M: OCCUPATIONAL AND ENVIRONMENTAL TOXINS

CASE STUDY 12

HISTORY AND EPIDEMIOLOGY

Smoke is generated as the result of thermal degradation of a material; it is a complex mixture of heated air containing suspended solid and liquid particles (aerosols), gases, and vapors. Particulates and aerosols typically make these thermal degradation products visible to the naked eye, resulting in the black, acrid substance so often thought of as “smoke”; however, thermal decomposition of common materials also results in the generation of gaseous substances that are invisible to the naked eye. The complex and ever-growing variety of materials used in our environment contributes to the broad spectrum of products present in typical smoke.^32,159 The chemical composition of the parent materials, oxygen availability, and temperature at the time of decomposition all help determine the combustion products found in smoke (Table 120–1).^118,127 As a result of these variabilities, specific thermal degradation products resulting from a fire are difficult to predict; in fact, even the composition of smoke is quite variable within the same fire environment.¹²⁷

Smoke inhalation is a complex medical syndrome involving diverse toxicologic injuries, making care of smoke-injured patients very challenging. These injuries occur both locally within the respiratory tract and systemically. It is, in fact, smoke inhalation—not thermal burns—that is the leading cause of death from fires. Cutaneous burns, however, found concurrently with smoke inhalation complicate airway management and fluid resuscitation and increase the risk of infection. Consequently, burn victims with smoke inhalation injury have higher morbidity and mortality rates than those with burns alone.^47,157,159

Compared with other industrialized countries, the United States has one of the highest rates of fire-related deaths in the world.^159,168 Throughout the United States, a fire department responds to a fire every 23 seconds.⁷¹ In 2015, the National Fire Protection Agency reported 1,345,500 fire incidents in the United States, and approximately 501,500 of these events were structural fires. There were 3,280 fire-related deaths and 15,700 fire-related injuries reported in 2015.⁷¹ On average, a civilian fire death occurs every 160 minutes, and a civilian injury from a structural fire occurs every 34 minutes.⁷¹ Seventy-eight percent of civilian fire deaths occur in home structural fires.⁷¹ An estimated 50% to 80% of fire-related deaths result from smoke inhalation rather than dermal burns or trauma, and deaths related to smoke inhalation occur much more prevalently in an enclosed-space environment.^{23,70,118,180} Studies indicate that from 10% to more than 40% of patients hospitalized in burn units develop complications of concomitant pulmonary injury.^11,50,74,81 The presence of inhalational injury in burn patients correlates with an increased risk of mortality and decreases the total body surface area (TBSA) of a burn that is needed to lead to death, more than doubling the risk of death per TBSA burn in some studies.^11,50,81

Disastrous enclosed-space fires are a frequent reminder of the role of inhalation injury in fire deaths. Before 1942, toxic inhalation was not considered in the etiology of morbidity and mortality of structural fire victims. However, in that year, a fire at the Cocoanut Grove Night Club in Boston resulted in a number of fatalities in which victims had no cutaneous burns. This led to the observation that high concentrations of toxic gases are generated in typical enclosed-space structural fires and may result in significant morbidity and mortality.¹²⁶ From 1955 to 1972, death from smoke inhalation injury increased threefold and was attributed to abundant use of newer synthetic materials for building and furnishings.²³ From 2006 to 2015 in the United States, an average of 24 catastrophic fires occurred per year, claiming an average of 132 lives each year.⁷¹ Despite improved firefighting resources, mass casualties from smoke inhalation continue. On November 24, 2012, a fire swept through the lower floors of a Bangladesh garment factory, killing 112 and trapping many others on the top floors until rescuers arrived. Hundreds of those trapped above the blaze sustained inhalation injuries.⁷ In 2013, 235 people died in a nightclub fire in Brazil when a fire ignited above the concert stage. Smoke inhalation resulted in many of the deaths and forced many others to seek medical treatment.¹³⁹ More recently, on December 3, 2016, 36 people were killed when a fire destroyed an Oakland, California, warehouse that was being used to stage a music event.¹⁴⁷ Interestingly, in 2011, explosions caused an unusually high number of catastrophic fires in the United States, highlighting the complex pathologies of fire victims with the potential for victims to have any combination of inhalation injury, burns, and trauma.⁶

