Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

NITROGEN OXIDES

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This management includes acute and chronic toxicity associated with nitrous oxide fume exposures. Nitrous oxide fumes are mixtures of varying proportions of five oxides, including nitric oxide (NO), nitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrogen tetroxide (N2O4), and nitrogen pentoxide (N2O5) (Gosselin et al, 1984).
    B) Nitrogen dioxide and nitrogen oxide (nitric oxide) are the primary toxicologic hazards, however, nitrogen oxide (nitric oxide) has much less pulmonary toxicity than nitrogen dioxide and is dealt with separately (Gosselin et al, 1984).

Specific Substances

    A) Nitrogen Trioxide (N2O3)
    1) Nitrous Anhydride
    2) Dinitrogen Trioxide
    3) CAS 10544-73-7
    Nitrogen Dioxide - NO2
    1) CAS 10102-44-0
    Nitrogen Tetroxide (N2O4)
    1) Dinitrogen Tetroxide
    2) Dinitrogen Tetroxide, Liquid
    3) Ntrogen Oxide
    4) Nitrogen Peroxide, Liquid
    5) Nitrogent Tetroxide
    6) Dinitrogen Tetroxide
    7) CAS 10544-72-6

Available Forms Sources

    A) FORMS
    1) Nitrous fumes consist of nitrous oxide (N2O), nitric oxide (NO), nitrogen trioxide (N2O3), nitrogen dioxide (NO2) and its dimer nitrogen tetroxide (N2O4), and nitrogen pentoxide (N2O5). Nitrogen dioxide is the principle hazard.
    B) SOURCES
    1) Nitric oxide, a colorless gas, is a principle constituent of smog and is oxidized to nitrogen dioxide by oxygen. Nitrogen dioxide is a reddish-brown gas. At low temperatures nitrogen dioxide exists as nitrogen tetroxide, a colorless gas.
    2) Nitrogen oxides are released in the reaction between nitric acid and any organic material, in the exhaust from metal cleaning, in the gases from electric arc welding, in electroplating, in engraving, in dynamite blasting, in diesel engine exhaust, in burning of nitrocellulose, in combustion of some shoe polishes, and in grain silos.
    3) Nitrogen oxides are also formed following reaction between nitric acid and copper from pennies (Sriskandan & Pettingale, 1985).
    C) USES
    1) Nitrous oxide is widely used as an anesthetic and has been measured in the air of operating rooms at concentrations exceeding 100 ppm (Gray, 1989).
    2) Nitrogen oxides are formed endogenously in the lung and respiratory tract by the enzyme, nitric oxide synthetase, and may play a role in airway and smooth muscle relaxation. Nitric oxide inhalation therapy may be beneficial to some persons with asthma, adult respiratory distress syndrome (ARDS), or pulmonary hypertension (Gaston et al, 1994).
    3) Nitrogen dioxide can be formed from the nitrates in corn and hay by anaerobic bacterial fermentation; it may occur at 200 to 2,000 ppm in silos (Epler, 1989).
    4) Ice resurfacers, powered by internal combustion engines, may produce NO2 (Anderson, 1971).
    5) Nitrogen dioxide levels may be increased inside homes where gas stoves are used for cooking (Goldstein et al, 1988) or kerosene heaters are used for heat (Adgate et al, 1992). Koo et al (1990) found that women in Hong Kong increased their nitrogen dioxide exposure levels by 18% if they used kerosene, LP gas, or similar fuels for cooking at home.
    6) FIREFIGHTERS: May be exposed to burning mattresses, chemicals, or nitrocellulose x-ray film that give off dangerous nitrogen oxides (Haddad & Winchester, 1990).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Exposure to nitrogen oxides is usually via inhalation and may result in acute or chronic changes of the pulmonary system including pulmonary edema, pneumonitis, bronchitis, bronchiolitis, fibrosing bronchiolitis, bronchiolitis obliterans, emphysema and possibly methemoglobinemia.
    B) Exposure to low concentrations of nitrogen oxides usually results in mild and transient symptoms including a slight cough, fatigue and nausea. Very concentrated exposures may result in immediate coughing, choking, headache, nausea, abdominal pain and dyspnea.
    C) Following exposure, there may be a latent period of 5 to 72 hours, before inflammation of the lungs develops causing exudation into alveolar spaces. Clinical deterioration may then occur.
    0.2.4) HEENT
    A) Conjunctivitis may occur.
    0.2.5) CARDIOVASCULAR
    A) A weak rapid pulse and circulatory collapse may develop.
    0.2.6) RESPIRATORY
    A) Cough, hyperpnea and dyspnea may be seen. Rapid and shallow respirations, mild or violent coughing and physical signs of acute lung injury may develop. Acute lung injury may be delayed 4 to 24 hours.
    B) Nitrogen dioxide can cause bronchospasm, and acute or chronic obstructive lung disease (after repeated/chronic exposure), and may increase susceptibility to respiratory virus infections.
    0.2.7) NEUROLOGIC
    A) Fatigue, restlessness, anxiety, mental confusion, lethargy, and loss of consciousness may be noted.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting and abdominal pain may develop.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia may occur with nitric oxide exposures.
    0.2.14) DERMATOLOGIC
    A) Cyanosis may occur.

Laboratory Monitoring

    A) Monitor pulmonary function. Chest x-ray may be diagnostic of acute lung injury. Monitor pulse oximetry and arterial blood gases as clinically indicated.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) SUPPORT
    1) Treatment of exposures to nitrogen oxide is supportive. Treatment should be directed towards maintaining oxygenation by using oxygen or assisting ventilation if necessary. In patients with bronchiolitis, steroids may be beneficial in decreasing the amount of inflammation. Methemoglobinemia and mild acidosis may be present, but specific treatment for these conditions is usually unnecessary.
    B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    C) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    D) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    E) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.

Range Of Toxicity

    A) Death due to airway obstruction from edema of the glottis has not been well documented, but is estimated to occur with nitrogen dioxide concentrations greater than 100 ppm. The odor of nitrogen dioxide is perceptible at 1 to 3 ppm. Symptoms generally appear at 13 ppm.

