124: Simple Asphyxiants and Pulmonary Irritants

The respiratory system is responsible for gas exchange, elimination of certain xenobiotics, insensible water loss, temperature regulation, and minor metabolic processes. The principle function of the respiratory system is gas exchange, which occurs in the greater than 300 million alveoli that make up approximately 90% of the human lung volume. The average resting adult inhales about 8 L/min of air (a tidal volume of about 500 mL) and averages 16 breaths/min, and this volume can be increased exponentially by increasing the respiratory rate and tidal volume as occurs during exertion. In a 24-hour period, an average adult human at rest will have been exposed to 11,500 L of air. There are a number of protective systems within the respiratory system to prevent exposure to xenobiotics, but these systems can be overwhelmed. The principles of respiratory system function are covered extensively in Chap. 29.

The respiratory tract performs several important physiologic functions. Its most important role involves the transfer of oxygen to hemoglobin across the pulmonary endothelium. This transfer facilitates oxygen distribution throughout the body to permit effective cellular respiration. Diverse xenobiotics may act at unique points in this distribution pathway to limit or impair tissue oxygenation. For example, whereas opioids and neuromuscular blockers may induce hypoventilation, carbon monoxide and methemoglobin inducers prevent loading and unloading of oxygen onto and off of hemoglobin. Certain xenobiotics prevent adequate oxygenation of hemoglobin at the level of pulmonary gas exchange. Two mechanistically distinct groups of xenobiotics are capable of interfering with gas exchange: simple asphyxiants and pulmonary irritants. Impairment of transpulmonary oxygen diffusion, regardless of the etiology, reduces the oxygen content of the blood and may result in tissue hypoxia.

Unlike most xenobiotic exposures, simple asphyxiant and pulmonary irritant poisonings frequently occur on a mass scale because of the nature of the inhalational route. For example, the large-scale emission of carbon dioxide from Lake Nyos, a carbonated volcanic crater lake in Cameroon, West Africa, resulted in nearly 2000 human deaths and many more livestock deaths (Chap. 2).¹⁷ In this disaster, simple asphyxiation was likely because medical evaluation of both survivors and fatalities demonstrated neither signs of cutaneous or pulmonary irritation nor toxicologic abnormalities.²⁰⁶ The widespread use of compressed liquefied gases, which expands several hundredfold on depressurization or warming, account for a substantial number of workplace injuries.^128,188

Irritant gases similarly may result in mass casualties. For this reason, chlorine and phosgene were used in battle during World War I, resulting in thousands of Allied deaths (Chap. 132).⁸⁷ Atmospheric sulfur dioxide and oxides of nitrogen are the primary components of photochemical smog. During the London Fog incident in 1952, 4000 deaths occurred primarily from respiratory causes.¹⁷⁶ Similar smog incidents have occurred across the globe. Relatedly, the diverse irritants found in fire smoke are a major cause of death after smoke inhalation.¹⁸⁵

Unexpected release of other irritant inhalants may lead to large-scale poisoning. In 1984, an inadvertent release of methylisocyanate in Bhopal, India, resulted in immediate and persistent respiratory symptoms in approximately 200,000 local inhabitants, with approximately 2500 deaths.^18,57

Isolated exposures to individuals occur as well, often in workplaces, and more frequently in contained spaces (eg, indoors). Additionally, the use of simple asphyxiation as a painless and relatively undetectable method for committing suicide and, paradoxically, for euphoric experiences, can be found in books, on the Internet, and in the medical literature.^71,79,81,167

Simple asphyxiants work primarily by displacing oxygen from ambient air, unlike chemical asphyxiants, which cause cellular hypoxia and are discussed in Chaps. 125, 126, and 127. Virtually every gas, excluding oxygen, is capable of acting as a simple asphyxiant.

Pathophysiology

Simple asphyxiants displace oxygen from ambient air, thereby reducing the fraction of inspired oxygen (FiO₂) in air to below 21%, and result in a decrease in the partial pressure of oxygen. The partial pressure is a measure of the contribution of oxygen to the total inspired air and is based on both FiO₂ and barometric pressure. For example, because the ambient pressure at sea level (less water vapor, 47 mm Hg) is 713 mm Hg and the percentage of oxygen is 21%, the partial pressure of oxygen in the lungs is 150 mm Hg. However, this relationship is not applicable at other barometric pressures. For example, at the summit of a mountain, the reduced barometric pressure results in a decrease in the partial pressure of oxygen despite a near-normal FiO₂. The barometric pressure decreases in a linear fashion with altitude (above sea level) and increases with descent below sea level. This reduced partial pressure may be insufficient to allow adequate oxygen saturation, and supplemental oxygen becomes necessary. As barometric pressure decreases, exposure to simple asphyxiant gases may further reduce the oxygen partial pressure to life-threatening levels. Conversely, underwater divers reduce their FiO₂ to below 21% by adding simple asphyxiant gases, such as helium, to their breathing mixture to avoid oxygen toxicity, yet they still maintain adequate oxygenation. This is because the elevated barometric pressure increases the partial pressure of oxygen to normal amounts despite the addition of an asphyxiant gas. However, systemically poisonous gases that enter the breathing mixture would have a magnified effect, given their increased partial pressure at depth.

Conceptually, simple asphyxiants have no pharmacologic activity. For this reason, exceedingly high ambient concentrations of these gases are necessary to produce asphyxia. Asphyxiation typically occurs in confined spaces or with rapid release of concentrated simple asphyxiants.

Clinical Manifestations

A patient exposed to any simple asphyxiant gas will develop characteristic clinical findings of hypoxia, or lack of oxygen at the cellular level (Table 124–1). These clinical findings are directly related to the reduction in the partial pressure of oxygen in ambient air, which leads to hypoxemia, or low oxygen content of the blood.¹²⁸ Cardiovascular and central nervous system (CNS) complications of simple asphyxiants predominate because these organs have the greatest oxygen requirements. As hypoxemia becomes severe, multisystem organ failure and death from tissue hypoxia may occur.⁵³ Postmortem findings are generally minimal, hampering the cause of death determination without historical evidence or advanced laboratory testing.¹²

During simple asphyxiation, carbon dioxide exchange is not impaired, and hypercapnia does not occur. Because dyspnea develops more rapidly from hypercapnia than hypoxemia, the breathlessness associated with physical or simple chemical asphyxiation does not develop until severe hypoxemia intervenes.^96,116 In these circumstances, victims may succumb to hypoxemia without ever developing the expected warning symptoms. In the case of carbon dioxide inhalation, hypercapnia may occur very rapidly, which itself may produce acute cognitive impairment.

Specific Xenobiotics

Noble Gases: Helium, Neon, Argon, and Xenon.

Noble gases, which are stored almost exclusively in the compressed form, have numerous industrial and medical roles. Argon is predominantly used as a shielding gas during welding operations, and it is also used in processing titanium and growing crystals. Neon is used in the manufacture of decorative lighting. Xenon, in its radioactive gaseous form, has diagnostic medical applications in ventilation–perfusion scans. Xenon is also used in lighting, solar simulators, digital projectors, and plasma display cells (along with neon). Helium has the lowest molecular weight and is the smallest member of the noble gas family of elements. Because of its lower lipid solubility, helium is used by divers to replace nitrogen to prevent nitrogen narcosis at depth (see Nitrogen). Even at diving gas mixtures of 50% helium, divers suffer no adverse effects as long as a normal partial pressure of oxygen is maintained by the mixture at depth. At depth, the quantity (molar quantity, not volume) of air inspired per breath is several-fold greater than at sea level. The lower density of helium than nitrogen results in a lower viscosity, with a marked decrease in flow resistance. This property of helium is the basis for its use in patients with increased airway resistance (Heliox mixture), such as those with asthma.

Helium is also used in magnetic resonance imaging scanners to keep the coils super cooled. During emergency shutdown of a superconducting electromagnet, an operation known as “quenching,” the liquid helium is rapidly boiled from the device and vented into the scanner room. This may displace oxygen from the environment and cause asphyxia.⁹⁰ Helium is also used in lung imaging studies and pulmonary function testing. Similarly, helium’s low viscosity has led to its use as an inflation gas for intraaortic balloons, for which rapid inflation and deflation are critical.

