Pulmonary Irritants

The respiratory tract has several anatomic features that prevent injury. Particulates approximately 30 µM in size are trapped on the surface of the nasal turbinates.¹ Nasal hairs filter larger particles, but smaller ones are inhaled into deeper parts of the respiratory tract. The airway surface liquid (ASL) is a thick mucous film that traps particles.¹ As the airway branches into smaller-diameter bronchioles, particles adhere to the respiratory mucosa, further limiting access to the lower respiratory tract. Together, the cilia and ASL form the mucociliary escalator that is responsible for carrying inhaled toxins towards the more proximal airways where they are expelled. Sensory receptors in the upper airways cause a reflexive cough to assist with expulsion.²

The extent of injury is determined by the characteristics of the particle and exposure setting. These include particle size, density, shape, duration of exposure, concentration of the inhalant, and water solubility. Particles 0.5 to 3 µM in size are deposited in the distal airways and alveoli.³ However, smaller particulates are exhaled because they behave like a gas.³ Inadequate ventilation in confined spaces may lead to higher concentrations of the toxin and more severe injury when exposure occurs.

The irritant’s water solubility (Table 187-1) is the primary characteristic that affects the type of injury and likelihood for acute lung injury (ALI). Very hydrophilic (water-soluble) irritants dissolve in the water of the mucosal secretions of the nose and upper airways. Symptoms are unpleasant and occur within seconds. Victims generally escape the exposure, thereby minimizing the risk for injury. Conversely, inability to escape may result in severe injury. Less hydrophilic (i.e., more lipophilic) irritants penetrate deeper into the respiratory tract, injuring the lower airways while sparing the upper airways. As a consequence, victims typically do not experience immediate symptoms and therefore remain in the contaminated area longer, resulting in a more severe injury.⁴^–⁵ Damage to the upper and lower airway occurs in prolonged exposures independent of the agent’s degree of water solubility.⁵ The mechanisms by which irritants damage the respiratory tract vary but include the direct effect of the irritant plus the inflammatory response generated from neutrophils and cytokines. Signs and symptoms include cough, sore throat, dyspnea, chest pain, wheezing, hypoxia, and rales. Rarely, patients have burns involving the skin and eyes.

TABLE 187-1 Pulmonary Irritants Arranged According to Water Solubility

High Solubility	Intermediate	Low Solubility
Ammonia	Chlorine	Phosgene
Chloramines	Hydrogen sulfide	Nitrogen oxides
Hydrochloric acid		Ozone
Hydrofluoric acid
Sulfur dioxide/sulfuric acid

General Care

Most patients exposed to chemicals present with only inhalational injuries, so care should initially focus on airway support and breathing. Bronchodilators are used to treat airway hyperreactivity.⁶^–⁷ Endotracheal intubation is sometimes indicated to prevent collapse of the upper airway due to edema⁷ or to treat hypoxia. White et al. recommend that a relatively large endotracheal tube be used to intubate patients exposed to highly water-soluble agents to prevent obstruction of the endotracheal tube from mucosal sloughing.⁸ If arterial blood gases (ABGs) provide evidence for an acid-base disorder, the median hospital length of stay is longer.⁹

Chemical burns account for only a small percentage of admitted burn patients.^7,¹⁰ However, patients with large dermal exposures in addition to the inhalational injury may have significant burns. In these situations, contaminated clothing should be removed and the wounds irrigated.⁶^–⁷ ¹⁰ Ammonia can cause injuries to the skin that result in intraepidermal blisters and necrosis of the dermis, leading to full-thickness tissue loss.¹¹

More commonly, patients have ocular injuries. Irritation to the eyes should be treated with copious irrigation. Irrigation may cause additional irritation to the eyes, resulting in confusion as to whether the irritation is due to the irrigation or to remaining irritants. Ocular pH testing can clarify whether additional irrigation is indicated. Irrigation should be continued until the ocular pH is neutral (7.4).⁶ The pH strip on a urine dipstick is a readily available way to assess ocular pH. Cycloplegics should be used to decrease pain and prevent morbidity from synechiae.⁷ If concern for ocular injury persists, a full examination should be done in consultation with an ophthalmologist.⁸