Clinical Effects

Summary Of Exposure

    A) Exposure to nitrogen oxides is usually via inhalation and may result in acute or chronic changes of the pulmonary system including pulmonary edema, pneumonitis, bronchitis, bronchiolitis, fibrosing bronchiolitis, bronchiolitis obliterans, emphysema and possibly methemoglobinemia.
    B) Exposure to low concentrations of nitrogen oxides usually results in mild and transient symptoms including a slight cough, fatigue and nausea. Very concentrated exposures may result in immediate coughing, choking, headache, nausea, abdominal pain and dyspnea.
    C) Following exposure, there may be a latent period of 5 to 72 hours, before inflammation of the lungs develops causing exudation into alveolar spaces. Clinical deterioration may then occur.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER - Increased body temperature may occur in patients with pulmonary symptoms following acute exposures (Tague et al, 2004; Zwemer et al, 1992; Horvath et al, 1978; Moskowitz et al, 1964).

Heent

    3.4.1) SUMMARY
    A) Conjunctivitis may occur.
    3.4.3) EYES
    A) CONJUNCTIVITIS - Irritation of the eyes has been reported.
    B) CORNEAL INJURIES/ANIMAL - Persisting corneal opacities were noted when rabbits were exposed for 8 hours to 70 ppm of NITROGEN DIOXIDE gas (Steadman et al, 1966). No significant corneal damage was noted when rabbits were exposed for 4 hours, up to 20 ppm of NITROGEN DIOXIDE gas (Grant & Schuman, 1993).
    3.4.6) THROAT
    A) Edema of the glottis with subsequent airway obstruction may occur (Tse & Bockman, 1970).

Cardiovascular

    3.5.1) SUMMARY
    A) A weak rapid pulse and circulatory collapse may develop.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) A weak, rapid pulse and circulatory collapse may develop (Tse & Bockman, 1970). Severe systemic hypotension may result from the effect of nitrite and/or nitrate ions in the blood (Prys-Roberts, 1967).