All noble gases, when compressed, form cryogenic liquids, which expand rapidly to their gas phase on decompression. Liberation of these gases in closed spaces may result in either asphyxiation or freezing injuries, or both.⁹⁰ Xenon, unlike the other noble gases, has unique anesthetic properties because of its high lipid solubility and inhibition of N-methyl-d-aspartic acid (NMDA) receptors.⁹⁰ The other noble gases have no known direct toxicity.

Short-Chain Aliphatic Hydrocarbon Gases: Methane, Ethane, ­Propane, and Butane.

The short-chain aliphatic hydrocarbon gases are primarily used in the compressed form as fuel.

Methane (CH₄) has no known direct toxicity. Animals can breathe a mixture of 80% methane and 20% oxygen without manifesting hypoxic symptoms because their FiO₂, and thus their oxygen content, essentially is normal. Methane, also known as “natural gas” and “swamp gas,” may be present in high ambient concentrations in bogs of decaying organic matter. In addition, compressed natural gas is now used as an alternative fuel for automotive use. Methane exposure is an occupational hazard for miners who historically carried canaries into their workplace as an “early warning” sign for the presence of toxic gases and/or oxygen deficiency. Theoretically, the higher metabolic and respiratory rates of small animals (and children) make them more rapidly susceptible to gas exposures. Methane is also an explosive risk.

Methane is odorless and undetectable without sophisticated equipment.³⁶ For this reason, natural gas is intentionally adulterated with a small concentration of ethyl mercaptan, a stenching agent, which is responsible for the well recognized sulfur odor of natural gas. Cooking with natural gas may cause respiratory symptoms and pulmonary dysfunction.⁹⁹ However, methane itself is unlikely to be the cause, because its combustion is generally complete and ambient concentrations are negligible. It is likely that exposure to nitrogen dioxide (NO₂), one of the products of combustion of methane in air (70% nitrogen), is the explanation for these symptoms.

Ethane (C₂H₆) is an odorless gas that is a component of natural gas and is used as a refrigerant. It has characteristics similar to methane and is occasionally implicated as a simple asphyxiant. Propane (C₃H₈) is widely used in its compressed, liquefied form both as an industrial and domestic fuel, and as an industrial solvent. Butane (C₄H₁₀) is a common fuel and solvent. Deliberate butane inhalation from cigarette lighters or air fresheners for recreational purposes predominantly in adolescents is associated with cardiovascular dysfunction and cerebral damage (Chap. 84).^63,183

Carbon Dioxide (CO₂).

Although not a simple asphyxiant gas by definition because it produces physiologic effects, carbon dioxide closely resembles simple asphyxiants from a toxicologic viewpoint. Carbon dioxide gas has many practical industrial uses, such as production of carbonation in soft drinks and use as a shielding gas during welding. It is used in laboratories as a painless form of animal euthanasia and as a means of large-scale euthanasia of diseased livestock.¹⁵⁶ Carbon dioxide is widely used to extinguish fires because of its ability to safely displace oxygen from the local environment.⁷⁸ Dry ice, the frozen form of carbon dioxide, is an extremely cold substance (–141.3°F {–78.5°C}) that undergoes conversion from solid to gas without liquefaction, a process known as sublimation. Poisoning may occur when dry ice is allowed to sublimate in a closed space,³⁹ such as the cabin of a car or in a cold storage room at 39.2°F (4°C).^78,61 Furthermore, inadvertent connection of respirable gas hoses to carbon dioxide and other nonrespirable sources has occurred in both industrial^96,189 and medical¹⁰⁰ settings, with resultant worker and patient fatalities. This occurrence is uncommon because of the mandated use of engineering controls to prevent the incorrect connection of hose and source terminals.

Pharmacology and pathophysiology.

Carbon dioxide, an end product of normal human metabolism, dissolves in the plasma and is in equilibrium with carbonic acid (H₂CO₃). The pH at the central chemoreceptors, reflective of the dissolved carbon dioxide (PCO₂), is responsible for our respiratory drive, and PCO₂ is tightly controlled by the CNS through regulation of breathing.¹¹⁶ For this reason, exogenous carbon dioxide, combined with oxygen, was at one time used medically as a respiratory stimulant in neonates. Under normal conditions, ambient air contains approximately 0.03% CO₂. When ambient concentrations increase, uptake of carbon dioxide occurs, which further stimulates respiration,¹⁵³ increasing the uptake of ambient carbon dioxide. Accordingly, closed anesthesia systems use scrubbers containing sodium hydroxide (NaOH) to chemically eliminate exhaled carbon dioxide. Failure of the scrubber system results in increasing depth of anesthesia from hypercapnia-induced hyperventilation.

Clinical manifestations.

Carbon dioxide produces both acute and subacute poisoning syndromes. The latter occurs during hypoventilation when a patient fails to eliminate endogenous carbon dioxide, develops hypercapnia, and typically presents with gradual somnolence. This occurrence may be linked to respiratory failure, as in the case of emphysema or opioid poisoning, or it may be iatrogenic, as occurs during permissive hypercapnia.¹³⁸ Alternatively, intense carbon dioxide exposure may produce rapid and lethal poisoning. However, unlike other simple asphyxiants, experimental models of acute carbon dioxide poisoning in which a normal FiO₂ is maintained demonstrate that central nervous and respiratory system manifestations occur within seconds.^89,98 This finding suggests that CO₂ is not solely a simple asphyxiant, but also possesses a potential for systemic effects.

Nitrogen (N₂) Gas.

Although nitrogen, like carbon dioxide, may produce clinical effects independently of hypoxemia, most poisonings are characterized by the manifestations of simple asphyxiants. Nitrogen gas is used as a carrier gas for chromatography, as a fertilizer, as a cryogenic gas for surgery, and extensively in manufacturing. Poisoning by nitrogen gas is uncommon, but may occur after rapid evaporation of the liquid.^103,104

Pharmacology and pathophysiology.

Nitrogen is a colorless, odorless, and tasteless gas that makes up 78% by volume of air. Under standard conditions, it is an inert diatomic gas that has no direct physiologic toxicity.

Clinical manifestations.

Inadvertent connection of air-line respirator hoses to nitrogen and other inert gas sources results in acute asphyxiation, with unconsciousness occurring in approximately 12 seconds,^96,128,188 and death shortly thereafter. More indolent inhalational poisoning by nitrogen is characterized by impairment of intellectual function and judgment, giddiness, and euphoria, which is qualitatively similar to ethanol intoxication.¹³¹ More severely poisoned patients may manifest lethargy or coma.⁷⁰ Systemic absorption is not rapid, however, and prolonged, high-level exposure is required for poisoning. Nitrogen poisoning, also known as nitrogen narcosis, occurs in underwater divers while they are breathing air that contains 70% nitrogen. It has been called rapture of the deep (l’ivresse des grandes profondeurs) and has led to many deaths in the subaquatic environment. The underlying mechanism of nitrogen narcosis is unknown,⁵² but the simple structure and relatively high lipophilicity of nitrogen suggest a mechanism similar to that of the anesthetic gases.⁷⁰ To avoid nitrogen narcosis, a less lipid-soluble inert gas such as helium is generally substituted for nitrogen. Substitution with oxygen, although intuitively logical, is inappropriate because of the risk of oxygen toxicity (see Oxygen).

Dermal exposure to liquid nitrogen produces frostbite because of liquid nitrogen’s extremely cold temperature.¹⁶⁰ Ingestion of liquid nitrogen similarly produces a freezing injury of the gastrointestinal (GI) tract.^108,208 Rarely, bubbles introduced through the skin embolize through the vascular system and impair organ blood flow.⁶²

Treatment

Treatment of all individuals poisoned by simple asphyxiants begins with immediate removal of the persons from exposure and provision of ventilatory assistance. Provision of supplemental oxygen is preferable, but room air usually suffices. Hyperbaric oxygen therapy has shown no benefit in the majority of cases. Restoration of oxygenation through spontaneous or mechanical ventilation occurs after only several breaths. Support of vital functions is the mainstay of therapy, but is generally unnecessary after a brief exposure.

