Nitrogen Dioxide Lung Injury

Nitrogen dioxide (NO2) is a reddish brown, poorly soluble oxidant gas that penetrates to the terminal bronchioles and alveoli. Exposure occurs in farm silos (silo filler's disease, from fermenting fresh silage over the first 2 weeks), welding, especially in enclosed spaces, burning of nitrocellulose film, explosives and rocket fuel, combustion of fuel in poorly vented spaces, and ice resurfacing machines. NO2 reacts with lung water to form nitric and nitrous acids and free radicals.

Because the gas is poorly soluble, there is little upper airway irritation to warn the victim, and the patient may stay in the atmosphere. Concentration over 100 ppm causes severe pulmonary oedema; over 200 ppm can be fatal. The illness is classically biphasic: acute pulmonary injury, a relatively asymptomatic interval of 2 to 6 weeks, then late bronchiolitis obliterans with fever and progressive dyspnoea. Concentrations above 500 ppm cause methaemoglobinaemia and sudden death.

• Phase 1 (0 to 24 hours): mild cough, nausea, throat irritation, fatigue, then dyspnoea, tachypnoea, wheeze and non-cardiogenic pulmonary oedema 3 to 30 hours later.
• Phase 2 (a few days to 2 weeks): partial improvement.
• Phase 3 (2 to 6 weeks): recurrent fever, dry cough, progressive dyspnoea, fine crackles, cyanosis from bronchiolitis obliterans, with or without organising pneumonia.
• Methaemoglobinaemia: cyanosis unresponsive to oxygen, chocolate brown blood, headache.
• Red flags: hypoxaemia, tachypnoea over 30 breaths per minute, symptoms of silo exposure, brown sputum, drop in oxygen saturation after discharge.

• Exposure history (silo, welding, fire) with a latent period.
• Chest radiograph: normal early; bilateral patchy infiltrates or pulmonary oedema; late reticulonodular pattern or hyperinflation.
• Arterial blood gas and co-oximetry: hypoxaemia; methaemoglobin level over 10 percent suggests NO2 toxicity.
• High resolution CT in the late phase: patchy ground glass, centrilobular nodules, mosaic attenuation and air trapping on expiratory images (bronchiolitis obliterans), or organising pneumonia pattern.
• Spirometry: obstructive pattern (FEV1 reduced, FEV1/FVC below 0.70), air trapping.
• Bronchoscopy and lavage for exclusion of infection; biopsy shows obliterative bronchiolitis or organising pneumonia.
• Exclude infection, hypersensitivity pneumonitis, cardiogenic oedema, other irritant gas, and organic dust toxic syndrome.

• Remove from exposure, keep the patient at rest, oxygen 100 percent humidified; rescuers wear self-contained breathing apparatus because the silo atmosphere is lethal.
• Observe all exposed patients for at least 24 hours, since symptoms develop late; avoid exertion.
• Bronchospasm: salbutamol 2.5 to 5 mg nebulised every 4 hours as needed.
• Pulmonary oedema and ARDS: CPAP 5 to 10 cmH2O, or intubation and lung protective ventilation (tidal volume 6 mL/kg predicted body weight, PEEP 8 to 12 cmH2O); avoid fluid overload.
• Early corticosteroid: methylprednisolone 1 mg/kg intravenously once daily for 3 days after significant exposure, then prednisolone 1 mg/kg orally once daily (maximum 60 mg) for 2 to 3 weeks, tapered over a further 3 to 6 weeks; use with omeprazole 20 mg orally once daily. Starting prednisolone before the onset of bronchiolitis obliterans lowers the risk.
• Methaemoglobinaemia over 20 percent, or symptomatic: methylene blue 1 to 2 mg/kg intravenously over 5 minutes; repeat 1 mg/kg after 1 hour if needed; contraindicated in G6PD deficiency (use ascorbic acid and transfusion instead).
• Bronchiolitis obliterans: prednisolone 1 mg/kg orally once daily for 4 to 6 weeks then taper; azithromycin 250 mg orally three times a week for 6 to 12 months; inhaled budesonide formoterol 200/6 micrograms 2 puffs twice daily.
• Follow up: spirometry and chest radiograph at 2, 4, and 6 weeks after exposure, and CT if symptoms recur; long term spirometry at 3 and 12 months.
• Prevention: ventilate silos for 2 to 3 weeks after filling, keep the silo cover sealed, turn on blowers 30 minutes before entry, never enter alone, and use breathing apparatus.