Respiratory

    3.6.1) SUMMARY
    A) Cough, hyperpnea and dyspnea may be seen. Rapid and shallow respirations, mild or violent coughing and physical signs of acute lung injury may develop. Acute lung injury may be delayed 4 to 24 hours.
    B) Nitrogen dioxide can cause bronchospasm, and acute or chronic obstructive lung disease (after repeated/chronic exposure), and may increase susceptibility to respiratory virus infections.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) MECHANISM OF INJURY - The toxic mechanisms have not been fully elucidated. Nitrogen dioxide is a powerful oxidant and tissue damage may be the result of of free radical production followed by lipid peroxidation and cellular membrane destruction (Meulenbelt et al, 1993). When combined with moisture and water in the respiratory tract, nitrogen dioxide also slowly forms nitric and nitrous acid which aggravate the injury. It has been suggested that methemoglobinemia may occur as a result of absorption of the gas by the blood (Fleetham et al, 1978).
    a) The nitrates and nitrites formed from dissociation of nitric acid cause local and systemic tissue damage with inflammation of the lungs resulting in exudation into alveolar spaces (Ramirez & Dowell, 1971).
    2) SIGNS/SYMPTOMS - Cough, hyperpnea, hemoptysis and dyspnea may occur after exposures to nitrogen oxides. Rapid and shallow respirations, mild or violent coughing with frothy expectoration, and physical signs of pulmonary edema may develop. Acute lung injury may be delayed, occurring 4 to 24 hours following exposure to nitrous fumes (Proctor et al, 1988).
    3) CASE SERIES - A group of 18 steel workers were exposed to nitrogen oxides on several occasions because of malfunctions in a blast furnace. Shortly after exposure, 14 of them developed chest tightness and cough with deep breathing. After 15 to 30 minutes several of them developed shivers, exertional dyspnea, and a sensation of cold. One patient had an episode of hemoptysis. Symptoms resolved over one to two weeks. A patient with underlying asthma had an exacerbation. Four of the workers had bilateral lower lung infiltrates on chest radiograph, suggesting acute lung injury, which resolved after 24 hours. Initial lung function showed a significant restrictive pattern, which improved to baseline within one month (Tague et al, 2004).
    4) CASE REPORT -A 17-year-old male was admitted to the ICU with pneumonitis 24 hours following exposure to nitrogen dioxide at an ice-skating rink. His condition worsened during the next few hours, and he developed severe hypoxemia. Chest x-ray revealed parenchymatous infiltrative lesions and widened bronchi (Karlson-Stiber et al, 1996).
    5) Delayed acute lung injury, rales and wheezes may develop in the absence of immediate evidence of pulmonary damage (Douglas et al, 1989).
    B) ACUTE LUNG INJURY
    1) ACUTE LUNG INJURY (NON-CARDIOGENIC PULMONARY EDEMA) - Adult respiratory distress syndrome may develop following exposure to nitrogen dioxide (Ellenhorn & Barceloux, 1988). Death due to blockade of gas exchange in the lungs may occur within hours after the first evidence of pulmonary edema. Delayed pulmonary edema, rales and wheezes may develop in the absence of immediate evidence of pulmonary damage (Douglas et al, 1989).
    2) CASE REPORT - Non-cardiogenic pulmonary edema has been reported in a 17-year-old male hockey player within 24 hours after inhaling nitrogen oxides produced by a Zamboni machine used to resurface ice on a rink. The patient presented to the ED with dyspnea, tachycardia and tachypnea. Significant hypoxemia was reported. His condition improved over the next 3 days (Morgan, 1995).
    3) SILO-FILLER'S DISEASE has been described in grain silo workers with exposures to nitrogen oxides from freshly filled silos. A respiratory distress syndrome, presenting with dyspnea and progressing to pulmonary edema, may develop (Horvath et al, 1978; Moskowitz et al, 1964; Zwemer et al, 1992).
    a) CASE REPORT - A 20-year-old male experienced wheezing, pulmonary edema, hypoxia, and fever after working in a silo shortly after it had been filled. Treatment consisted of 3 months of steroid therapy (Moskowitz et al, 1964).
    b) CASE REPORT - Approximately 4 weeks following exposure to nitrogen oxides from a poorly ventilated silo chute, a 29-year-old male presented to the ED with tachypnea, dyspnea, cyanosis, and severe choking and coughing. A diagnosis of pulmonary edema was made. The patient went into respiratory insufficiency and died despite oxygen and aminophylline therapy (Weston et al, 1972).
    c) CASE SERIES - Zwemer et al (1992) report a case series of 20 patients diagnosed with Silo fillers disease. In 14 cases the presenting symptom was dyspnea. Nine patients complained of cough. In all but one, proper ventilation procedures were not followed. Four patients died as a result of the nitrogen oxide inhalational exposure.
    C) BRONCHOSPASM
    1) Nitrogen dioxide can cause bronchospasm (Epler, 1989).
    2) Mohsenin (1987) noted that asthmatics exposed to 0.5 ppm nitrogen dioxide developed heightened airway reactivity.
    3) CASE SERIES - No statistically significant untoward response to nitrogen dioxide was noted in 21 mildly asthmatic volunteers exposed to up to 3 ppm of NO2 in purified background air in an environmental-controlled chamber (Linn et al, 1986).
    4) CASE SERIES - In a pilot study, seven adult asthmatics who were exposed to nitrogen dioxide levels greater than 0.3 ppm during residential gas stove operation showed a trend toward decreased forced vital capacity and peak expiratory flow (Goldstein et al, 1988).
    5) Ussetti et al (1984) report an increase in the number of acute asthma attacks when NO2 air concentrations were elevated.
    6) Huang et al (1991) studied the effects of 5 minute low level exposures to NO2 in asthmatic children. They concluded that the short term exposures did not affect lung function and did not increase bronchial sensitivity to methacholine and allergens.
    7) CASE SERIES - Nitrogen dioxide (NO2) exposure from domestic gas cooking and airway response was evaluated in 16 adult non-smoking, mild to severe asthmatic women. Acute short term level of NO2 during gas cooking episodes and the mean exposure to NO2 from repeated cooking over a 2 week period were measured. Asthmatic status was monitored with peak expiratory flow rates (PEFR) before and after cooking. Results showed immediate airflow limitation following acute short term exposure to NO2. During the 2 week study period, mean NO2 exposure level (minimum and maximum concentrations of 37.3 and 135.6 mcg/m(3), respectively) positively correlated with frequency of rescue bronchodilator usage (Ng et al, 2001).
    D) OBLITERATIVE BRONCHIOLITIS
    1) BRONCHIOLITIS OBLITERANS - 2 to 4 weeks after a mild acute exposure to nitrogen dioxide, bronchioles may become obstructed with granulation tissue and fibrin plugs, manifested clinically by cyanosis and crackles (Epler, 1989).
    2) LATE BRONCHIOLITIS OBLITERANS - This more severe form involves scarring and irreversible airflow obstruction and is more rare than the acute form (Epler, 1989).
    E) DEAD - SUDDEN DEATH
    1) In bottom-loading silos, sudden death may occur, and is probably due to asphyxiation, whereas in top-unloading ones, it is usually due to nitrogen dioxide inhalation (Douglas et al, 1989).
    F) ACUTE RESPIRATORY INFECTIONS
    1) INCREASED SUSCEPTIBILITY TO INFECTIONS - In one study adult volunteers who were exposed to 1 or 2 ppm nitrogen dioxide had increased frequencies of infection by attenuated influenza A/Korea/82 virus compared to a control group, but the differences were not statistically significant (Goings et al, 1989).
    a) Because of the limitations of epidemiology, the role of nitrogen dioxide in respiratory infections at concentrations normally encountered in outdoor and indoor air remains unclear (Samet, 1989; Samet et al, 1992).

Neurologic

    3.7.1) SUMMARY
    A) Fatigue, restlessness, anxiety, mental confusion, lethargy, and loss of consciousness may be noted.
    3.7.2) CLINICAL EFFECTS
    A) SYNCOPE
    1) Restlessness, headache, lethargy, weakness, dizziness and loss of consciousness may occur (CDC, 1992).
    B) ANXIETY
    1) Anxiety and mental confusion may occur (CDC, 1992).
    C) SEQUELA
    1) Unexplained permanent neurologic sequelae were observed in 6 of 24 cases of nitrogen oxide exposure from a missile silo accident (Haddad & Winchester, 1990).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting and abdominal pain may develop.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Nausea, vomiting and abdominal pain may occur following acute inhalation exposures (CDC, 1992).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia may occur with nitric oxide exposures.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Clinically significant methemoglobinemia may occur with exposure to higher oxides of nitrogen (Clutton-Brock, 1967; Mohsenin, 1994).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Leukocytosis may develop in patients with acute pulmonary symptoms after inhalation of nitrogen oxides (Tague et al, 2004).

Dermatologic

    3.14.1) SUMMARY
    A) Cyanosis may occur.
    3.14.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) Cyanosis may be seen in patients with hypoxemia (Horvath et al, 1978; Moskowitz et al, 1964; Weston et al, 1972).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) NITROGEN DIOXIDE is listed in the 1978 NIOSH volume of Suspected Carcinogens (Clayton & Clayton, 1981b).