The irritant gases are a heterogeneous group of chemicals that produce toxic effects via a final common pathway: destruction of the integrity of the mucosal barrier of the respiratory tract (Table 124–2).

Pathophysiology

In the lung, irritant chemicals damage both the more prevalent type I pneumocytes and the surfactant-producing type II pneumocytes.¹¹¹ Neutrophil influx, recruited in response to macrophage-derived inflammatory cytokines such as tumor necrosis factor (TNF)-α, releases toxic mediators that disrupt the integrity of the capillary endothelial cells.^121,158 This host defense response results in accumulation of cellular debris and plasma exudate in the alveolar sacs, producing the characteristic clinical findings of the acute respiratory distress syndrome (ARDS). The specific mechanisms by which the irritant gases damage the pulmonary endothelial and epithelial cells vary. Many irritant gases require dissolution in lung water to liberate their ultimate toxicant, which often is an acid, as occurs when hydrogen chloride gas produces hydrochloric acid. The exact mechanism by which acids damage cells and induce an inflammatory response remains uncertain. Oxidation of intracellular proteins may result in rapid cytoskeletal shortening, creating spaces between endothelial cells and allowing fluid movement into the alveolar spaces.¹⁹⁴ Other gases, such as oxygen and ozone, induce pulmonary damage solely through free radical-mediated oxidative stress on the cellular membranes. Nitrogen dioxide (NO₂) and chlorine are characteristic of a group of gases that produce both acid and free radical oxidants. Furthermore, other respirable xenobiotics, such as metals, injure the respiratory tract through oxidant stress and other mechanisms. Because the precise toxicologic and pathophysiologic effects vary widely depending on the physicochemical properties of the xenobiotic, these mechanisms are covered more completely in the following specific discussions.

By virtue of its use as a war agent, phosgene has received more investigation than the other irritant gases. Although the specific mechanisms of toxicity of the other irritants remain poorly defined, they likely cause injury through a similar process. The acids liberated upon dissolution in the mucosal water react with functional groups on epithelial and endothelial cell membranes and, via cellular messengers, result in a complex inflammatory response.^170,145 Phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes and other cytokines such as TNF-α.¹⁷⁰ Leukotrienes are important chemotactic factors for neutrophils, which accumulate, liberate oxidants, and produce ARDS.⁹⁷ ARDS can be prevented in rabbits by tomelukast, a leukotriene receptor antagonist,⁸⁵ and by methylprednisolone, which blocks leukotriene synthesis; both of which are beneficial postexposure.⁸⁵ Ibuprofen, an inhibitor of the arachidonic acid cascade, and xenobiotics capable of reducing neutrophil influx, such as colchicine and cyclophosphamide, reduce lung injury and mortality in mice when they are administered shortly after phosgene exposure.^77,172 Intratracheal dibutyryl cyclic adenosine monophosphate (DBcAMP), a cAMP analog, and other cAMP amplifiers, such as terbutaline or aminophylline, inhibit the release of leukotrienes and reduce toxicity.^102,173 When administered 45 minutes after exposure to phosgene-poisoned rabbits, intratracheal N-acetylcysteine(NAC) decreases the formation of leukotrienes by an undefined means and limits the development of ARDS.¹⁷⁴ Presumably, administration via nebulization would prove similarly effective. Intravenous administration of NAC to patients with mild to moderate ARDS, none of whom had phosgene-induced pulmonary damage, improved systemic oxygenation and reduced their need for ventilatory support.¹⁹⁰ However, progression to respiratory failure was not altered.

Free radicals are highly reactive molecular derivatives, typically from oxygen or nitrogen which bind to and destroy tissue near their site of generation. Through initiation of a lipid peroxidative cascade, free radicals destroy lipid membranes and inhibit energy production through the electron transport chain (Chap. 12). Products of lipid peroxidation and cellular damage initiate neutrophilic influx, presumably in an immunologic attempt to combat a pathogen. Ironically, free radicals generated by the invading inflammatory cells contribute to pulmonary damage. Fortunately, the lung has both enzymatic (eg, superoxide dismutase, glutathione peroxidase, catalase) and nonenzymatic (eg, glutathione, ascorbate) antioxidant systems, which detoxify virtually all free radicals present in the lung.¹⁵⁴ However, the oxidant burden imposed by oxidant gases can preempt these detoxifying systems and produce cellular damage. For example, nebulization of manganese superoxide dismutase into the airway one hour after smoke inhalation, a form of oxidant lung injury, did not improve lung edema or pulmonary gas exchange.¹¹⁹ However, the observed benefit of NAC may also be related to improved hemodynamic function (Antidotes in Depth: A3).⁹¹

Clinical Manifestations

Regardless of the mechanism by which the mucosa is damaged, the clinical presentations of patients exposed to irritant gases are similar. Those exposed to gases that result in irritation within seconds generally develop mucosal injury limited to the upper respiratory tract. The rapid onset of symptoms is usually a sufficient signal to the patient to escape the exposure. Patients may present with nasal or oropharyngeal pain in addition to drooling, mucosal edema, cough, or stridor.¹⁹³ Conjunctival irritation or chemosis, as well as skin irritation, is often noted because concomitant ocular and cutaneous exposure to the gases usually is unavoidable. Gases that are less rapidly irritating may not provide an adequate signal of their presence and may not prompt expeditious escape by the exposed individual. In this case, prolonged breathing allows entry of the toxic gas farther into the bronchopulmonary system, where delayed toxic effects may subsequently be noted. Tracheobronchitis, bronchiolitis, bronchospasm, and ARDS are typical inflammatory responses of the airway and represent the spectrum of acute lower respiratory tract injury.

Experimental models assessing the water solubility of a gas to predict the location of its associated lesions have largely agreed with the clinical data.¹⁰⁵ However, exceptions to this relationship of a gas and its expected toxicity are common. For example, in situations in which escape from ongoing exposure is prevented, patients may develop lower respiratory tract injury after prolonged exposure to acutely irritating gases. Alternatively, rapid onset of upper respiratory irritation may be noted in patients after exposure to concentrated gases that are generally associated with delayed symptomatology. Exposure to exceedingly high concentrations of any irritant gas may produce hypoxemia analogous to that resulting from exposure to a simple asphyxiant gas.

The most characteristic and serious clinical manifestation of irritant gas exposure is ARDS.^{13,20,162,163} ARDS consists of the clinical, radiographic, and physiologic abnormalities caused by pulmonary inflammation and alveolar filling that must be both acute in onset and not attributable solely to pulmonary capillary hypertension as occurs in patients with congestive heart failure.^{13,20,162,163} ARDS is a nonspecific syndrome resulting from diverse physiologic insults such as sepsis or trauma. Patients with ARDS may present with dyspnea, chest tightness, chest pain, cough, frothy sputum, wheezing or crackles, and arterial hypoxemia. Typical radiographic abnormalities include bilateral pulmonary infiltrates with an alveolar filling pattern and a normal cardiac silhouette that differentiate this syndrome from congestive heart failure.

In 2012, the diagnostic criteria for ARDS was updated as a consensus guideline known as the Berlin Definition.^9,10 The draft definition proposed three mutually exclusive strata of ARDS based on the degree of hypoxemia (Table 124–3). Some essential changes of the new definition include: acute was defined as one week or less; the term acute lung injury (ALI) was discontinued; measuring the PaO2/FiO2 ratio now requires a specific amount of positive end-expiratory pressure (PEEP); chest radiograph criteria have been clarified to improve interrater reliability; the pulmonary capillary wedge pressure (PCWP) criterion was removed; and additional clarity was added to improve the ability to exclude cardiac causes of bilateral infiltrates.

Specific Xenobiotics

Acid- or Base-Forming Gases Highly Water-Soluble Xenobiotics

Ammonia (NH₃).