Corticosteroids

Only limited literature exists concerning the value of corticosteroids for adjuvant treatment of inhalant-induced ALI, so consensus and evidence-based recommendations do not exist. Data from animal studies suggest corticosteroids may be beneficial for the treatment of inhalant-induced ALI, but additional research is needed. In a blinded randomized controlled trial of rats exposed to ammonia, corticosteroids were not better than placebo.¹²

Chester et al.¹³ published a case report which described two sisters who were simultaneously exposed to chlorine. Both were treated in an emergency department (ED). One of the sisters was admitted to a hospital and treated for 4 days with a corticosteroid. The other sister was discharged from the ED and did not receive therapy with corticosteroids. At follow-up a year later, the sibling who received corticosteroids had a forced expiratory volume in one second (FEV₁) in the normal range, whereas her sister had an FEV₁ of only 80% to 85% of the predicted value.¹³ Multiple authors have discussed using corticosteroids in the treatment of patients with ALI from toxic inhalants,^9,¹⁴^–¹⁸ and one review discouraged the use of these agents because of concerns about unspecified adverse effects.⁸

No randomized controlled trials have investigated corticosteroid treatment of ALI from direct pulmonary inhalants, but there are randomized trials studying the use of corticosteroids for treatment of ALI resulting from all causes.¹⁹^–²⁰ A randomized controlled trial by the Acute Respiratory Distress Syndrome (ARDS) Network enrolled 180 patients, including 110 with ALI from direct lung injury.²⁰ For the most part, these 110 patients had pneumonia and/or aspiration pneumonitis. The number of patients with ALI due to a toxic inhalation was not specified, so it is unclear whether the results of this trial can be generalized to patients with ALI from a toxic inhalation. Another trial also suffered from a similar limitation.¹⁹

Specific Examples

High Water Solubility

Ammonia and Chloramines

Anhydrous ammonia [ammonia (NH₃)] is a colorless gas that is lighter than air at room temperature. It has a very pungent odor which can be detected when the concentration of the gas is ≥5 parts per million (ppm).²¹ Anhydrous ammonia is the third most abundantly produced chemical in the world, and it has many household and industrial uses.²¹ Ammonia was first isolated in its pure gaseous form in 1790, and the first suspected inhalational poisoning was reported in 1841.⁷ Ammonia is transported under pressure as a liquid, and it can cause a hypothermic injury when it is decompressed to normal atmospheric pressure. Ammonia is used as a fertilizer, an explosive, and a chemical weapon.²¹ It is also used in the production of paper and pulp, in the refrigeration and petroleum industry, and in the production of dyes, plastics, and fibers.^8,¹⁶ Accidents and exposures involving ammonia are increasingly common, as this substance is a key intermediate in the illicit production of methamphetamine.¹¹

Because of its high water solubility, clinical manifestations of exposure to ammonia gas present immediately. People generally escape the exposure before becoming symptomatic, as the odor threshold of approximately 5 to 50 ppm is much lower than the irritant threshold of 400 ppm.^10,²² However, ammonia is associated with olfactory fatigue,²¹ so people may believe they have removed themselves from an exposure when they have not. Ocular injuries are associated with exposures to concentrations ≥700 ppm. Exposures to concentrations between 2500 and 4500 ppm can lead to death within 30 minutes, largely due to airway obstruction.^8,²¹ Concentrations of ammonia ≥5000 ppm are rapidly fatal.^7,^10,²²

The extent of injury depends upon the duration of exposure, depth of inhalation, gas concentration, and pH of the gas.^11,²³ Interestingly, anhydrous ammonia itself is not caustic.²⁴ When it dissolves in water, such as in the mucous membranes, it forms ammonium hydroxide (NH₄OH), a strong base.^11,²¹ The dissociation of ammonium hydroxide into hydroxyl ions (see below) also damages tissues and causes liquefaction necrosis.^7,¹⁰

Ammonium hydroxide formation and its dissociation:

NH₃ + H₂O ↔ NH₄OH ↔ NH₄OH → NH₄⁺ + OH⁻

Injury to the mucosa leads to sloughing of the mucosal barrier, formation of cellular debris, edema, hemorrhage, and smooth-muscle contraction. Collectively, these effects of ammonia toxicity can precipitate airway obstruction. In one case report, injury after a massive exposure was so severe the patient required bilateral lung transplantation.¹⁰

Injuries occur first to the eyes, oropharynx, and upper respiratory tract, owing to ammonia’s high water solubility. After prolonged exposure to ammonia or after exposure to a high concentration of the gas, the lower respiratory tract is also injured.²⁴ Ocular injuries (or their sequelae) include conjunctivitis, ulceration, iritis, cataract formation, blepharospasm, and glaucoma. Ammonia also causes hypoxia when it displaces oxygen in the lower respiratory tract.

Chloramines (see below) are nitrogenous chlorinated compounds. They are very irritating gasses produced when household bleach reacts with ammonia. Symptoms due to exposure to chloramines are typically very mild and occur very quickly, allowing potential victims to escape. However, if there is prolonged exposure or exposure to a high concentration of the gas, the patient can have injuries typical of any highly water-soluble irritant.

Chloramine production:

3 NaOCl + 2 NH₃ ↔ NH₂Cl + NHCl₂ + 3 NaOH. B, NH₂Cl + H₂O ↔ HOCl + NH₃

Intermediate Water Solubility

Chlorine

Chlorine is a green-yellow gas with a very pungent odor that is twice as dense as air. It was discovered in the 1770s and soon became useful as a commercial agent.¹⁷^–¹⁸ Its odor can be detected at concentrations as low as 0.2 ppm.¹⁸ Its intermediate solubility in water promotes damage at all levels of the respiratory tract.²⁵ Exposures to chlorine concentrations greater than 430 ppm have resulted in death.¹⁷ Chlorine causes cellular injury by the generation of oxygen free radicals and oxidation of functional groups in cellular components.⁹

Chlorine has many uses. France and Germany used it as a chemical warfare agent during World War I. Today, people are exposed at home or during industrial accidents. Exposure at home can occur while chlorinating a pool or swimming. Chlorine gas is also produced when bleach containing hypochlorite is mixed with an acid. Industrial uses include water purification, textile and paper bleaching, chemical and plastic manufacturing, and disinfection.¹⁸

Chlorine gas directly damages the respiratory mucosa when it combines with water to form hypochlorous and hydrochloric acids (see below). Free radicals are formed which propagate an inflammatory response, leading to neutrophil recruitment and cytokine release. Epithelial cell necrosis and increased pulmonary microvascular permeability have been demonstrated in animal models.²⁶

Chlorine:

Cl₂ + H₂O → HCl + HOCl

The end result is edema and hemorrhage of the respiratory tract, with bronchiolar mucosal destruction and formation of exudate-filled alveoli. These responses predispose the respiratory tract to bacterial superinfection and ALI. Patients present with inflammation of the conjunctivae and upper respiratory tract, ALI, and respiratory failure. They develop bronchospasm, rales, a sore throat, cough, tachycardia, tachypnea, and hypoxia. Tachycardia is a result of pain, coughing, and hypoxia.

The value of nebulized sodium bicarbonate (NSB) to neutralize hydrochloric acid is debatable,⁹ but this therapeutic intervention likely has no adverse effects.²⁵ The use of NSB is based on the assumption that there is a benefit from neutralization of the acids formed after chlorine exposure.^15,²⁷ The solution for nebulization is prepared by mixing 2 mL of 7.5% sodium bicarbonate with 2 mL of normal saline,¹⁵ or 3 mL of 8.4% sodium bicarbonate with 2 mL of normal saline.²⁷