Genotoxicity

    A) Chromosome aberrations and mutations in lung cells were evident in an in vivo animal study following inhalation of NO2 and NO. Negative results were obtained for chromosome aberrations in lymphocytes and spermatocytes or micronuclei in bone marrow after NO2 inhalation (Victorin, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor pulmonary function. Chest x-ray may be diagnostic of acute lung injury. Monitor pulse oximetry and arterial blood gases as clinically indicated.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Arterial blood gases should be monitored. Methemoglobin levels should be monitored if methemoglobinemia is suspected.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Monitor pulmonary function tests.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Posterior/anterior chest x-ray may be diagnostic and prognostic.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Symptomatic patients should be observed in a controlled setting for 24 to 36 hours for delayed respiratory effects (Ellenhorn & Barceloux, 1988).
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Asymptomatic patients that have been observed for several hours following an exposure, and remain asymptomatic, may be treated as outpatients. The patient should be instructed to return to a health care facility if any symptoms develop (Ellenhorn & Barceloux, 1988).
    B) Patients that were initially symptomatic who become asymptomatic after 24 to 36 hours of observation may be released with arrangement of follow-up appointment to assess pulmonary status (Ellenhorn & Barceloux, 1988).
    C) Close outpatient follow-up should be continued in patients who develop adult respiratory distress since these patients are at high risk to develop bronchiolitis obliterans within several weeks (Ellenhorn & Barceloux, 1988).

Monitoring

    A) Monitor pulmonary function. Chest x-ray may be diagnostic of acute lung injury. Monitor pulse oximetry and arterial blood gases as clinically indicated.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) The general concept regarding medical therapy in cases of toxic pneumonitis or pulmonary edema is administration of oxygen, beta2 agonists if there are signs of airway obstruction and, when required, mechanical ventilation with PEEP.
    B) ACUTE LUNG INJURY
    1) Treatment of acute lung injury (pulmonary edema) caused by nitrogen dioxide inhalation should be directed toward the reversal of ventilatory failure by using oxygen and assisting ventilation.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    C) CORTICOSTEROID
    1) Although clinical improvement and improvement in pulmonary function tests have been attributed to the administration of corticosteroids (Ramirez & Dowell, 1971), there is no conclusive evidence that steroids alter the course of nitrogen dioxide-induced pulmonary edema or prevent subsequent bronchitis or bronchiolitis.
    2) According to the recommendations from the Swedish Poison Information Centre, patients who have been exposed to an irritating gas such as nitrogen dioxide should be treated with high doses of budesonide or beclomethasone. Initially a dose of 4 mg (10 inhalations of 0.4 mg) is given and this is followed by 2 mg one to five times during the first 24 hours. Pretreatment with an inhaled beta2 agonist is also recommended. Systemic treatment with IV betamethasone 8 to 16 mg is also recommended in cases of moderate to heavy exposure (Karlson-Stiber et al, 1996).
    3) Many patients appear to have benefited from the use of steroids, experiencing a recurrence of symptoms with cessation of steroid treatment that regressed again as soon as steroids were reinstated (Haggerty et al, 1982; Jonas, 1984; Maurer, 1985; Brey & Seidenfeld, 1981; Fleetham et al, 1978). Many sources recommend steroid treatment as the main adjunct to respiratory support (Haddad & Winchester, 1990; AMA, 1985).
    D) HYPERBARIC OXYGEN THERAPY
    1) Hyperbaric oxygen was found to increase mortality in mice exposed to 1,100 ppm nitrogen dioxide then treated with oxygen pressurized at 1.8 atmospheres (Pelled et al, 1973).
    E) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    F) EXPERIMENTAL THERAPY
    1) ASCORBIC ACID
    a) Nash (1990) proposed that a 1 gram oral dose of ascorbic acid would temporarily protect against the subsequent toxic effects by competing with the sensitive sites for freshly absorbed nitrogen dioxide gas.
    b) Additional studies are needed to demonstrate the safety and efficacy of this treatment.
    2) CHLORPHENTERMINE
    a) Hastings et al (1987) suggested pretreatment with chlorphentermine offered partial protection against NO2 toxicity in a mouse model.
    b) Additional studies are needed to demonstrate the safety and efficacy of this treatment.
    3) DEFEROXAMINE
    a) Meulenbolt et al (1992) found decreased severity of catarrhal pneumonitis and less pronounced perivascular edema in rats treated with intravenous deferoxamine (100 milligrams/kilogram/day) following a 10 minute inhalation exposure to 175 parts per million nitrogen dioxide.
    b) Additional studies are needed to demonstrate the safety and efficacy of this treatment.

Range Of Toxicity

Summary

    A) Death due to airway obstruction from edema of the glottis has not been well documented, but is estimated to occur with nitrogen dioxide concentrations greater than 100 ppm. The odor of nitrogen dioxide is perceptible at 1 to 3 ppm. Symptoms generally appear at 13 ppm.

Minimum Lethal Exposure

    A) ACUTE
    1) Death due to airway obstruction from edema of the glottis has not been well-documented but is estimated to occur with nitrogen dioxide concentrations greater than 100 ppm (Tse & Bockman, 1970).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) NITROGEN DIOXIDE -
    a) Acute high-level inhalation exposure of (> 200 ppm) can cause a biphasic clinical response consisting of acute laryngospasm and bronchospasm followed by the development of pulmonary edema in 8 to 24 hours. In one to 4 weeks, the development of bronchiolitis obliterans may occur with exacerbation of earlier symptoms (Mayorga, 1994).
    b) High level exposures have been reported to cause tachypnea, tachycardia, cyanosis, dyspnea, hemoptysis and chest pain, vomiting, headache, vertigo, weakness, syncope and death (Horvath et al, 1978).
    c) A one hour exposure to 2 ppm of NO2 in susceptible individuals has been reported to cause an airway hyperreactivity (Mohsenin, 1994).
    d) ODOR TOLERANCE - The odor of nitrogen dioxide is perceptible at 1 to 3 ppm. Symptoms of mucous membrane irritation generally do not appear until concentrations are greater than 13 ppm (Tse & Bockman, 1970).
    e) LOW DOSE NITROGEN DIOXIDE -
    1) VIRAL INFECTION SUSCEPTIBILITY - A group of 22 adult volunteers who were exposed to 1 or 2 ppm nitrogen dioxide under controlled conditions for 2 hours per day over 3 consecutive days had increased frequencies of infection by attenuated influenza A/Korea/82 virus compared to a control group, but the differences were not statistically significant. These exposure conditions did not produce any significant changes in pulmonary function or nonspecific airway reactivity to a methacholine challenge (Goings et al, 1989).
    2) EXERCISE - Nine healthy athletes were acutely exposed to 0.18 and 0.3 ppm NO2 for 30 minutes while exercising. No statistically significant changes were found in forced expiratory volume (FEV), resistance, peak expiratory flow rate (PEFR), and maximal expiratory flow at 50% forced vital capacity (FVC) (Kim et al, 1991).
    3) METHACHOLINE CHALLENGE - Eighteen healthy nonsmokers were exposed to 2 ppm nitrogen dioxide for 1 hour. No changes in their baseline FEV, FVC, and other pulmonary function tests, but airway reactivity to methacholine challenge was significantly increased (Mohsenin, 1988).
    f) Exposure to nitrogen dioxide for 60 minutes at the following concentrations has been associated with the following effects -
    CONC. (ppm)EFFECTREFERENCE
    1Equiv resp effects Impaired dark visionMayorga, 1994
    5Reversible resp effectsMayorga, 1994
    25Immediate respiratory irritation Chest painNIOSH, 1976
    50Pulmonary edema Possible lung lesionsNIOSH, 1976
    100Pulmonary edema DeathProctor et al, 1988
    1000Immediate incapacitation (15 minute exposure) DeathMayorga, 1994

