What every clinician needs to know
Toxicants refer to toxic substances that are introduced into the environment for utilization in warfare, various industries, and households, which when inhaled can lead to a spectrum of illnesses. This chapter will discuss the clinical syndromes involving the respiratory tract and the lung parenchyma that occur in relation to the direct irritant or other toxic effects of the gas. Syndromes resulting from secondary allergic or immune-mediated responses to inhaled toxic agents, such as occupational asthma and hypersensitivity pneumonitis (HP), will not be discussed.
Symptoms and signs of irritant gas inhalation injury vary and can occur immediately after exposure or have a delayed reaction, producing injury anywhere along the respiratory tract, from the nares to the alveoli. Injuries to the nasopharynx and larynx are generally more immediate, as these areas are most susceptible to both thermal injury and the highest concentrations of the irritant, especially the water-soluble agents. Injury to the tracheobronchial tree can result in airway edema, bronchorrhea, and bronchoconstriction a few hours following exposure. As a result, exposure may lead to inflammatory changes, including tracheitis, bronchitis, bronchospasm or bronchiolitis.
Injuries to the epithelium and the capillary-endothelial interface in the distal airways and alveoli are associated with increased permeability, presenting with delayed clinical sequelae, such as interstitial edema, diffuse alveolar damage, or acute respiratory distress syndrome (ARDS). The extent of injury is influenced by the intensity of the exposure, solubility of the gas, chemical reactivity and toxicity, as well as particle size. Host factors which have been reported to contribute to the extent of injury include age, use of respiratory protection, as well as co-morbid conditions.
Common agents in inhalation injury
Asphyxiants (Carbon monoxide, Hydrogen Cyanide)
Blistering agents – Mustards
In general, immediate removal of the patient and any rescue personnel from the exposure is of primary importance, but cannot always be readily achieved without risks. Injury or death in first responders is a considerable problem that must be avoided by vigilant attention, preparation, and appropriate personal protections. In terms of managing the victim exposed to irritants, protecting the airway is of utmost priority. If uncertainty exists, proceeding with intubation is recommended. Management of ensuing hypoxemia will most likely be necessary for patients with significant exposures. For those patients who develop acute lung injury (ALI) or ARDS, management principles are similar to those with ALI/ARDS from other causes. This includes lung protective ventilation strategies and optimal fluid balance, though specific supporting data is limited for such recommendations.
If bronchoconstriction/bronchospasm is present, bronchodilators (albuterol, loevosalbutamol, or racemic epinephrine in normal saline) have been recommended to relieve airway obstruction. Following inhalation injury, continued airway clearance with both pharmacologic agents and mechanical methods are essential. Mucolytics, such as N-acetylcysteine (NAC) and aerosolized heparin, can be used and have been proposed to decrease lung injury, although controlled trials are pending. The role of other specific treatment strategies, including the role of glucocorticoids, will be discussed below with each irritant agent. In cases of toxic inhalation gas exposures, special care must be taken to assure that first responders and healthcare providers are protected from primary and secondary exposures during rescue efforts.
In general, with the exception of hydrogen cyanide, there are no specific diagnostic tests to detect for inhalation of most toxic agents. Diagnosis is based on exposure history and symptoms, knowledge of the environmental risks and testing of the exposure areas. The standard for confirming a diagnosis of inhalation injury is via direct airway examination with fiberoptic bronchoscopy. Findings on bronchoscopic evaluation include, but are not limited to: carbonaeceous deposits, erythema, edema, bronchorrhea, mucosal sloughing, necrosis, and bronchial obstruction.
Evidence of lung parenchymal involvement can also be evaluated with high resolution computed tomography (HRCT), although limitations include optimal timing and interpretation in the setting of normal bronchoscopy. Findings of ground glass opacification with or without consolidations and interstitial markings on HRCT can be used to complement bronchoscopy findings and assist in determining the severity of the inhalation injury. Pulmonary hemorrhage is reportedly unusual as a presentation of irritant gas inhalation injury and should raise suspicion of other disorders.
Source: At room temperatures, chlorine is a greenish-yellow gas and has a strong pungent odor. Because chlorine is denser than air, it tends to settle in low lying areas. Its odor threshold for detection by exposure victims is below its toxic level and serves as a warning of its presence that may be helpful. Chlorine species are highly reactive and intensely irritating. Exposures can occur from unintentional industrial exposures, including accidental release during transport, during water purification, inhalation from swimming pool-related accidents and inhalation using household cleaning products.