Ammonia is a common industrial and household chemical used in the synthesis of plastics and explosives, and as a fertilizer, a refrigerant, and a cleaner. The odor is characteristic and may be an effective warning signal of exposure and stimulus to avoid further exposure. Dissolution of NH₃ in water to form the base ammonium hydroxide (NH₄OH) rapidly produces severe upper airway irritation. Patients with exposures to highly concentrated NH₃ or exposures for prolonged periods may develop tracheobronchial or pulmonary inflammation. Experimental inhalation of nebulized high-dose ammonia causes ARDS within 2 minutes of exposure.¹⁷⁹ Ultrastructural study of the lungs from two individuals dying acutely of ammonia inhalation revealed marked swelling and edema of type I pneumocytes consistent with ARDS.³⁵ Chronic inhalation of low concentrations of NH₃ or repetitive exposure to high concentrations of ammonia may cause pulmonary fibrosis.³¹

Chloramines.

This series of chlorinated nitrogenous compounds (Fig. 124–1) includes monochloramine (NH₂Cl), dichloramine (NHCl₂), and trichloramine (NCl₃). The chloramines are most commonly generated by the admixture of ammonia with sodium hypochlorite (NaOCl) bleach, often in an effort to potentiate their individual cleaning powers.⁷² Interestingly, the addition of bleach to septic systems may result in liberation of the chloramines after the reaction of bleach with urinary nitrogenous compounds.¹²⁹ On dissolution of the chloramines in the epithelial lining fluid, hypochlorous acid (HOCl), ammonia, and oxygen radicals are generated, all of which act as irritants. Although less water soluble than ammonia, the chloramines typically promptly result in symptoms. Because these initial symptoms are often mild, however, they may not prompt immediate escape, resulting in prolonged or recurrent exposure with pulmonary and ocular symptoms predominating.⁴¹ Exposure to trichloramine occurs at indoor swimming pools⁴³ and is responsible for inducing permeability changes in the pulmonary epithelium, the consequences of which are not yet understood.³⁸

Hydrogen chloride (HCl).

The largest and most important use of hydrogen chloride gas is in the production of hydrochloric acid. Dissolution of hydrogen chloride gas in lung water after inhalation similarly produces hydrochloric acid.^34,152 Pyrolysis of polyvinyl chloride (PVC), a plastic commonly used in pipe fabrication, generates HCl and is an occupational hazard for firefighters.¹⁴¹ By adsorbing to respirable carbonaceous particles generated in the fire, HCl may be deposited in the alveoli and produce pulmonary toxicity.

Hydrogen fluoride (HF).

Hydrogen fluoride and its aqueous form, hydrofluoric acid, are used in the gasoline, glassware, building renovation, and semiconductor industries. Hydrogen fluoride gas dissolves in epithelial lining fluid to form the weak acid hydrofluoric acid. The intact HF molecule is the predominant form in solution, and few free hydronium ions (H₃O⁺) are liberated. Low-dose inhalational exposures may result in irritant symptoms,^200,212 and large exposures may cause bronchial and pulmonary parenchymal destruction.^30,200 Death after inhalation may result from ARDS, but usually is related to systemic fluoride poisoning independent of the route of exposure because of the resultant calcium binding and subsequent hypocalcemia and hyperkalemia^26,59 (Chap. 107).

Sulfur dioxide and sulfuric acid (SO₂ and H₂SO₄).

Sulfur dioxide has multiple industrial applications and is a byproduct found in the smelting and oil refinery industries. It may also be generated by the inadvertent mixing of chemicals, such as an acid with sodium bisulfite (NaHSO₃). Sulfur dioxide is highly water soluble and has a characteristic pungent odor that provides warning of its presence at concentrations well below those that are irritating. In the presence of catalytic metals (Fe, Mn), environmental sulfur dioxide is readily converted to sulfurous acid (H₂SO₃) within water droplets. Sulfurous acid is a major environmental concern and the cause of “acid rain.” Exposure to atmospheric sulfur dioxide results in a roughly dose-related bronchospasm, which is most pronounced and difficult to treat in patients with asthma. Inhalation of sulfurous acid or dissolution of sulfur dioxide in epithelial lining fluid produces typical pathologic and clinical findings associated with ARDS.¹⁵⁹ In addition to the effect of acid generation upon dissolution, sulfur dioxide may cause oxidative damage to the lungs.¹²⁷ Large acute exposure to either xenobiotic produces the expected acute irritant response of both the upper and lower respiratory tracts,⁴⁴ and pulmonary dysfunction (see Asthma and Reactive Airways Dysfunction Syndrome) may persist for several years.¹⁴⁹

Intermediate Water-Soluble Xenobiotics

Chlorine (Cl₂).

Chlorine gas is a valuable oxidizing agent with various industrial uses, and occupational exposure is common. Chlorine gas was used as a chemical warfare agent by both the French and the Germans in World War I (Chap. 132). Although chlorine gas is not generally available for use in the home, domestic exposure to chlorine gas is common. The admixture of an acid to bleach liberates chlorine gas (Fig. 124–2).^80,135 Because the anionic component of the acid is not involved in the reaction, combining hypochlorite with virtually any acid, such as phosphoric, hydrochloric, or sulfuric acid, may result in the release of chlorine gas. As such, inappropriate mixing of cleaning products is the cause of most nonoccupational exposures.¹³⁵ Rarely, patients have intentionally generated chlorine gas in this manner for purportedly “pleasurable” purposes.¹⁵⁵ Concentrated chlorine gas may be generated when aging swimming pool chlorination tablets, such as calcium hypochlorite [Ca(OCl)₂] or trichloro-s-triazinetrione (TST), decompose^118,213 or are inadvertently introduced to a swimming pool while swimmers are present.^15,205 Inadvertent mixture of Ca(OCl)₂ and TST results in excessive chlorine gas generation and may also be explosive.¹¹⁸ Acute chlorine toxicity may occur when there is a failure of the system when compressed chlorine gas is used for direct chlorination of public swimming pools^15,204 or for drinking water systems. Occasional mass poisoning may occur during scientific, industrial, or transportation incidents.^42,198

Mass exposure has also been reported when a chlorine storage tank was being recycled, and it ruptured.⁴⁰ The odor threshold for chlorine is low, but distinguishing toxic from permissible air concentrations may be difficult until toxicity is manifest. The intermediate solubility characteristics of chlorine result in only mild initial symptoms after moderate exposure and permit a substantial time delay, typically several hours, before clinical symptoms develop. Chlorine dissolution in lung water generates HCl and hypochlorous (HOCl) acids. Hypochlorous acid rapidly decomposes into HCl and nascent oxygen (O). The unpaired nascent oxygen atom produces additional pulmonary damage by initiating a free radical oxidative cascade. Although the majority of life-threatening chlorine poisonings occur after acute, large exposures, patients with chronic, low-concentration exposure or recurrent, moderate concentration poisonings may manifest increased bronchial responsiveness.^5,69,76

Hydrogen sulfide (H₂S).

Hydrogen sulfide exposures occur most frequently in the waste management, petroleum, and natural gas industries,⁹² although poisoning occurs in asphalt, synthetic rubber, and nylon industry workers as well. It is also rarely seen in hospital workers using acid cleaners to unclog drains clogged with plaster of Paris sludge.¹⁴⁸ Hydrogen sulfide is present in natural sources such as volcanic emission, in caves, and in sulfur springs. It is a decay product of organic material found in sewers or manure pits. Hydrogen sulfide, hydrogen fluoride, and phosphine are differentiated from the other irritant gases by their ability to produce significant systemic toxicity. Hydrogen sulfide inhibits mitochondrial respiration in a fashion similar to that of cyanide (Chap. 126).^64,157

H₂S has the distinctive odor of “rotten eggs,” which, although helpful in diagnosis, is not specific. Despite a sensitive odor threshold of several parts per billion,¹⁵⁷ rapid olfactory fatigue ensues, providing a misperception that the exposure and its attendant risk have diminished. At low and moderate concentrations (≤500 ppm), upper respiratory tract mucosal irritation occurs and is the principal toxicity.¹⁹² The rapidity of death in patients exposed to high H₂S concentrations makes it likely that either simple asphyxiation or cytochrome oxidase inhibition is causal in most cases.

Phosgene (carbonyl chloride {COCl₂}).