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) NITROGEN DIOXIDE
    1) TCLo- (INHALATION)HUMAN:
    a) 6,200 ppb for 10M (RTECS, 2002)
    b) 90 ppm for 40M (RTECS, 2002)
    B) NITROGEN OXIDE
    1) TCLo- (INHALATION)HUMAN:
    a) 24 mg/kg for 2H (RTECS, 2002)
    C) NITROGEN TETROXIDE

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Oxides of nitrogen are synthesized by living cells from arginine (Hibbs et al, 1987).

Toxicologic Mechanism

    A) SILO-FILLERS DISEASE -
    1) Normally there is a low concentration of nitrates in growing plants such as corn, but high nitrate soils, drought in immature plants, ultraviolet radiation in increasing intensities or duration favors the accumulation of nitrates by plants (Grayson, 1956).
    2) The potassium nitrate in the plants is changed into potassium nitrite and oxygen by anaerobic bacterial fermentation. The nitrites then combine with organic acids in the silage to form nitrous acid. As the temperature of the silage rises with fermentation, the nitrous acid decomposes into water and a mixture of nitrogen oxides which include nitrogen trioxide (N2O3), nitric oxide (NO), nitrogen dioxide (NO2), and nitrogen tetroxide (N2O4) (Grayson, 1956).
    3) NO2 gas begins to form within hours after silo filling and toxic levels may be produced for 2 to 6 weeks. Levels may reach 2,000 ppm (Epler, 1989).
    4) Several hours after exposure, patients commonly develop fever, cough, and progressive dyspnea and may progress to bronchiolitis obliterans or death (Epler, 1989).
    B) PULMONARY INJURY -
    1) Nitrogen oxides react slowly with water in the respiratory tract to form nitric and nitrous acid. These acids cause irritation and inflammation of the respiratory tract. Nitrogen oxides tend to reach the distal airways and lung parenchyma due to their limited water solubility and therefore inefficient upper-airway absorption. Injury tends to be more prominent in these areas (Adgate et al, 1992).
    2) Lipid autoxidation and free radical reactions have been postulated as the mechanism of nitrogen dioxide-induced pulmonary damage (Coffin & Stokinger, 1977; Selgrade et al, 1981; Haagsman & van Golde, 1985)
    3) Elsayed (1994) suggests that during the initial stages of exposure to NO2 (first 24 hrs), inhalation causes damage and degeneration of type I cells and decreased metabolic activities below control level which may be an 'Injury Phase'.
    a) In the following 48 to 72 hrs, type II cells proliferate and cover the basement membrane, possibly associated with an inflammatory response. This increase in response may be a 'Repair Phase'. Thereafter, massive destruction occurs, resulting in cell death.
    4) Increases in both the amount of surfactant lipids and the lipid synthesizing capacity, due to the proliferation of Type II cells has resulted from exposures to relatively high concentrations of nitrogen dioxide in animal models (Haagsman & van Golde, 1985; Arner & Rhoades, 1973).
    5) Both a decreased amount of surfactant lipids and a decreased capacity to synthesize these lipids occur with long term exposures to relatively low concentrations of NO2 in animal models (Haagsman & van Golde, 1985).
    6) Acute exposures to nitrogen dioxide (50 and 140 parts per million for 1 hour) produced immediate elevations in pulmonary protein and wet lung weight in a mouse model. Lactate dehydrogenase, beta-glucuronidase, choline kinase, and protease inhibitors were also elevated 2 days following acute exposure (Siegel et al, 1989)
    7) Subacute exposure to nitrogen dioxide (50 and 140 parts per million for 4-hours/day for 5 days) produced mild elevations in nonenzymatic parameters (pulmonary protein and wet lung weight) and larger elevations of enzymatic parameters (lactate dehydrogenase, beta-glucuronidase, choline kinase, and protease kinase) in a mouse model (Siegel et al, 1989).
    a) Increased urinary excretion of hydroxyproline, an amino acid abundant in collagen, has been found in animal studies, but results in humans with elevated exposures to nitrogen dioxide are conflicting. Urinary excretion of desmosine, a catabolic product of elastin involved in pulmonary interstitium, was increased in infants requiring high oxygen concentrations in the first 3 weeks of life, but again, inconsistent results were obtained in young children and their mothers who resided in homes with higher NO2 levels (Adgate et al, 1992).