Little data on the use of NSB exist. There are case reports describing rapid and successful improvement in patients after a single NSB treatment.¹⁴^–¹⁵ No adverse events were reported in a retrospective review of poison center data involving 86 patients treated with NSB.²⁷ Only 17 of the 86 patients required hospital admission. Among the admitted patients, mean hospital length of stay was 1.4 days. The timing and number of treatments and other adjunctive therapies varied among patients. Although unable to prove its efficacy, the authors concluded that NSB was potentially beneficial.²⁷ A double-blind study of ED patients concluded that NSB was useful for treating patients with reactive airway dysfunction syndrome (RADS) secondary to chlorine gas exposure.²⁸ Forty-four patients with RADS who were treated with corticosteroids and β₂-agonists were pseudorandomized to receive either NSB or a nebulized placebo. Patients were placed in either the control or treatment group based on an even/odd presentation system (patients numbered 1, 3, 5, etc. were placed into one group, while patients 2, 4, 6, etc. were placed in the other group). To be diagnosed with RADS in this series, patients without preceding disease had to develop pulmonary complaints within 24 hours of a single exposure and have symptoms persist for at least 3 months. The patients who received NSB had significantly higher FEV₁ values.²⁸

Low Water Solubility

Phosgene

Phosgene (COCl₂ or carbonyl chloride) is a colorless gas that is more dense than air.²⁹ It was used as a chemical agent during World War I. Today, exposures occur during the synthesis of plastics and industrial materials, from decomposition of chlorinated hydrocarbons, or during the accidental heating of chlorofluorocarbons. The global consumption of phosgene was 5 million metric tons in 2006.³⁰ Concentrations above 500 ppm/min are associated with fatalities.³¹

Phosgene’s odor has been described as similar to that of freshly mown hay. Even with its low odor threshold of 0.4 to 1.5 ppm, people may not remove themselves from an exposure because of its pleasant smell and/or development of olfactory fatigue.³¹ These factors combined with its minimal acute irritant effects cause people to suffer prolonged exposures, permitting the gas to enter the lower airways and leading to development of ALI, since dose determines degree of damage.³¹

Phosgene damages the respiratory tract by denaturing proteins and irreversibly disrupting the structure of cellular membranes.³¹ It also promotes depletion of glutathione and other endogenous antioxidants.³⁰^–³¹ Phosgene forms hydrochloric acid (HCl) when it reacts with water in mucous membranes.²⁹ These pathophysiologic effects result in pulmonary edema and hypoxia.³²

Symptoms may initially include minor upper respiratory tract irritation. Patients then enter a latent phase and may improve clinically but still have ongoing biochemical injury. This latent phase can last hours; its duration is inversely proportional to the inhaled dose.³¹ The latent period is followed by ALI and pulmonary edema.³¹ The smell of gas or irritative effects have no prognostic significance,^29,³¹ so cases of only moderate exposure to phosgene warrant further observation. Patients with a normal chest x-ray and without any signs or symptoms can be discharged after 8 hours of observation.³¹ Admitted patients who require endotracheal intubation should be treated with a protective ventilation strategy.³²

Multiple treatment strategies target the reduction of inflammation produced by phosgene.³¹ N-acetylcysteine (NAC), aminophylline, isoproterenol, ibuprofen, and corticosteroids have all been studied in animal models.³³^–³⁷ Sciuto et al. tested multiple interventions after exposing rabbits and mice to phosgene.³⁴ The rabbit model demonstrated improvement in multiple variables including decreased intratracheal pressure, increased cyclic adenosine monophosphate (cAMP) concentration in the lung tissue and decreased leukotriene formation after receiving aminophylline and intratracheal instillation of NAC and isoproterenol. The 12-hour survival rate was improved in mice exposed to phosgene after treatment with intraperitoneal ibuprofen, although survival at 24 hours was not affected.³⁴ Others suggest that NAC ameliorates injury by helping to avoid depletion of glutathione.³⁵^–³⁶ In a rabbit model, corticosteroids given 1 hour before exposure to phosgene prevented damage from leukotrienes and other lipoxygenase derived products. Survival was not studied.³³ In a porcine model, treatment with intravenous (IV) methylprednisolone or inhaled budesonide after exposure to phosgene failed to decrease mortality at 24 hours.³⁷ Borak and Diller suggested treating patients with methylprednisolone (250 mg IV) or NAC (20 mL of a 20% nebulized solution).³¹