PATHOPHYSIOLOGY

Toxic thermal degradation products are classified into three categories: simple asphyxiants, irritant gases, and chemical asphyxiants (Table 120–2). Simple asphyxiants, such as carbon dioxide, exert their toxicity by displacing oxygen, resulting in an oxygen-deprived environment, thereby decreasing the amount of oxygen available for absorption.⁵⁹ To further complicate this issue, combustion also consumes oxygen, further reducing the available oxygen in the environment.⁵⁹

Irritant gases are chemically reactive compounds that exert a local effect on the respiratory tract, primarily through the production of acids, alkalis, or reactive oxygen species (ROS) (Chap. 121). Irritant gases affect all levels of the airway, and in general, their damage leads to swelling and obstruction of the airway, ultimately impairing oxygenation. For irritant gases, the degree of water solubility is the most important chemical characteristic in determining the timing and anatomic location of respiratory tract injury. Highly water-soluble xenobiotics, such as ammonia and hydrogen chloride, primarily injure the upper airway by rapidly combining with mucosal water, leaving little of the parent compound to travel farther down the airway. These xenobiotics quickly damage mucosal cells, which subsequently release mediators of inflammation or ROS.^{30,96,113,137} This rapid reaction produces early irritation, potentially providing a warning to the victims that the environment is unsafe and prompting escape. After more than a trivial exposure, the intense inflammatory response increases microvascular permeability and allows movement of fluid from the intravascular space into the tissues of the upper airway.¹⁷ This inflammation is potentiated by thermal injury, which, because of the efficient cooling mechanisms of the respiratory tract, primarily occurs in the supraglottic airway. The loosely attached underlying tissue of the supraglottic larynx becomes markedly edematous, causing upper airway obstruction within minutes to hours.⁷⁹ The obstruction often progresses to the point of complete upper airway occlusion.¹⁴⁴ Xenobiotics with low water solubility, such as phosgene and oxides of nitrogen, react with the upper respiratory mucosa more slowly and do not elicit the irritation and aversion stimulus that prompts an escape response. These xenobiotics more typically reach the distal lung parenchyma, where they react slowly to create delayed toxic effects. Xenobiotics with intermediate water solubility, such as chlorine and isocyanates, are more likely to result in damage to both the upper and lower respiratory tracts. In addition to water solubility, other factors, such as concentration of the inhaled xenobiotic, duration of exposure, particle size, respiratory rate, absence of protective reflexes, and preexisting disease, influence the region of respiratory tract injury. For example, as the concentration of a highly water-soluble irritant gas increases, more chemical is presented to the lower airway, possibly leading to damage of the lower respiratory tract. In addition, patients with loss of consciousness increase their exposure secondary to their loss of protective reflexes.^8,68 Damage to the tracheobronchial tree is mediated by many of the same mechanisms as those of the pharynx and hypopharynx: inhaled particulates and toxic gases result in deposition of corrosives and oxidants. Direct thermal injury is less likely to occur as a result of the efficient cooling ability of the upper airways.¹¹³ Direct injury to the tracheobronchial tree and an intense inflammatory response, evoked in part by airway nociceptive sensory neurons, leads to an increase in airway resistance from mucosal edema, bronchoconstriction, and accumulation of intraluminal debris and airway secretions.^{17,83,102,163} Increased tracheobronchial vascular permeability contributes to interstitial edema of the airways and increased airway resistance. Bronchoconstriction and subsequent wheezing are caused by a reflex response to toxic mucosal injury and a response to mediators of inflammation.^68,164 Damaged cells release chemotactic factors that stimulate production of an exudate rich in protein, including fibrin and inflammatory cells.^54,169 This injury ultimately results in sloughing of the mucosa, which combines with inflammatory cells and exudate to create casts in the airways.⁵⁴ Casts can block both the small and large airways, increasing airway resistance and mechanically preventing passage of oxygen to the alveoli.⁴³