During World War I, phosgene was an important weapon of mass destruction that produced countless deaths (Chap. 132). Currently, phosgene is used in the synthesis of various organic compounds, such as isocyanates, and it occasionally produces poisoning. It is a byproduct of heating or combustion of various chlorinated organic compounds.¹⁸¹

Exposure to phosgene initially may produce limited manifestations, but may result in acute mucosal irritation after intense exposure. In fact, the pleasant odor of fresh hay, rather than prompting escape, ironically may promote deep and prolonged breathing of the toxic gas. The most consequential clinical effect related to phosgene exposure is delayed ARDS.^27,169 Because of the accumulation of a significant alveolar burden of phosgene, symptoms generally are severe after they occur. The delay in onset may take up to 24 hours, so prolonged observation of patients thought to be phosgene-poisoned is warranted. The mechanism of phosgene toxicity is dependent on the dissolution of the gas into the fluid of the epithelial lining with resultant liberation of hydrochloric acid and reactive oxygen species (ROS).¹⁶⁹

Oxidant Gases.

Rather than acidic or alkaline metabolites, free radicals mediate the pulmonary toxicity of certain irritant gases. Many of the chemicals discussed participate in both acid–base and oxidant types of injury. However, the clinical distinction between acid- or alkali-forming agents and oxidant gases is difficult but ultimately may prove therapeutically relevant.

Oxygen (O₂).

Oxygen toxicity is uncommon in the workplace but, ironically, is common in hospitalized patients. Although O₂ may produce CNS and retinal toxicity, pulmonary damage is more common.¹⁸⁰ Several clinical studies indicate that humans can tolerate 100% O₂ at sea level for up to 48 hours without significant acute pulmonary damage.^37,56 Under hyperbaric conditions (2.0 atmospheres absolute), such as during compressed-air diving or while inside a pressurized hyperbaric chamber, oxygen toxicity may develop within 3 to 6 hours.⁴⁷ ARDS occurs in approximately 5% of patients administered hyperbaric oxygen for therapeutic purposes.¹⁸⁰ Delayed pulmonary fibrosis, presumably from healing of subclinical injury, may develop in patients breathing lower concentrations of O₂ at sea level for shorter periods.

Although it appears paradoxical that O₂, an essential molecule, may be deleterious at elevated concentrations, it is not. In mitochondria, O₂ plays a critical role as the ultimate acceptor for electrons completing the electron transport chain. It is this same potent oxidizing activity that allows O₂ to remove electrons from other compounds generating the reactive oxygen intermediates.¹⁶⁴

Generation of ROS, including superoxide (), hydroxyl radical (OH·), hydrogen peroxide (HOOH), singlet oxygen (O·), and nitric oxide (NO), produces cellular necrosis, increases pulmonary capillary permeability, and induces apoptosis.^142,164 NO, produced by inducible NO synthase (iNOS) in the setting of oxidative stress, is directly cytotoxic or may combine with superoxide anions to form the more reactive oxidant peroxynitrite (ONOO^–).⁹³ Experimental prevention of these effects by administration of either parenteral NAC,^165,207 a chemical antioxidant, or superoxide dismutase, an enzymatic antioxidant,^37,199 suggests that the mechanism of toxicity relates to the oxidant, or electrophilic, effects of these ROS (Chap. 12). Although several other therapies have shown promise in preventing oxygen-mediated toxicity, none has yet proven to be valuable for patients who already manifest pulmonary toxicity. Current techniques for preventing pulmonary oxygen toxicity emphasize reduction of the inspired oxygen concentration by use of PEEP ventilation, although this approach failed to prove beneficial in at least one clinical trial.¹⁴ The potential role of liquid ventilation of the lung with perfluorocarbons to prevent or treat pulmonary oxygen toxicity remains under investigation.¹⁴

Oxides of nitrogen (NO_x).

Oxides of nitrogen are a series of variably oxidized nitrogenous compounds.⁷³ The most important substances included in this series are the stable free radicals nitrogen dioxide (NO₂) and nitric oxide (NO), as well as nitrogen tetroxide (dinitrogen tetroxide [N₂O₄]), nitrogen trioxide (N₂O₃), and nitrous oxide (N₂O). The oxides of nitrogen are of limited value in industrial operations, although they may be generated during welding and brazing. NO₂, in addition to hydrogen cyanide, is produced in the pyrolysis of nitrocellulose, which is a substantial component of radiographic film. For example, a fire in the radiology department of the Cleveland Clinic in 1929 resulted in 125 casualties, with virtually all deaths resulting from cyanide or NO₂ gas poisoning.⁸² NO₂ toxicity may occur when propane-driven ice-cleaning machines are used in indoor ice skating rinks with poor ventilation, thereby allowing accumulation of the generated NO₂.¹¹⁴ Military exposure to high NO₂ concentrations may occur during closed-space fires, such as in submarines.¹²⁰ NO₂ also causes silo filler’s disease, in which the toxic gas generated during decomposition of silage accumulates within the silo shortly after grain storage, eliminating rodents that feast on the grains.^60,215 In the absence of ventilation, high concentrations of NO₂ may accumulate in the silo such that an individual entering the silo is rapidly asphyxiated from the depletion of oxygen.⁸³ Additionally, substantial quantities of NO₂ remaining after incomplete ventilation may produce the delayed-onset pulmonary toxicity characteristic of silo filler’s disease. Chronic indoor exposure to NO₂, generated during cooking⁹⁹ or outdoor exposure to photochemical smog, of which the oxides of nitrogen are a component, may predispose individuals to the development or exacerbation of chronic lung diseases.

The various oxides of nitrogen may directly oxidize respiratory tract cellular membranes, but more typically generate reactive nitrogen intermediates, or radicals, such as ONOO^–, which subsequently damage the pulmonary epithelial cells.¹⁴⁶ In addition to generating oxidant cascades, dissolution in respiratory tract water generates nitric acid (HNO₃) and NO, which produce injury consistent with other inhaled acids. In fact, inhalation of HNO₃ produces the same clinical and pathologic syndrome.⁸⁶ Antioxidants afford significant protection to human endothelial cells exposed to NO₂, indicating an important role of free radicals in the toxicology of these xenobiotics.²⁰¹

NO, an endogenous compound important as a neurotransmitter and vasorelaxant, is used clinically as exogenous inhalational therapy for pulmonary hypertension and ARDS.¹⁹⁵ In patients with ARDS not resulting from sepsis (although not specifically from inhalational injury), low concentrations of inhaled NO (5 ppm) did not improve the clinical outcome.¹⁹⁵ However, one patient with NO₂ pulmonary toxicity improved clinically after NO therapy, so further consideration is warranted.¹¹² Furthermore, its use in premature infants with respiratory distress syndrome is well accepted.¹⁶⁸ NO is less soluble in the fluid lining the epithelial surfaces than are the other oxides of nitrogen and produces irritant effects after large exposures.^88,211 Its pulmonary oxidative toxicity, the manifestations of which are typical of the oxidant gases, is substantially enhanced by conversion to reactive nitrogen intermediates such as ONOO^–.¹⁹ This radical selectively interacts with tyrosine to produce nitrotyrosine, which may subsequently serve as a marker for oxidant damage.⁸⁸ NO may be absorbed from the lung and is rapidly bound by hemoglobin to form nitrosylhemoglobin and methemoglobin.

Ozone (O₃).

Ozone is abundant in the stratospheric region found between 5 and 31 miles above the planet. Ozone is formed by the action of ultraviolet light on oxygen molecules, thus reducing the amount of solar ultraviolet irradiation reaching earth. The ozone concentration in passenger aircrafts may at times be above regulatory limits,¹⁸² although a specific relationship with the development of clinical effects in airline crew members is elusive.¹³⁶ Ozone is another important component of photochemical smog and, as such, contributes to chronic lung disease.^32,202 It is produced in significant quantities by welding and high-voltage electrical equipment and in more moderate doses by photocopying machines and laser printers. Because of its high electronegativity (only fluorine is higher), ozone is one of the most potent oxidizing agents available. For this reason, it is used as a bleach, particularly as an alternative to chlorine in water purification and sewage treatment.