Toxicity: Tissue injury may result from exposure to chlorine and its metabolites – hydrochloric acid (HCl), hypochlorous acid (HOCl), and resulting oxygen free radicals. Chlorine is a highly water-soluble compound that when dissolved in water on the mucosal surfaces form hydrochloric and hypochlorous acids, as follows:
Cl2 + H2O ⇔ HOCl + HCl
Hydrochloric acid is highly water-soluble and consequently primarily affects the epithelia of the ocular conjunctivae and upper respiratory mucous membranes. Acute symptoms include lacrimation, as well as nasal and mucous membranes irritation. The acute symptoms may be followed by hoarseness, cough, a choking sensation, chest pain and dyspnea.
Pulmonary edema is the major lower airway finding associated with chlorine toxicity and clinically can lead to hypoxia and respiratory failure. Intense bronchospasm as well as cell necrosis also can result. The onset of pulmonary edema can be minutes or hours following exposure, depending upon severity.
Treatment: The initial approach to toxic chlorine exposure is to remove the individual from the hazardous environment immediately if at all possible. Given the density of chlorine, it is important to remove the patient from the environment in which the exposure occurred and remove clothing that might be saturated with the gas. Bedrest has been recommended for moderate-to-severe exposure because increased activity reportedly may quicken the onset of pulmonary edema.
Use of bronchodilators has been recommended for consideration in treating associated bronchospasm. Secondary bacterial infection risks should also be considered. Treatment of chlorine gas inhalation injuries with corticosteroids is controversial and is supported by several animal studies and case reports, but no human clinical comparative study. In the absence of complications, the adverse effects of chlorine inhalation injury generally resolve in 3 to 5 days.
Source: Phosgene is a very commonly used industrial chemical compound in the production of dyes, pesticides and plastics.
Toxicity: Phosgene has relatively low water solubility and therefore tends to spare the nose and upper airway. The main clinical toxic effects are more distant in the respiratory bronchioles and alveoli. When phosgene interacts with water, hydrochloric acid is released, leading to damage of the alveolar-capillary interface and subsequent pulmonary edema. At low-level exposures, toxic effects are commonly mild cough and dyspnea coupled with chest discomfort. At higher concentrations, a more severe cough with laryngospasm and possible pulmonary edema may occur. Episodes of sudden death have resulted from very intense exposures of phosgene which may have been due to severe laryngospasm. Symptoms are normally apparent within several hours following phosgene exposure.
Treatment: Similar to chlorine exposure, pulmonary edema is the most serious symptoms of phosgene toxicity. Bedrest has been recommended to help reduce the risk of pulmonary edema following an exposure. Pulmonary edema following phosgene inhalation is not due to hypervolemia, thus, diuretics are considered contraindicated. Respiratory failure is a risk, and, anticipating deterioration, there should be a low threshold for intubation. Alternative treatments with pentoxifylline, steroids, NSAIDs and intra-tracheally administered N-acetylcysteine have been shown to mitigate lung injury in some animal models, though human clinical trial data is limited regarding the effectiveness of these agents in phosgene exposure.
Source: The farming industry is the main consumer of ammonia, using approximately one third of all ammonia produced in the U.S. as components of fertilizer and animal feed. Ammonia is also used in the production of pharmaceuticals, explosives, pesticides, textiles, flame-retardants, plastics, paper and petroleum products, rubber and cyanide. Ammonia is also found in many common household cleaning products. Ammonia is released in gas phase with the combustion of many of the compounds listed above, leading to high risk for substantial inhalation exposure.
Toxicity: Because ammonia is highly water-soluble, it is well absorbed by the upper respiratory tract mucosa. However, ammonia is somewhat unique in having a propensity to affect both the upper and lower airways proximally and distally. Ammonia forms ammonium hydroxide, a potent alkali that can lead to tissue necrosis of lower airways. Symptomatically, ammonia exposure can present with bronchospasm, acute lung injury, increased pulmonary secretions and cough.
Treatment: Management of toxic exposure to ammonia is largely supportive. Medical therapy is directed towards management of hypoxia, bronchospasm, acute lung injury, hypovolemia and burns of the skin and eyes.
Source: Sulfur dioxide is a chemical compound commonly released through the burning of rubber products and the combustion of coal, oil and cooking fuel.
Toxicity: Sulfur dioxide is very irritating to the airway mucosa and eyes even at low concentrations. It can lead to the destruction of ciliated mucosa that can predispose patients to secondary pulmonary bacterial infection. High concentration sulfur dioxide exposures may be fatal with both lower and upper airway injury and can lead to diffuse pulmonary edema.
Treatment: Management of toxic exposure to sulfur dioxide is largely supportive, with airway and ventilatory support.
Source: Various occupations can predispose patients to exposures, including arc welders, firefighters, military and aerospace personnel, and those working with explosives. Nitrogen dioxide toxicity is also observed in conditions where NO2 is formed from non-combustible sources, such as in silo fillers, where nitrogen dioxide is a by-product of anaerobic fermentation of crops.