Physicochemical

Physical Characteristics

    A) NITROGEN DIOXIDE: reddish-brown gas with irritating odor (Budavari, 1989); yellow liquid (ITI, 1988)
    B) NITROGEN OXIDE: blue liquid and solid or colorless gas (Sax & Lewis, 1989)
    C) NITROGEN PENTOXIDE: colorless hexagonal crystals (Budavari, 1989)
    D) NITROGEN TETROXIDE: colorless gas (Budavari, 1989)

Molecular Weight

    A) NITROGEN DIOXIDE: 46.01 (Clayton & Clayton, 1982)
    B) NITROGEN OXIDE: 30.01 (Clayton & Clayton, 1982)

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) Cattle commonly show signs of salivation, respiratory distress, methemoglobinemia, severe dyspnea, and death (Humphreys, 1988). Animals may die instantly or days or months later (Beasley et al, 1989).
    11.1.10) PORCINE/SWINE
    A) Pigs inhaling silo gas experience pulmonary alveolar edema and hyperemia, manifested by severe respiratory distress and death. Pigs surviving the acute effects of exposure did not develop bronchiolitis obliterans (Humphreys, 1988).
    11.1.13) OTHER
    A) OTHER
    1) Cattle, swine and horses in barns are most commonly exposed when a silo attached to the barn is filled with silage. NO2 is heavier than air, and will settle down through the chute and into the silo room and barn. Animals should not be allowed in the barn or near the silo for at least 48 hours after filling (Beasley et al, 1989).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) INHALATION - Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    11.2.5) TREATMENT
    A) RUMINANTS/HORSES/SWINE
    1) MAINTAIN VITAL FUNCTIONS - as necessary.
    2) ARTIFICIAL RESPIRATION - Severe respiratory depression will lead to anoxia and death. Respiration must be supported with the necessary combination of oxygen, intubation or tracheostomy, and positive pressure ventilation.
    3) FLUIDS - Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour. Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliter/kilogram/minute (2.4 liters/ hour for an 880 pound horse).
    4) METHYLENE BLUE - CATTLE - If methemoglobinemia is present, dose with methylene blue 1 to 4% solution. Maintain a 4.4 to 8.8 milligrams/kilogram intravenous drip until clinical improvement is noted. Dose may be repeated; monitor animal for improvement of clinical signs since overdosage can exacerbate methemoglobinemia (Howard, 1986).
    5) CORTICOSTEROIDS - High-dose, long-term corticosteroids may alleviate the pulmonary edema and clinical signs (Beasley et al, 1989).
    6) ANTIMICROBIAL THERAPY - Broad spectrum antibiotics are indicated to combat bronchopneumonia.
    a) HORSES - Trimethoprim-sulfadiazine dosed at 25 milligrams/kilogram sulfadiazine intramuscularly or per os every 12 hours (Robinson, 1987).
    b) CATTLE - Neomycin is dosed at 88 milligrams/kilogram intramuscularly or subcutaneously every 8 hours. NOTE: This product is only approved for oral and intramammary use. Withdrawal period of 120 days prior to slaughter. Ampicillin is dosed at 22 milligrams/kilogram subcutaneously every 12 hours. Withdrawal period of 60 days prior to slaughter (Howard, 1986).
    c) SWINE - Ampicillin is dosed at 10 milligrams/kilogram intramuscularly (Howard, 1986).
    7) RECOVERY may require 1 to 6 months and some pulmonary changes may be irreversible (Beasley et al, 1989).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) INHALATION - Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) LABORATORY FINDINGS--PREMORTEM -
    1) Methemoglobinemia is commonly seen in cattle.
    2) AIR QUALITY - Potassium iodide papers are available which turn dark when exposed to NO2 gas (Beasley et al, 1989).
    b) LABORATORY FINDINGS--POSTMORTEM -
    1) Postmortem findings include cyanosis, pulmonary congestion and edema, hemorrhage, emphysema, and microscopically, pulmonary mast cells are ruptured and degranulated (Beasley et al, 1989).

Sources

    A) SPECIFIC TOXIN
    1) NO2 gas production is greatest in alfalfa silage, and concentrations often reach 1500 ppm during the first 48 hours after filling a silo (Beasley et al, 1989).