The pulmonary toxicity associated with ozone primarily results from its high reactivity toward unsaturated fatty acids and amino acids with sulfhydryl functional groups.^21,101 Ozonation and free radical damage to the lipid component of the membrane initiate an inflammatory cascade, with resultant influx of inflammatory cells.^22,158 Reactive nitrogen species are also implicated, as NO synthase knockout mice are relatively protected from ozone-induced inflammation and tissue injury.⁶⁷ Increased permeability of the pulmonary epithelium results in alveolar filling from the transudation of proteins and fluids characteristic of ARDS. Antioxidant agents (eg, vitamin E) that react preferentially with free radicals before membrane damage occurs prevent or limit the pulmonary toxicity of ozone.

Miscellaneous Pulmonary Irritants

Methylisocyanate.

Methylisocyanate (MIC; Fig. 124–3) is one of a series of compounds sharing a similar isocyanate (N=C=O) moiety. Toluene diisocyanate (TDI) and diphenyl-methane diisocyanate (MDI) are important chemicals in the polymer industry. In those exposed to MIC in Bhopal, ARDS was evident both clinically and radiographically.¹³⁰ MIC is a significantly more potent respiratory irritant than the other regularly used isocyanate derivatives such as TDI.⁶ Cyanide poisoning does not occur, and empiric antidotal therapy is not indicated.

Riot control agents: capsaicin, chlorobenzylidenemalononitrile, and chloroacetophenone.

Historically, riot control agents (Fig. 132–5), commonly called Mace, consisted primarily of chloroacetophenone (CN) or chlorobenzylidenemalononitrile (CS).²⁴ Both are white solids that are dispersed as aerosols. The dispersion is generally accomplished through mixture with a pyrotechnic agent such as a grenade or with a volatile organic solvent in a personal protection canister. Because the delivery systems of these agents are of limited sophistication and are subject to prevailing environmental conditions, dosing is unpredictable, and unintended self-poisoning is common.²⁴ After low-concentration exposure, ocular discomfort and lacrimation alone are expected, accounting for the common appellation tear gas. The effects are transient, and complete recovery within 30 minutes is typical, although long-lasting pulmonary effects may occur (see Asthma and Reactive Airways Dysfunction Syndrome).¹⁶¹ Closed-space or close-range exposure, as well as physical exertion during exposure, may produce significant ocular toxicity, dermal burns, laryngospasm, ARDS,¹⁹⁶ or death.²⁴ Because of their high potential for severe toxicity, CN and CS were replaced for civilian use by oleoresin capsicum (OC), also known as pepper spray or pepper mace. Although capsaicin, its active component, is considerably less toxic, it is occasionally responsible for pneumonitis²³ and death.¹⁸⁶

Capsaicin interacts with the vanilloid receptor-1 (VR1), which was recently renamed the transient receptor potential vanilloid-1 (TRPV1).¹⁹¹ Stimulation of this receptor invokes the release of substance P, a neuropeptide involved with transmission of pain impulses. Substance P also induces neurogenic inflammation, which, in the lung, results in ARDS and bronchoconstriction (see Asthma and Reactive Airways Dysfunction Syndrome).¹⁹¹ The severe pulmonary toxicity of CS and CN likely is related to their ability to alkylate tissues in a manner similar to nitrogen mustard.⁴⁸

Metal pneumonitis.

Acute inhalational exposures to certain metal compounds produce clinical effects identical to those of the chemical irritants. For example, zinc chloride (ZnCl₂) fume is used as artificial smoke because of the dense white character of the fume, and an aqueous solution is still used as a soldering flux. Exposure to zinc chloride fumes for just a few minutes is associated with ARDS and death^66,94,95 (Chap. 103). Cadmium oxide (CdO) is generated during the burning of cadmium metal in an oxygen-containing environment, as occurs during smelting or welding (Chap. 91). The refining of nickel using carbon monoxide (Mond process) produces nickel carbonyl [Ni(CO)₄], a volatile pulmonary oxidant¹⁷⁵ (Chap. 99). Inhalation of volatilized elemental mercury,¹³⁴ which occurs during the vacuuming of mercury spills or home extracting of precious metals, may be toxic. Although at sufficient concentrations, many of these metal exposures produce warning symptoms, severe toxicity may occur even in the absence of warning symptoms. The mechanism of toxicity may relate to overwhelming oxidant stress with a pronounced inflammatory response as measured by serum cytokines (eg, TNF-α) concentrations.⁹⁵ Experimental findings suggest a role for inactivation of natural antioxidant systems.²¹⁴ Patients with metal-induced pneumonitis present with chest tightness, cough, fever, and signs consistent with ARDS. Metal pneumonitis is distinguishable from other causes of ARDS only by history or, retrospectively, by elevated serum or urine metal concentrations.⁸ In particular, metal pneumonitis should be differentiated from the more common and substantially less consequential metal fume fever, discussed later in this chapter. In addition to standard supportive measures, patients with acute metal-induced pneumonitis should be hospitalized and receive corticosteroids.⁹⁵ Chelation therapy has no documented benefit for treatment of patients with ARDS, but should be used based on conventional indications.

Standard and Supportive Measures

Management of patients with acute respiratory tract injury begins with meticulous support of airway patency by limiting bronchial and pulmonary secretions and maintaining oxygenation. Although various theoretical and experimental treatment modalities have been proposed, supportive care remains the mainstay of therapy. Supplemental oxygen, bronchodilators, and airway suctioning should be used if clinically indicated. Nitrovasodilators, diuretics, and morphine have little role in the management of patients with ARDS, although low-dose morphine may prove beneficial as an anxiolytic.^3,150 Corticosteroid therapy, designed to reduce the inflammatory host defense response, frequently improves surrogate markers of pulmonary damage,^123,124 such as oxygenation status, but generally offers little outcome enhancement in patients with ARDS.^4,147 Clinical data on the efficacy of corticosteroids used in human beings exposed to pulmonary irritants is limited and inconclusive. There might be some benefit in the first 14 days after an exposure, but methylprednisolone was associated with increased mortality at 60 and 180 days (when steroids were continued after the first 14 days). A recent article reviewed animal studies published from 1966 to January 2010 and did not find a benefit in animal studies, especially after severe exposures.⁵⁴ Importantly, most studies of ARDS involve predominantly septic or traumatized patients, with few patients suffering from inhalational poisoning. Because the inflammatory response initiated by bacterial endotoxin differs from that caused by irritant gases, the applicability of these studies to the treatment of poisoned individuals is limited. There is an interesting report of simultaneous, presumably equivalent chlorine exposure in two sisters, with improved outcome in the sister who received steroid treatment.⁴⁵ Most available research evaluates parenterally administered corticosteroids, although animal models demonstrate a beneficial effect of nebulized beclomethasone^84,54 and nebulized budesonide^209,54 after acute chlorine poisoning. Nebulized budesonide compared to intravenous betamethasone had similar effects.⁵⁴ However, a human pretreatment model of inhaled budesonide fails to document a substantive alteration of the effects of ozone inhalation.¹³⁷ Ketoconazole, an antifungal agent with antiinflammatory effects,¹ and nonsteroidal antiinflammatory agents, such as ibuprofen,¹⁷¹ variably improve experimental lung function or mortality in patients with ARDS of various nontoxicologic etiologies and have little current role in the therapeutic armamentarium. Furthermore, most of the aforementioned studies assess acute outcome and not long-term effects in survivors. Because corticosteroids experimentally reduce the late fibroproliferative phase during lung recovery, they ultimately may prove beneficial. Overall, there is little reason to suspect any specific benefit of corticosteroids and other antiinflammatory drugs in most poisoned patients. However, because most studies demonstrate some benefit and little identifiable risk, corticosteroid use appropriately remains routine and based largely on local practices.