Toxicity: Several mechanisms are involved in NO2 induced lung toxicity. NO2 is converted to NO, HNO3 (nitric acid), and HNO2 (nitrous acid) in distal airways and is toxic to ciliated airway cells and surrounding pneumocytes. Free radicals in the terminal bronchioles following exposure lead to protein oxidation, lipid peroxidation and subsequent cell membrane damage. Toxic NO2 exposure also alters macrophage and immune function with an increased susceptibility to infection. Clinically evident injury is usually delayed at onset for up to 72 hours.
Treatment: The primary treatment of nitrous dioxide induced respiratory illness is supportive therapy directed at correction of hypoxemia, respiratory failure, and secondary infection. High-dose corticosteroids have been used in the treatment of pulmonary manifestations but supportive data is only anecdotal.
Source: Hydrogen sulfide (both a chemical irritant and an asphyxiant) is present largely in industrial processes, including petroleum refining, tanning, mining, wood-pulp processing, rayon manufacturing, sugar-beet processing, and hot-asphalt paving. Toxicity occurs at the industrial level from oil drilling, wastewater treatment, and natural gas field leaks. Hydrogen sulfide also occurs in nature from organic decomposition of sulfur compounds, hence the name, “swamp gas” or “sewer gas.” However, physicians should be aware that the mixture of household products can also produce this toxic gas, leading to potential inhalation injury.
Toxicity: The major route of exposure and toxicity of hydrogen sulfide is via inhalation. It is a colorless, flammable, highly toxic, and slightly heavier than air gas that can accumulate in enclosed, poorly-ventilated, and low-lying areas. The strong “rotten egg” odor of the gas is not a reliable warning sign for toxicity due to olfactory fatigue at high concentrations or continuous low concentrations. Exposure at low concentrations (50ppm) can immediately affect the nose, throat, and lower respiratory tract, causing bronchial or lung parenchymal hemorrhage. Higher concentrations can cause immediate or delayed effects (up to 72 hours) with bronchitis and pulmonary edema.
Treatment: Management is generally supportive with immediate removal of the patient from the environment, high flow 100% oxygen, and early recognition for intubation in severe cases. Additional medications include inhalation of amyl nitrite with injections of 3% sodium nitrite (to induce methemoglobinemia) and aerosolized bronchodilators for bronchospasm. Hyperbaric oxygen therapy may be utilized as well, as oxygen promotes sulfide metabolism.
Chemical compounds that impair oxygen exchange at the cellular level are commonly referred to as asphyxiants. Common compounds in this group include carbon monoxide and hydrogen cyanide.
Source: Carbon monoxide is formed when organic compounds burn incompletely. The most common sources are motor vehicle exhaust, smoke from fires, engine fumes and non-electric heaters. Carbon monoxide poisoning is often associated with malfunctioning or obstructed exhaust systems.
Toxicity: Carbon monoxide causes adverse effects in humans by combining with hemoglobin to form carboxyhemoglobin (HbCO) in the blood, which cannot adequately transport oxygen. Carbon monoxide is rapidly transported across the alveolar membrane and preferentially binds with hemoglobin in place of oxygen and shifts the hemoglobin-oxygen dissociation curve to the left, further impairing oxygen unloading at the tissue level. The reduced oxygen-carrying capacity of the blood, leads to tissue hypoxia. Additionally, myoglobin and mitochondrial cytochrome oxidase may also be to be adversely affected by carbon monoxide poisoning.
Treatment: The treatment for carbon monoxide poisoning is high-dose oxygen. If poisoning is severe a hyperbaric pressure chamber may be used to give even higher doses of oxygen, and reduce the carboxyhemoglobin levels.
Source: Hydrogen cyanide is released from combustion of a number of products, including polyurethane, plastics, furniture and mattresses, as well as the burning of wool, silk and carpets. Hydrogen cyanide poisoning most commonly occurs in the face of smoke inhalation injury, often concurrently with carbon monoxide poisoning. In such settings, the red blood cell cyanide level has been reported to correlate more closely with mortality than the carbon monoxide level during co-exposures. Hydrogen cyanide exposures also occur following industrial accidents and intentional exposures (military and terrorism).
Toxicity: The primary effect of cyanide poisoning consists of the impairment of oxidative phosphorylation, a process whereby oxygen is utilized for the production of essential cellular energy sources in the form of ATP (adenosine triphosphate). A necessary part of this process is transfer of electrons from NADH (nicotinamide adenine dinucleotide, supplied via the Kreb’s Cycle) to oxygen via a series of electron carriers. This is catalyzed by the cytochrome oxidase enzyme system in the mitochondria, and the impairment arises from the inhibition by cyanide of cytochrome oxidase a3. A number of other complex interactions of cyanide have also been implicated in its toxic pathophysiology.