References

General Bibliography

    1) AMA: Nitrogen dioxide; Effects of Toxic Chemicals on the Reproductive System, American Medical Association, Council on Scientific Affairs, Chicago, IL, 1985.
    2) Adgate JL, Reid HF, & Morris R: Nitrogen dioxide exposure and urinary excretion of hydroxyproline and desmosine. Arch Environ Health 1992; 47:376-384.
    3) Anderson DE: Problems created for ice arenas by engine exhaust. Am Ind Hyg Assoc J 1971; 32:790-801.
    4) Arner EC & Rhoades RA: Long-term nitrogen dioxide exposure. Arch Environ Health 1973; 26:156-160.
    5) Artigas A, Bernard GR, Carlet J, et al: The American-European consensus conference on ARDS, part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling.. Am J Respir Crit Care Med 1998; 157:1332-1347.
    6) Beasley VR, Dorman DC, & Fikes JD: A Systems Affected Approach to Veterinary Toxicology, University of Illinois, Urbana, IL, 1989.
    7) Brey RL & Seidenfeld RJ: Lung toxicity resulting from exposure to nitrogen dioxide: a possible occurrence due to Titan missile accidents. Ariz Med 1981; 38:344-348.
    8) Brower RG, Matthay AM, & Morris A: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng J Med 2000; 342:1301-1308.
    9) Budavari S: The Merck Index, 11th ed, Merck & Co, Inc, Rahway, New Jersey, 1989.
    10) CDC: Nitrogen dixoide and carbon monoxide intoxication in an indoor ice arena - Wisconsin, 1992. CDC: MMWR 1992; 41(21):383-385.
    11) Cataletto M: Respiratory Distress Syndrome, Acute(ARDS). In: Domino FJ, ed. The 5-Minute Clinical Consult 2012, 20th ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2012.
    12) Clayton GD & Clayton FE: Patty's Industrial Hygiene and Toxicology, Vol 2B. Toxicology, 3rd ed, John Wiley & Sons, New York, NY, 1981b.
    13) Clayton GD & Clayton FE: Patty's Industrial Hygiene and Toxicology, Vol 2C, Toxicology, 3rd ed, John Wiley & Sons, New York, NY, 1982.
    14) Clutton-Brock J: Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth 1967; 39:388-392.
    15) Coffin DL & Stokinger HE: Biological effects of air pollutants. In: Stern AC (Ed): Air Pollution, Vol 11, 3rd ed, Academic Press, New York, NY, 1977, pp 231-260.
    16) Douglas WW, Hepper NGG, & Colby TV: Silo-Filler's disease. Mayo Clin Proc 1989; 64:291-304.
    17) Dunipace AJ, Beaven R, Noblitt T, et al: Mutagenic potential of toluidine blue evaluated in the Ames test. Mutat Res 1992; 279(4):255-259.
    18) Ellenhorn MJ & Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, Elsevier, New York, NY, 1988.
    19) Epler GR: Silo-filler's disease: a new perspective. Mayo Clin Proc 1989; 64:368-370.
    20) Euler GL, Abbey DE, & Hodgkin JE: Chronic obstructive pulmonary disease symptom effects of long-term cumulative exposure to ambient levels of total oxidants and nitrogen dioxide in California Seventh-day Adventist residents. Arch Environ Health 1988; 43:279-285.
    21) Fleetham JA, Munt PW, & Turncliffe BW: Silo-filler's disease. Can Med Assoc J 1978; 119:482-484.
    22) Gaston B, Drazen JM, & Loscalzo J: The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149:538-551.
    23) Goings SAJ, Kulle TJ, & Bascom R: Effect of nitrogen dioxide exposure on susceptibility to influenza A virus infection in healthy adults. Am Rev Respir Dis 1989; 139:1075-1081.
    24) Goldstein E, Peek NF, & Parks NJ: Fate and distribution of inhaled nitrogen dioxide in rhesus monkeys. Am Rev Respir Dis 1977; 115:403-412.
    25) Goldstein IF, Lieber K, & Andrews LR: Acute respiratory effects of short-term exposures to nitrogen dioxide. Arch Environ Health 1988; 43:138-142.
    26) Gosselin RE, Smith RP, & Hodge HC: Clinical Toxicology of Commercial Products, 5th ed, Williams & Wilkins, Baltimore, MD, 1984.
    27) Grant WM & Schuman JS: Toxicology of the Eye, 4th ed, Charles C Thomas, Springfield, IL, 1993.
    28) Gray WM: Occupational exposure to nitrous oxide in four hospitals. Anaesthesia 1989; 44:511-514.
    29) Grayson RR: Silage gas poisoning: nitrogen dioxide pneumonia: a new disease in agricultural workers. Ann Intern Med 1956; 45:393-408.
    30) Haagsman HP & van Golde LMG: Lung surfactant and pulmonary toxicity. Lung 1985; 163:275-303.
    31) Haas CF: Mechanical ventilation with lung protective strategies: what works?. Crit Care Clin 2011; 27(3):469-486.
    32) Haddad LM & Winchester JF: Clinical Management of Poisoning and Drug Overdose, 2nd ed, WB Saunders Company, Philadelphia, PA, 1990.
    33) Haggerty MA, Soto-Green M, & Reichan LB: Silo-filler's disease in rural . Morbid Mortal Wkly Rep 1982; 31:389-391.
    34) Hedberg K, Hedberg CW, & Iber C: An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. JAMA 1989; 262:3014-3017.
    35) Herman MI, Chyka PA, & Butlse AY: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111-113.
    36) Hibbs JB, Taintor RR, & Vavrin Z: Macrophage cytotoxicity: role of L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 1987; 235:473-476.
    37) Hix WR & Wilson WR: Toluidine blue staining of the esophagus: a useful adjunct in the panendoscopic evaluation of patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1987; 113(8):864-865.
    38) Hjelt K, Lund JT, Scherling B, et al: Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84(4):365-370.
    39) Horvath EP, doPico GA, & Barbee RA: Nitrogen dioxide-induced pulmonary disease. J Occupation Med 1978; 20(2):103-110.
    40) Howard JL: Current Veterinary Therapy: Food Animal Practice 2, Saunders, Philadelphia, PA, 1986.
    41) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    42) Humphreys DJ: Veterinary Toxicology, 3rd ed, Bailliere Tindall, London, UK, 1988.
    43) ITI: Toxic and Hazardous Industrial Chemicals Safety Manual, The International Technical Information Institute, Tokyo, Japan, 1988.
    44) Jonas DO: Case for diagnosis. Milit Med 1984; 149:481-485.
    45) Karlson-Stiber C, Hojer J, & Sjoholm A: Nitrogen dioxide pneumonitis in ice hockey players. J Intern Med 1996; 239:451-456.
    46) Kiese M , Lorcher W , Weger N , et al: Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. Eur J Clin Pharmacol 1972; 4(2):115-118.
    47) Kim SU, Koenig JQ, & Pierson WE: Acute pulmonary effects of nitrogen dioxide exposure during exercise in competitive athletes. Chest 1991; 99:815-819.
    48) Kollef MH & Schuster DP: The acute respiratory distress syndrome. N Engl J Med 1995; 332:27-37.