Irritant xenobiotics that reach the alveoli injure the lung parenchyma.¹¹⁹ Corrosives, proteolytic enzymes, reactive free radicals, and mediators of inflammation all contribute to acute respiratory distress syndrome (ARDS).^{89,132,164,178} Pathophysiologic changes of ARDS decrease lung compliance and bacterial defenses and lead to ventilation–perfusion mismatch with intrapulmonary shunting, increased extravascular lung water, and microvascular permeability.^{40,164,169,173} Lung compliance is further decreased by atelectasis when xenobiotics inactivate pulmonary surfactant.^119,129 In animal studies, patchy atelectasis rapidly occurs after smoke inhalation.¹¹⁹ In addition, ventilation–perfusion mismatch occurs when pulmonary blood flow is diverted both by hypoxia and vasoactive mediators of inflammation.^98,122 Xenobiotics cause additional injury by impairing clearance by the mucociliary apparatus, altering alveolar macrophage function, and impairing phagocytosis of bacteria, all of which predispose to pulmonary infections and sepsis.^18,55,73,143 The combination of the delayed toxic effects of some inhaled xenobiotics and the slowly developing inflammatory response helps explain the progression of parenchymal injury during the first 24 hours after smoke exposure.

Thermal degradation of organic material produces finely divided carbonaceous particulate matter (soot) suspended in hot gases. These carbonaceous particles adsorb other combustion products from the environment, including metals, aldehydes, organic acids, and other reactive chemicals.^88,137 Soot adheres to the mucosa of the airways, allowing adsorbed irritant xenobiotics to desorb and react with the mucosal surface moisture. The deposition of these particles in the respiratory tract depends on their size, with particles of 1 to 3 µm reaching the alveoli.¹¹¹ Irritant gases can also adsorb on aerosol droplets and alter the site of gas deposition.⁷² This pattern of chemical deposition and desorption from soot or aerosols appears to worsen inhalational injury by enhancing and prolonging exposure to irritants in a fire environment. Accordingly, experimental animals demonstrate markedly decreased lung injury when exposed to toxic gases from smoke that was filtered to remove particulates.⁸⁸

Nitric oxide plays a significant role in the pathogenesis of smoke inhalation–induced lung injury.^51,108,171 Combined smoke inhalation and burn injury results in an upregulation of inducible nitric oxide synthase (iNOS) mRNA synthesis in animal models and subsequently results in increased activity of iNOS.^{51,53,108,152} Increased concentrations of nitric oxide results in myocardial contractile dysfunction with subsequent hypotension.¹⁵² Nitric oxide also increases vascular permeability with resultant edema.¹⁰⁸ One possible mechanism is the formation of the highly reactive peroxynitrite (ONOO^–) radical from the combination of nitric oxide and ROS, which leads to alveolar capillary membrane damage and subsequent ARDS.^51,108 Inhibition of iNOS reduced lung injury in combined smoke inhalation and burn injury in an ovine model.⁵²

Chemical asphyxiants considered are primarily carbon monoxide (CO) and cyanide. These chemical asphyxiants impair extrapulmonary oxygen delivery, or utilization, the route of exposure being commonly smoke inhalation, without much, if any direct pulmonary toxicity, per se. Incomplete combustion of organic materials generates CO, which is considered the most common serious acute hazard to victims of smoke inhalation injury (Chap. 122).^1,166 Carbon monoxide binds heme and prevents oxygen from binding to the heme of the hemoglobin tetramer; it also hinders the release of oxygen from any remaining oxygenated hemes, shifting the oxyhemoglobin dissociation curve to the left. Overall, this process creates a functional anemia. Carbon monoxide also works at the tissue level, binding myoglobin in cardiac and skeletal muscle and cytochrome oxidase in all tissues.^38,80,160 The combination of these features impairs aerobic respiration systemically. It also impairs oxygen utilization by the myocardium, contributing to myocardial dysfunction and potentially hypotension, which further hinders oxygen delivery to tissues. Other mechanisms of toxicity induced by CO include induction of oxidative stress and lipid peroxidation of the central nervous system.¹⁶⁰

Cyanide is produced from combustion of organic nitrogen-containing products that are present in common building materials, such as insulations and laminates.¹²⁷ High concentrations of cyanide are measured in air samples from fires, and elevated blood cyanide concentrations occur in both survivors as well as those who die in enclosed space fires.^59,156 Like CO, cyanide impairs aerobic respiration and has at least an additive, if not synergistic, effect with CO in smoke inhalation toxicity (Chaps. 122 and 123).^110,123,136 Combustion of nitrogen-containing materials also generates oxides of nitrogen, which are irritants and rarely induces the formation of methemoglobin (Chap. 124).