The clinical similarities among patients with irritant gas exposure and other etiologies of ARDS suggest that similar management principles should be applied. Prone positioning during ventilation,^7,74 PEEP,⁶⁸ and inverse-ratio ventilation are successful in enhancing the oxygenation of patients with ARDS of various causes but are not necessarily successful in improving outcome. Lower tidal volume mechanical ventilation using 6 mL/kg and plateau pressures 30 cm H₂O attenuated the inflammatory response¹⁴³ and resulted in lower mortality and less need for mechanical ventilation than traditional volume ventilation with 12 mL/kg.^2,132 Although not specifically evaluated in any of these studies, there are sound theoretical reasons to believe that all of these modalities should improve oxygenation in poisoned patients as well. Although it is always important to reduce the inspired concentration of oxygen to below 50% as rapidly as possible, patients poisoned by irritant gases may be even more susceptible to oxygen toxicity as a result of depletion of endogenous antioxidant barriers.¹⁷⁸

Neutralization Therapy

A therapy unique to several of the acid- or base-forming irritant gases is chemical neutralization. Although contraindicated in acid or alkali ingestion, the large surface area of the lung and the relatively small amount of xenobiotic present allow dissipation of the heat and gas generated during neutralization. Case studies suggest that nebulized 2% sodium bicarbonate may be beneficial in patients poisoned by acid-forming irritant gases.²⁰⁴ The vast majority of these cases involve chlorine gas exposure, and most patients received other symptomatic therapies as well.²⁸ Although there appears to be no specific benefit for patients exposed to chloramine, nebulized bicarbonate therapy appears to be safe.¹⁴⁴ A prospective evaluation of patients poisoned with chloramine and chlorine gas did not show any clinically significant difference between the group getting nebulized sodium bicarbonate and the control group, although there was a small but statistical improvement in forced expiratory volume in one second (FEV₁) at 120 and 240 minutes in the group that received nebulized sodium bicarbonate.¹¹ Any sodium bicarbonate solution used should be sufficiently diluted to prevent irritation. Typically, 1 mL of 7.5% or 8.4% sodium bicarbonate solution is added to 3 mL sterile water (resulting in an approximately 2% solution for nebulization).

Whether nebulized sodium bicarbonate therapy alters the natural course of irritant-induced pulmonary damage remains uncertain. The fact that many irritants produce concomitant oxidant injury suggests that it may not. Nebulized 4% sodium bicarbonate administered to chlorine-poisoned sheep improved oxygenation, but failed to decrease mortality rates.⁴⁶ Therefore, patients receiving nebulized bicarbonate therapy require observation beyond the time of symptom resolution. Because administration of neutralizing acids for alkaline irritants, such as ammonia, has not been attempted, their use cannot be recommended at this time (Antidote in Depth: A5).

Antioxidants

Antioxidants include reducing agents such as ascorbic acid, NAC,¹⁰⁶ free radical scavengers such as vitamin E, and enzymes such as superoxide dismutase. Studies in humans have noted both increased¹⁶⁶ and decreased²⁹ endogenous antioxidant concentrations in bronchoalveolar lavage fluid in patients with ARDS. Although the concept of treating pulmonary oxidant stress with antioxidants or free radical scavengers is intriguing, most currently available evidence suggests that these xenobiotics offer negligible benefit.^133,140 The rapid onset of the self-perpetuating destructive effects initiated by redox reactions may hinder any postexposure therapy. This interpretation is supported by pretreatment models in which antioxidants are effective at preventing or at least limiting the pathologic effects. Use of these and other newer therapies targeted against inflammatory mediators or the oxidative cascade are in the earliest investigative stages.

Xenobiotic-Directed Therapy

Patients with inhalational exposure to hydrogen fluoride should undergo frequent electrocardiographic evaluations and correction of serum electrolytes. Administration of nebulized 2.5% calcium gluconate, prepared as 1.5 mL 10% calcium gluconate plus 4.5 mL 0.9% sodium chloride solution or sterile water, should be considered to limit systemic fluoride absorption.^107,113,200 By binding fluoride ion locally, nebulized calcium may prevent fluoride-induced cellular and systemic toxicity. Systemic calcium salts should be administered as needed to correct hypocalcemia (Chap. 107 and Antidotes in Depth: A29).

Current therapy for inhalation of capsaicin, or of any tear gas, is primarily supportive. Extracorporeal membrane oxygenation has been used in children to maintain oxygenation in the presence of severe pulmonary toxicity resulting from capsaicin exposure.²³ Although no antidotes currently are available, the newly developing insight into the receptor mechanism of capsaicin suggests that a receptor active agent may hold future promise.

Advanced Pharmacologic Therapy

Perfluorocarbon Partial Liquid Ventilation.

Partial liquid ventilation involves the intrapulmonary administration of perfluorocarbons, which are inert liquids with low surface tension and excellent oxygen-carrying capacity. Studies in patients with nonchemically induced ARDS suggest that exfoliated tissue, and presumably persistent xenobiotic, may be effectively lavaged from the bronchopulmonary tree with this method.⁵¹ Perfluorocarbons improve oxygenation and may have an antiinflammatory effect, as demonstrated by reduced oxidant lung injury after liquid ventilation in animals.⁵⁰ Although it may prove to be a highly useful therapy in the future, the limited availability, high cost, and lack of demonstrated efficacy of this therapy make it suitable only for academic and research settings.⁵¹

Exogenous Surfactant

Several other developments may prove useful in the general management of patients with ARDS. Surfactant replacement therapy initially received attention as a treatment for patients with ARDS because of its beneficial effects in infant respiratory distress syndrome. Although several experimental and clinical studies suggested the safety and efficacy of surfactant therapy in patients with ARDS, large randomized, controlled clinical trials fail to show a benefit on survival.¹⁸⁴ Patients who received surfactant had a greater improvement in gas exchange during the 24-hour treatment period than patients who received standard therapy alone, suggesting the potential benefit of a longer treatment course.¹⁸⁴ But because most studies involved patients with sepsis-related ARDS, the inability to show a beneficial effect may not adequately reflect the potential of surfactant in irritant gas-induced ARDS.¹⁵¹ Many oxidant gases inactivate endogenous surfactant, although the specific effects on exogenous surfactant are not well understood.¹⁵¹

Nebulized Epinephrine.

There are early studies being performed in animal models to evaluate the efficacy of nebulized epinephrine to attenuate the acute injury to lung tissue caused by smoke inhalation. A study in sheep suggests that nebulized epinephrine (4 mg) attenuates pulmonary dysfunction and decreases pulmonary hyperemia without systemic effects like hyperglycemia and elevated plasma catecholeamines.¹¹⁰

A particulate, or dust, is a solid dispersed in a gas. Dust is a substantial source of occupational particulate exposure and is an important cause of acute pulmonary toxic syndromes. A respirable particulate must have an appropriately small size (generally <10 microns) and aerodynamic properties to enter the terminal respiratory tree. Nonrespirable particulates, also called nuisance dusts, are trapped by the upper airways and are not generally thought to cause pulmonary damage. In distinction from the irritant gases, there is no unifying toxic mechanism among the respirable particulates. Many of the particulate diseases, such as asbestos exposure and its sequelae, are chronic in nature; only the acute or subacute syndromes are discussed here.

Inorganic Dust Exposure

Silicosis is a range of pulmonary diseases associated with inhalation of crystalline silica (SiO₂), or quartz. It typically occurs in workers involved in occupations in which rock or granite is pulverized, including mining, quarry work, and sandblasting. Although typically a chronic disease, intense subacute exposure may produce acute silicosis in a few weeks and death within 2 years. The mechanism of toxicity probably relates to the relentless inflammatory response generated by the pulmonary macrophages.¹³⁹ These cells engulf the indigestible particles and are destroyed, releasing their lytic enzymes and oxidative products locally within the pulmonary parenchyma. Patients present with dyspnea, cor pulmonale, restrictive lung findings, and classic radiographic findings. Treatment is limited and includes steroids and supportive care.

Silica combined with other minerals is referred to as silicates, the most important of which include asbestos and talc. Talc, or magnesium silicate [(Mg₃Si₄)O₁₀(OH)₂], is widely used in industry, but its use in the home has been curtailed over the past two decades because of cases of severe pulmonary injury.¹¹⁷ Much of the toxicity of talc is related to free silica or asbestos contamination. Improvement after acute massive exposure may be accompanied by progressive pulmonary fibrosis.

