and pulmonary edema
• Asthma
• Upper respiratory tract infection
• Lower respiratory tract infection
• Methemoglobinemia
• Farmer lung
• Smoke inhalation
• Carbon monoxide toxicity
• Miliary tuberculosis
• Chlorine gas toxicity
• Hydrogen sulfide toxicity
• Phosgene toxicity

Prognosis

Prognosis will vary depending on intensity, duration, and frequency of exposure to nitrogen dioxides. However, most patients can expect to make a full recovery after an initial acute nitrogen dioxide exposure, provided adequate supportive care is available. Extensive critical care support with mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) may be required to bridge the patient through acute toxicity and allow time for healing and recovery.

Complications

Following the initial acute toxicity of chemical pneumonitis, a third phase develops 2 to 8 weeks later when a patient may develop bronchiolitis obliterans. A patient may experience fever, chills, wheezing, cough, dyspnea, chest pain. In this stage, the chest radiograph can be normal or show small, diffuse nodules. This stage may respond to systemic corticosteroids based on anecdotal evidence.[6]

Consultations

All patients with significant exposure require admission to a monitored setting for at least a 24-hour observation. Consultation with the local poison control center and/or medical toxicologist is recommended.  Consultation with a critical care physician or pulmonary medicine physician may also be appropriate.

Deterrence and Patient Education

The ACGIH (American Conference of Governmental Industrial Hygienists) recommends a TWA (time-weighted average) of 3ppm for nitrogen dioxide and 5ppm STEL (short-term exposure limit). NIOSH (National Institute for Occupational Safety and Health) recommends a PEL (permissible exposure limit) of 5 ppm.  

The U.S. Environmental Protection Agency (EPA) maintains a national ambient air quality standard (NAAQS) for nitrogen oxides of 1-hour maximum daily concentration of 100 ppb and an annual standard at a level of 53 ppb. 

The World Health Organization (WHO) recommends current guidelines of 40 mcg/m^3 as an annual mean and 200 mcg/m^3 as a 1- hour mean. 

Pearls and Other Issues

• Nitrogen dioxide exposures may occur secondary to stored silage in grain silos, "Zamboni" ice resurfacers, electroplating, or as a combustive byproduct of nitrogen fuel.
• Acute exposures should be admitted for 24 hours to observe for signs of delayed pneumonitis.
• Be aware of nitrogen dioxide's triphasic illness and assess for signs and symptoms 2 to 8 weeks after initial exposure.
• Treatment includes removal from source, supportive care for any acute lung injury, and steroids in the setting of bronchiolitis obliterans.

Enhancing Healthcare Team Outcomes

Nitrogen dioxide exposed patients may present with nonspecific signs and symptoms of airway irritation or may initially be asymptomatic.  Eliciting a thorough occupational and/or environmental exposure history is paramount in making the proper clinical diagnosis and initiating appropriate treatment. Nitrogen dioxide also has the potential to cause significant morbidity and mortality, given its delayed and chronic effects. An emergency physician is almost always involved in the care of the acutely exposed patient. It is essential to consult with a medical toxicologist on any suspected or confirmed cases. If a patient develops lung injury as a result of nitrogen dioxide toxicity, a pulmonologist or critical care physician should also be consulted to help manage chronic and prolonged cases. [Level 3] Local public health authorities may also need to be involved in investigating workplace exposures.[3] 

The interprofessional team provides care starts with the emergency medical technicians, triage nurses, and emergency department personnel. Toxicology pharmacists or clinicians may assist in the pharmaceutical aspects of management and care, including performing medication reconciliation and verifying dosing, reporting any concerns to the managing clinicians. Critical care nurses monitor patients, administer treatment, and ensure communication between the team. [Level 5]

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References

1.

Perez-Lauterbach D, Nahum R, Ahmad H, Topeff JM, Dossick D, Cole JB, Arens AM. Dose-Dependent Pulmonary Injury Following Nitrogen Dioxide Inhalation From Kinepak^™ Detonation. J Emerg Med. 2019 Aug;57(2):177-180. [PubMed: 31060842]

2.

Kido Y, Mitani A, Isago H, Takeshima H, Narumoto O, Tanaka G, Yamauchi Y, Takai D, Ohishi N, Nagase T. Successful treatment of pulmonary injury after nitrogen oxide exposure with corticosteroid therapy: A case report and review of the literature. Respir Med Case Rep. 2017;20:107-110. [PMC free article: PMC5257191] [PubMed: 28138425]

3.

Meaden CW, Kashani JS, Vetrano S. Pulmonary Edema Occurring after Nitric Acid Exposure. Case Rep Emerg Med. 2019;2019:9303170. [PMC free article: PMC6350573] [PubMed: 30775039]

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Amaza IP, Kreidy MP. Silo-Filler's Disease: One Health System's Experience and an Update of the Literature. J Agromedicine. 2020 Jan;25(1):8-13. [PubMed: 30879430]

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Ruth-Sahd LA, White KA. Bronchiolitis obliterans organizing pneumonia. Dimens Crit Care Nurs. 2009 Sep-Oct;28(5):204-8. [PubMed: 19700963]

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Lee LT, Ho CH, Putti TC. Bronchiolitis obliterans organizing pneumonia following nitric acid fume exposure. Occup Med (Lond). 2014 Mar;64(2):136-8. [PubMed: 24319049]

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Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J. 2011 Nov;104(11):757-61. [PubMed: 22024786]

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Ashurst J, Wasson M. Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. Del Med J. 2011 Jul;83(7):203-8. [PubMed: 21954509]

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Pauli SA, Leake SJ, Björck M, Willmott PR. Atomic imaging and direct phase retrieval using anomalous surface x-ray diffraction. J Phys Condens Matter. 2012 Aug 01;24(30):305002. [PubMed: 22713776]

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Jayalakshmi TK, Shah S, Lobo I, Uppe A, Mehta A. Acute lung injury following exposure to nitric acid. Lung India. 2009 Oct;26(4):149-51. [PMC free article: PMC2876705] [PubMed: 20532002]

Disclosure: Alexandra Amaducci declares no relevant financial relationships with ineligible companies.

Disclosure: John Downs declares no relevant financial relationships with ineligible companies.