Depending on the fuel, other combustion products are aerosolized and act by local irritation or systemic toxicity. Metal oxides, hydrocarbons, hydrogen fluoride, and hydrogen bromide are formed in some fire environments, contributing to toxicity. In addition, antimony, cadmium, chromium, cobalt, gold, iron, lead, and zinc are often recovered from air samples taken during fires and from soot removed from the surface of the trachea and bronchi of fire victims.^19,45 Fires at industrial sites, clandestine drug laboratories, transportation incidents, and natural disasters, (eg, erupting volcanoes) produce additional unique toxic inhalants.

CLINICAL MANIFESTATIONS

The primary clinical problem in smoke inhalation victims is respiratory compromise; therefore, clinical evaluation should specifically address this issue. Additionally, toxicity from inhaled chemicals, such as CO and cyanide, can lead to cardiovascular dysfunction and hypotension and can directly and indirectly impair mental status. Clinical symptoms suggestive of significant smoke exposure include ocular, mouth, and throat irritation. Cough, chest tightness, and complaints of dyspnea are common.

On examination, soot on the body, face, or airway is suggestive of inhalational injury.^66,68 Burns to the face or singed hairs of the head, face, or nasal passages are associated with an increased risk of inhalational injury but are not present in all patients with significant inhalational injury.^66,68,144 Changes in voice and difficulty managing airway secretions are important signs of progressive airway edema. Visualization of the vocal cords by laryngoscopy is sometimes difficult secondary to soot accumulation, secretions, or edema. Ophthalmic examination should occur in all patients who either complain of ocular symptoms or whose symptoms are unable to be obtained because of unresponsiveness. Thermal and chemical injury results in conjunctival injection, corneal ulcerations and blepharospasm. Rhonchi, crackles, and wheezing on chest auscultation are suggestive of inhalational injury, but these finding are often delayed by 24 to 36 hours and are a poor prognostic indicator if present on initial patient presentation.^66,144 Breath sounds, including wheezing, become virtually inaudible in patients with severe bronchospasm because of gravely diminished air movement.

Tachycardia and tachypnea occur secondary to hypoxemia and systemic xenobiotic toxicity. Hypotension occurs secondary to hypoxemia and systemic toxicity and presents with faint or absent peripheral pulses.¹⁵² Altered mental status, including agitation, confusion, or coma, is most often attributable to hypoxia from either pulmonary compromise or cellular hypoxia, but altered consciousness also results from direct effects of systemic xenobiotics, such as CO, or from concomitant trauma or drug or alcohol intoxication.⁸

DIAGNOSTIC TESTING

Diagnostic studies should focus on assessing for airway and pulmonary injury as well as the ability of the patient to oxygenate and ventilate. An arterial blood gas (ABG) analysis with cooximetry and chest radiography (CXR) should be obtained initially in all patients with smoke inhalation. Health care professionals should obtain a rapid lactate concentration in all seriously ill patients with smoke inhalation to aid in evaluation of possible cyanide toxicity.

An ABG analysis assesses both pulmonary function (gas exchange) and blood pH. The presence of metabolic acidosis is an early clue to tissue hypoxia or cyanide poisoning. Serial measurements of arterial oxygenation and ventilation are helpful in identifying progressive hypoxemia or ventilatory failure. The accuracy of oxygen saturation measurement depends on the method used. Measurement of oxygen saturation by transcutaneous pulse oximetry is unreliable in patients with smoke inhalation because it overestimates oxygen saturation in the presence of carboxyhemoglobin.^9,29,167 Similarly, oxygen saturation calculated from standard ABG analysis is unreliable in the setting of an elevated blood CO concentration. An ABG analysis without cooximetry calculates the saturation of hemoglobin from the PaO₂ and does not account for the dysfunctional carboxyhemoglobin. In the setting of smoke inhalation, oxygen saturation is most accurately determined by cooximetry, which directly measures oxygenated and deoxygenated hemoglobin. Acute respiratory distress syndrome is a common complication of smoke inhalation and is defined as acute onset diffuse alveolar filling with hypoxemia not otherwise explained by congestive heart failure or fluid overload.⁴ Acute respiratory distress syndrome is classified as mild, moderate, or severe based on the degree of impairment as determined by the ratio of partial pressure of dissolved oxygen (PO₂) to ratio (Fraction of inspired oxygen {FiO₂}) (Chap. 28).⁴