Organic Dusts

Inhalation of dusts from cotton or similar natural fibers, usually during the refinement of cotton fibers (byssinosis), produces chest tightness, dyspnea, and fever that typically begin within 3 to 4 hours of exposure. Similar reactions may occur after inhalation of hay, silage, grain, hemp, or compost dust. Symptoms often resolve during the workweek but return after a weekend hiatus. Byssinosis is probably caused by an endotoxin present on the cotton and is not immunologic in nature.²¹⁰ “Grain fever” is caused by a respirable compound associated with grain dust, as occurs during harvesting, milling, and transporting.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is the final common pathway for many different organic dust exposures.¹⁸⁷ The name attached to the individual syndrome typically identifies the associated occupation or substrate. For example, bagassosis is the term associated with sugar cane (bagasse), and farmer’s lung is the term associated with moldy hay, although both conditions are caused by thermophilic Actinomycetes spp. When associated with puffball mushroom spores (Lycoperdon spp), the syndrome is called lycoperdonosis (Chap. 120); when caused by bird droppings, it is called bird fancier’s lung. The implicated allergen is capable of depositing in the pulmonary parenchyma and eliciting a cell-mediated (type IV) immunologic response. Clinical findings include fever, chills, and dyspnea beginning 4 to 8 hours after exposure. The chest radiograph usually is normal, but may reveal diffuse or discrete infiltrates. Progressive disease is associated with a honeycombing pattern on the radiograph and a restrictive lung disease pattern on formal pulmonary function testing. Treatment includes corticosteroids and avoidance of the antigen.

Metal Fume Fever and Polymer Fume Fever

Metal fume fever is a recurrent influenzalike syndrome that develops several hours after exposure to metal oxide fumes generated during welding, galvanizing, or smelting. Although most symptoms of metal fume fever are similar to those expected with irritant gas exposures (dyspnea, cough, chest pain), the presence of fever, typically 100.4°F to 102.2°F (38°C–39°C), distinguishes the syndromes.²⁵ In addition, patients may experience headache, metallic taste, myalgias, and chills. Direct pulmonary toxicity probably does not occur, and patients with metal fume fever generally have normal chest radiographs. Interestingly, acute tolerance develops, so repeat daily exposures produce progressively milder symptoms. However, the tolerance disappears rapidly, and after a short work hiatus such as a weekend, the original intensity resumes, thus accounting for the designation “Monday morning fever.” Many metal oxides are capable of eliciting this syndrome, but it is noted most frequently in patients who have welded galvanized steel, which contains zinc. Metal fume fever also occurs commonly after the high-temperature welding of copper-containing compounds, thus accounting for the historical appellation “brass foundry workers ague.” There is a strong association between welding-related metal fume fever and welding-related respiratory symptoms suggestive of occupational asthma.⁶⁵ Serum and urine metal concentrations typically are not elevated after the acute event, although they may be chronically elevated from daily occupational exposure. The etiology of metal fume fever is debated, but the syndrome has features suggestive of both an immunologic and a toxic etiology.²⁵ Antigen release with immunologic response appears to be responsible for the induction of symptoms. On subsequent exposure, proinflammatory cytokines, such as TNF-α, and various interleukins can be detected in bronchoalveolar lavage fluid.¹⁰⁹ However, because symptoms may occur with the first exposure to fumes, a direct toxic effect on the respiratory mucosa presumably exists.¹²² Exposure to certain metal fumes, such as cadmium oxide or other zinc compounds, may produce direct toxic effects on the pulmonary parenchyma.¹²²

The management of patients with metal fume fever is supportive and includes analgesics and antipyretics. There is no specific antidote, and chelation therapy should not be instituted unless otherwise indicated; patients with ARDS probably have metal toxicity (eg, cadmium pneumonitis). The natural course of metal fume fever involves spontaneous resolution within 48 hours. Persistent symptoms are rare and should prompt investigation for metal toxicity.

A remarkably similar syndrome occurs subsequent to inhaling pyrolysis products of fluorinated polymers (eg, Teflon), which is aptly termed polymer fume fever.¹⁷⁷ Patients develop self-limited viral illness-type symptoms several hours after exposure to the fumes. As with metal fumes, very large exposures to polymer fumes may result in direct pulmonary toxicity. Supportive care is the therapy of choice.

Asthma and Reactive Airways Dysfunction Syndrome

Asthma, or reversible airways disease, is a clinical syndrome that includes intermittent episodes of dyspnea, cough, chest pain or tightness, wheezes on auscultation, and measurable variations in expiratory airflow. Episodes typically are triggered by a xenobiotic or physical stimulus and resolve over several hours with appropriate therapy. The underlying process is immunologic in most cases, with allergen-triggered release of inflammatory mediators causing bronchiolar smooth muscle contraction and subsequent inflammation. Because asthma affects 5% to 10% of the world’s population and the triggers often are nonspecific, it is not surprising that work-aggravated asthma is extremely common. The patients are previously sensitized, and the initial irritant exposure causes bronchospasm or similar symptoms. Thus, work-aggravated asthma is discovered early in the worker’s employment, and a more appropriate workplace or occupation can be pursued.

Occupational asthma, or asthma occasioned by a workplace exposure to a sensitizing xenobiotic, accounts for perhaps 10% to 17% of all newly diagnosed asthma in adults.^115,197 Casual exposure to one of the 250 or more known sensitizers (Table 124–4) is usually associated with a latency period of weeks or months of exposure before symptom onset. After symptoms begin, however, they recur consistently after reexposure to the inciting trigger agent. Occupational asthma with latency may be IgE dependent, in which case it is identical to allergic asthma, or is IgE independent.²⁰³ The IgE-dependent form is most commonly associated with high-molecular-weight compounds (>5000 Da) or with certain haptenic low-molecular-weight agents (eg, acetic anhydride). The low-molecular-weight agents (eg, nickel, isocyanates) more typically cause IgE-independent disease, which manifests as the delayed reaction pattern of cell-mediated, or type IV, hypersensitivity. Because contact with a trigger may be difficult to avoid in either case, reassignment or an outright occupational change may be required. Treatment for exacerbations is comparable to standard asthma therapy and includes bronchodilators and corticosteroids.

Acute exposure to irritant gas may result in the development of a persistent asthmalike syndrome also termed reactive airways dysfunction syndrome (RADS), irritant-induced asthma, or occupational asthma without latency. Virtually every irritative xenobiotic is reported to cause this syndrome, and those not yet described probably are simply unrecognized. Although asthma typically is associated with massive inhalational exposure, as occurred after the World Trade Center collapse,¹⁶ occasional patients are susceptible to low-level exposure.³³ RADS is often compared to occupational asthma because both disorders are chemically induced and most frequently occur after chemical exposure in the workplace.⁴⁹ However, in comparison with those who develop occupational asthma, patients who develop RADS have a lower incidence of atopy and are exposed to agents not typically considered to be immunologically sensitizing.³³ In addition, the airflow improvement with β₂-adrenergic agonist therapy is significantly better in patients with occupational asthma.⁷⁵ Bronchial biopsy performed in patients with RADS generally reveals a chronic inflammatory response.⁷⁵ RADS may have a neurogenic etiology,¹²⁵ as opposed to an immunologic origin as in patients with occupational asthma, which may differentiate these clinically similar diseases on a mechanistic basis. Neurogenic inflammation results from increased vascular permeability, presumably secondary to release of substance P from unmyelinated sensory neurons (C fibers).⁵⁸ Neurogenic inflammation is inhibited by substance P depletors, such as capsaicin, and enhanced by substances that inhibit neutral endopeptidase, the enzyme responsible for degradation of substance P.¹²⁶ The role of corticosteroids is undefined, but animal models suggest an antiinflammatory benefit, and they are widely used.⁵⁵ Recovery may take months, with the delay related to either ongoing low-level exposures to endopeptidase inhibitors or persistent irritation of impaired tissue by environmental irritants such as pollution.

• Although the spectrum of xenobiotics capable of causing pulmonary toxicity is large, the pathologic changes are rather limited.

• Gases that have little or no irritant potential or systemic toxicity cause simple asphyxiation, in which the ambient atmosphere has a diminished oxygen concentration.

• Parenchymal irritation occurs after exposure to acid forming or free radical generating gases and may progress to severe toxicity manifesting as ARDS.

• RADS is described in patients after exposure to virtually all of the irritant gases.

• Treatment of all such exposures centers on symptomatic and supportive care.

References