Treatment: Both hydroxocobalamine or a combination of nitrite/sodium thiosulfate are approved for treatment of cyanide poisoning in the United States. Hydroxocobalamine is rapidly becoming the treatment of choice in most cases, and is approved for use in suspected cyanide (not yet confirmed) poisoning situations. In the setting of smoke inhalation injury, hydroxocobalamin may be a better alternative if there are concerns for carboxyhemoglobin level elevations that cause the formation of methemoglobinemia by nitrite treatment to be contraindicated.
Source: Nitrogen mustard is a vesicant blistering agent that has been used as a military weapon throughout the 20th century. Large stockpiles of nitrogen mustard still exist.
Toxicity: Nitrogen mustard can be absorbed quickly through the skin, mucous membranes and respiratory tract. Nitrogen mustard causes epithelial layer sloughing of the proximal airways and more distal lower airways. Clinically mustard exposures present with dyspnea and wheezing from the pulmonary standpoint. Symptoms are often delayed for hours to days after initial exposure, but subclinical changes occur earlier. Secondary infection is common following acute mustard inhalation exposure and may be further exacerbated by systemic immune-compromise from bone-marrow suppression following high-dose exposures. Chronic stricture formation may develop months to years after exposure. Whether obstructive or other late sequelae occur from mustard exposure is controversial.
Treatment: Treatment is supportive, with a low threshold for intubation and ventilatory support following acute exposure. The role of steroids is unclear. Chronic strictures have been treated with recurrent dilation and stent placement as needed.
Patients should be monitoring and followed up based on the individual gas exposure and whether or not there is a specific treatment or antidote. Otherwise, treatment is primarily supportive and patients should be observed closely for resolution of the primary presenting symptoms and signs. Depending on the exposure, it is important to watch out for late pulmonary sequelae, which may manifest clinically between 10 to 14 days after initial exposure.
For instance, patients exposed to ammonia, nitrogen oxides, sulfur dioxide may subsequently develop bronchiolitis obliterans (BO). In some of these cases, the BO is initially accompanied by – but may be followed by – the appearance of organizing pneumonia (BOOP) which may be diffuse and present as ARDS. Although these syndromes can resolve completely, some may progress to late pulmonary fibrosis.
Inhalation of toxic gases leads to injury through a variety of mechanisms. Commonly, inhalation of irritant gases causes inflammation of the airway when gas particles dissolve in the respiratory mucosa, causing acidic or alkaline free radical release. Toxic inhalants may be directly toxic to the respiratory tract (including such gases as ammonia, nitrogen dioxide and sulfur dioxide), which induce a response resulting in systemic inflammatory damage, or can cause asphyxiation through displacement of oxygen or oxygen utilization (cyanide, carbon monoxide).
The extent of exposure and subsequent effects depend on several factors, including the concentration of toxin in the atmosphere, the duration of exposure and particle size. The concentration-time product may not be linearly related to damage effects. Particle size is an important factor because it determines whether the agent will penetrate the respiratory tract and where it will be deposited. More water-soluble gases (ammonia, chlorine, sulfur dioxide and hydrogen chloride) are rapidly absorbed in the upper airway, causing mucosal membrane irritation that can immediately alert individuals to the exposure and potentially facilitate recognition (possibly reducing subsequent exposure).
Less soluble gases (nitrogen oxides, phosgene, ozone) may not dissolve until they are well into the distal airways and thus, result in more prolonged exposure prior to recognition. The deeper penetrating gases are less likely to produce the warning signs of a toxic exposure, resulting in severe bronchiolitis, and symptoms may not develop until a considerable post exposure lag-time (often 12 hours or more). A common pathologic finding of distal airway injury from these gases is diffuse alveolar damage, clinically manifested as ARDS.
Due to lack of consistent diagnostic methods, the incidence of inhalation injury from all chemical irritants is not readily available. Treatment is mainly supportive; however, early detection of signs and symptoms may decrease the risk of long-term pulmonary sequelae. In cases of severe burn injury, mortality is increased when there is involvement of inhalation injury. In addition, studies have shown that mortality rises when there is concomitant inhalation injury and pneumonia present compared to inhalation injury alone. Although empiric treatment with antibiotics is not routinely recommended, evaluating for early signs of infection is essential.
A majority of the patients with mild to moderate irritant exposure have a self-limited course with full recovery seen within 48 to 72 hours. Most patients do not show spirometry changes and do not report significantly decreased quality of life.
Rare long term pulmonary sequelae, often associated with severe exposure, include tracheal stenosis, bronchiectasis, bronchiolitis obliterans, and interstitial fibrosis. The severity of the airway and lung parenchymal injury depends on the extent of exposure, type of irritant, and host factors, most notably age.
What's the evidence?
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