Cooximetry measures both carboxyhemoglobin and methemoglobin levels and is recommended in those with significant exposure or signs or symptoms of smoke inhalation.^39,179 When using blood sampling, either arterial or venous samples will accurately measure carboxyhemoglobin levels.⁹⁹ Noninvasive bedside pulse cooximetry is a rapid screening tool for the detection of CO; its use is becoming more prevalent in clinical practice, although device enhancement will be essential (Chap. 28).^146,150 Unfortunately, the carboxyhemoglobin level alone is a poor predictor of the severity of smoke inhalation because a low or nondetectable level does not exclude the possibility of developing inhalation injury.^105,153 Methemoglobin levels are rarely significantly elevated in fire victims. Because methemoglobin can further reduce oxygen-carrying capacity and contribute to morbidity, methemoglobin levels should also be included in the initial laboratory evaluation.^75,149

Currently, blood cyanide analysis is of little clinical utility because results of analysis are not typically available for hours or days, and therapy should never await laboratory confirmation of the presence of cyanide. Accurate measurement depends on acquiring the sample soon after exposure because cyanide is rapidly eliminated from the blood.^12,85 Blood pH and lactate are more useful tools in acutely assessing for cyanide exposure. A blood lactate concentration of 10 mmol/L or greater suggests cyanide poisoning, as defined by a blood cyanide concentration of 40 micromol/L (1 mg/L), and supports the administration of empiric antidotal treatment to critically ill fire-exposed patients.¹²

Chest radiography is recommended early in the assessment of patients with smoke inhalation but is an insensitive indicator of pulmonary injury.^134,173 In one series of patients admitted to the intensive care unit (ICU) with smoke inhalation, no significant differences in the duration of either mechanical ventilation or duration in the ICU stay were observed between those who exhibited abnormal findings on the first CXR examination and those without abnormalities.⁶⁶ The most frequent abnormal findings on initial CXR are diffuse alveolar and interstitial changes, found in up to 34% of patients.⁶⁶ Serial CXR after a baseline study are generally more helpful in detecting evolving pulmonary injury after smoke inhalation (Fig. 120–1).⁶⁸ Subtle findings within 24 hours of exposure include perivascular haziness, peribronchial cuffing, bronchial wall thickening, and subglottic edema.^92,158 Widespread airway disease usually occurs more than 24 hours after inhalation injury and typically suggests ARDS, aspiration, infection, or volume overload.¹⁵⁸

Computed tomography (CT) of the lungs is a more sensitive modality than plain radiography for detecting early pulmonary injury after smoke inhalation.^86,131,141 Computed tomography scanning allows for evaluation of the lung parenchyma and emerging data suggests CT scanning has some value as a “virtual bronchoscopy” for diagnosis and prediction of complications. However, no data are currently available to support improved patient outcomes when using this radiographic modality. Therefore, at this time we recommend against the routine use of CT scanning in patients with smoke inhalation.

In intubated patients, diagnostic fiberoptic bronchoscopy remains the standard in assessing smoke inhalational injury.¹⁵⁴ Bronchoscopy allows for direct visualization of the upper airways, allows for grading of the injury, and helps to determine those at risk for developing inhalational injury.^2,114,154 Bronchoscopy does not visualize the distal airways or lung parenchyma, which helps account for the discrepancies between studies correlating grading of bronchoscopy injury severity and outcome.¹⁵⁴ Early diagnostic bronchoscopy has yet to show an improvement in patient outcome, but because it aids in diagnosis and helps assess the severity of injury, it is reasonable to perform in intubated patients with suspicion of inhalation injury.^2,114,125

MANAGEMENT

From oxygen acquisition to cellular utilization, the final common pathophysiologic effect from smoke injury is hypoxia. Basic critical care strategies that optimize oxygen delivery and utilization are of primary importance in treatment. After the patient is removed from the source of exposure and oxygen is administered, the primary problems that the clinician must treat are the effects of thermal injury and irritant gases on the airway and systemic effects of cellular asphyxiants. High-flow humidified oxygen should accompany initial resuscitation in symptomatic patients. In critically ill patients insert two large-bore intravenous (IV) lines and provide appropriate fluid resuscitation as clinically warranted to optimize perfusion and aid in oxygen delivery. The clinical effects of smoke exposure and their appropriate treatment are described in Fig. 120–2.