    49) Lindenmann J, Matzi V, Kaufmann P, et al: Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report. Inhal Toxicol 2006; 18(13):1047-1049.
    50) Linn WS, Shamoo DA, & Avol EL: Dose-response study of asthmatic volunteers exposed to nitrogen dioxide during intermittent exercise. Arch Environ Health 1986; 41:292-296.
    51) Marquez A & Todd M: Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract 1959; 10:1548-1550.
    52) Maurer WJ: Silo-filler's disease: a historical perspective and report of a case. Wisc Med J 1985; 84:13-16.
    53) Mayorga MA: Overview of nitrogen dioxide effects on the lung with emphasis on military relevance. Toxicology 1994; 69(3):175-192.
    54) Mohsenin V: Airway responses to 2.0 ppm nitrogen dioxide in normal subjects. Arch Environ Health 1988; 43:242-246.
    55) Mohsenin V: Human exposure to oxides of nitrogen at ambient and supra-ambient concentration. Toxicology 1994; 89(3):301-312.
    56) Morgan WKC: 'Zamboni Disease' - Pulmonary edema in an ice hockey player. Arch Intern Med 1995; 155:2479-2480.
    57) Moskowitz RL, Lyons HA, & Cottle HR: Silo filler's disease. Clinical, physiologic and pathologic study of a patient. Am J Med 1964; 36:457-462.
    58) NHLBI ARDS Network: Mechanical ventilation protocol summary. Massachusetts General Hospital. Boston, MA. 2008. Available from URL: http://www.ardsnet.org/system/files/6mlcardsmall_2008update_final_JULY2008.pdf. As accessed 2013-08-07.
    59) Nemec K: Antidotes in acute poisoning. Eur J Hosp Pharm Sci Pract 2011; 17(4):53-55.
    60) Ng TP, Seet CSR, & Tan WC: Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women. Thorax 2001; 56:596-601.
    61) Pelled B, Schechter Y, & Alroy G: Deleterious effect of oxygen at ambient and hyperbaric pressure in the treatment of nitrogen dioxide poisoned mice. Am Rev Res Dis 1973; 108:1152-1157.
    62) Proctor NH, Hughes JP, & Fischman ML: Chemical Hazards of the Workplace, 2nd ed, JB Lippincott Co, Philadelphia, PA, 1988.
    63) Product Information: PROVAYBLUE(TM) intravenous injection, methylene blue intravenous injection. American Regent (per FDA), Shirley, NY, 2016.
    64) Product Information: methylene blue 1% IV injection, methylene blue 1% IV injection. American Regent, Inc (per manufacturer), Shirley, NY, 2011.
    65) Product Information: methylene blue 1% intravenous injection, methylene blue 1% intravenous injection. Akorn, Inc. (per manufacturer), Lake Forest, IL, 2011.
    66) Prys-Roberts C: Principles of treatment of poisoning by higher oxides of nitrogen. Brit J Anaesth 1967; 39:432-439.
    67) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1990; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    68) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    69) Ramirez RJ & Dowell AR: Silo-filler's disease: nitrogen dioxide-induced lung injury. Long term follow-up and review of literature. Ann Intern Med 1971; 74:569-576.
    70) Robinson NE: Current Veterinary Therapy in Equine Medicine 2, Saunders, Philadelphia, PA, 1987.
    71) Samet JM, Lambert WE, & Skipper BJ: A study of respiratory illnesses in infants and nitrogen dioxide exposure. Arch Environ Health 1992; 47:57-63.
    72) Samet JM: Nitrogen dioxide and respiratory infection (editorial). Am Rev Respir Dis 1989; 139:1073-1074.
    73) Sax NI & Lewis RJ: Dangerous Properties of Industrial Materials, 7th ed, Van Nostrand Reinhold Co, New York, NY, 1989.
    74) Selgrade MK, Mole ML, & Miller FJ: Effect of NO2 inhalation and vitamin C deficiency on protein and lipid accumulation in the lung. Environ Res 1981; 26:422-437.
    75) Shepherd G & Keyes DC: Methylene blue. In: Dart,RC, ed. Medical Toxicology, 3rd ed. 3rd ed, Philadelphia, PA, 2004, pp -.
    76) Siegel PD, Bozelka BE, & Reynolds C: Phase-dependent response of the lung to NO2 irritant insult. J Environ Pathol Toxicol Oncol 1989; 9:303-315.
    77) Sriskandan K & Pettingale KW: Numismatist's pneumonitis: a case of acute nitrogen dioxide poisoning. Postgrad Med J 1985; 65:819-821.
    78) Stanford SC , Stanford BJ , & Gillman PK : Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24(10):1433-1438.
    79) Steadman BL, Jones RA, & Rector DE: Effects on experimental animals of long-term continuous inhalation of nitrogen dioxide. Toxicol Appl Pharmacol 1966; 9:160-170.
    80) Stolbach A & Hoffman RS: Respiratory Principles. In: Nelson LS, Hoffman RS, Lewin NA, et al, eds. Goldfrank's Toxicologic Emergencies, 9th ed. McGraw Hill Medical, New York, NY, 2011.
    81) Tague I, Llewellin P, Burton K, et al: Cold blast furnace syndrome: a new source of toxic inhalation by nitrogen oxides. Occup Environ Med 2004; 61(5):461-463.
    82) Teunis BS, Leftwich EI, & Pierce LE: Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101:527-531.
    83) Tse RL & Bockman AA: Nitrogen dioxide toxicity. Report of four cases in firemen. JAMA 1970; 212(8):1341-1344.
    84) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. U.S. Food and Drug Administration. Silver Spring, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. As accessed 2011-07-26.
    85) Victorin K, Busk L, & Cederburg H: Genotoxic activity of 1,3-butadiene and nitrogen dioxide and their photochemical reaction products in Drosophila and in the mouse bone marrow micronucleus assay. Mutat Res 1990; 228:203-209.
    86) Victorin K: Review of the genotoxicity of nitrogen oxides. Mutation Res 1994; 317:43-55.
    87) Weast RC: CRC Handbook of Chemistry and Physics, CRC Press, Inc, Boca Raton, FL, 1981.
    88) Weston JT, Liebow AA, & Dixon MG: Untoward effects of exogenous inhalants on the lung. J Forensic Sciences 1972; 17(2):199-279.
    89) Willson DF, Truwit JD, Conaway MR, et al: The adult calfactant in acute respiratory distress syndrome (CARDS) trial. Chest 2015; 148(2):356-364.
    90) Wilson DF, Thomas NJ, Markovitz BP, et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. A randomized controlled trial. JAMA 2005; 293:470-476.
    91) Winek CL, Collom WD, & Martineau P: Toluidine blue intoxication. Clin Toxicol 1969; 2:1-3.
    92) Zwemer FL, Pratt DS, & May JJ: Silo filler's disease in state. Am Rev Respir Dis 1992; 146:650-653.
    93) do Nascimento TS, Pereira RO, de Mello HL, et al: Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol 2008; 58(6):651-664.