Critical airway compromise is often present upon initial hospital presentation or develops in the ensuing hours.^67,144 A major pitfall in the management of smoke inhalation is failing to appreciate the possibility of rapid deterioration. History and physical findings help to determine significant thermal injury or smoke exposure and the potential for clinical deterioration. Early airway intervention is recommended as a seemingly patent airway develops progressive obstruction that can make subsequent intubation difficult or impossible. For signs of current or impending airway compromise, upper airway patency must be rapidly established. When obvious oropharyngeal burns are observed, upper airway injury almost certainly is present. Singed hairs of the head, face, or nasal passages and soot or carbonaceous sputum in the oropharynx or nares signify potential for airway edema.

Direct evaluation of the upper airway, preferably with fiberoptic endoscopy, is essential for assessing patients at high risk for inhalation airway injury.^67,68,79 When evidence of upper airway injury exists, early endotracheal intubation should be performed under controlled circumstances, with preparations for advanced or surgical airway interventions in the event that orotracheal intubation cannot be easily established. Other indications for early intubation include coma, stridor, and full-thickness circumferential neck burns.^10,67,68,144 Edema of injured tissue, including that of the airway, is worsened with substantial fluid resuscitation in burned patients; therefore, we recommend early intubation for patients with any amount of inhalation injury and concomitant dermal burns undergoing fluid resuscitation.^{67,68,117,144}

Even if overt injuries are not visualized, distal injury is often present and underestimated.⁶⁷ Pathophysiologic changes in the lung results in progressive hypoxia over hours to days. Basic treatment of progressive respiratory failure includes continuous positive airway pressure, mechanical ventilation using lung protective strategies, positive end-expiratory pressure (PEEP), and vigorous clearing of pulmonary secretions.¹²⁰ Decreased lung compliance is common secondary to cast formation, tissue damage, and atelectasis.^109,120 Recommendations for limiting barotrauma in mechanically ventilated patients include using a low tidal volume (6–8 mL/kg) and PEEP and allowing permissive hypercapnia as necessary.^97,109,159 The fraction of inspired oxygen should be weaned to below 0.4 as rapidly as tolerated to limit oxygen toxicity.¹⁰⁹ Frequent airway suctioning, chest physiotherapy, and therapeutic bronchoscopy clear inspissated secretions, plugs, and casts.^43,109,116 Because xenobiotics and soot can coat the airway in smoke inhalation victims, early bronchoscopy with bronchoalveolar lavage would intuitively be logical in an attempt to decontaminate the airway, similar to irrigation for dermal exposure. However, because only one study suggests that early and scheduled therapeutic bronchoscopy improves overall morbidity in patients with smoke inhalation, we recommend the use of bronchoscopy and bronchoalveolar lavage for therapeutic purposes on a case-by-case basis as needed for clearing airway obstruction.³⁴

High-frequency percussive ventilation (HFPV), a method of ventilation that combines a high-frequency low tidal volume with pressure control ventilation, has been studied as an alternative to conventional forms of ventilation in patients with inhalational injury. Studies suggest that HFPV improves lung function by aiding the clearance of intraluminal airway debris and recruiting alveoli.¹⁴⁸ Several studies have investigated the use of HFPV in ventilated patients with inhalational injury. Limited evidence suggests that HFPV decreases peak pulmonary pressures, limits barotrauma, decreases the incidence of pneumonia, and improves the mortality rate in patients with smoke inhalation injury.^{37,42,62,109,140} Therefore, HFPV is reasonable to use in patients in whom conventional low tidal volume lung protective strategies fail to provide adequate oxygenation. The role of extracorporeal membrane oxygenation (ECMO) in victims of smoke inhalation is unclear. Although multiple case reports document its use in patients with inhalational injury, there is limited evidence and no high-quality studies to support its use in smoke inhalation injury.^5,128 However, as expertise in the use of ECMO has greatly progressed in recent years, it seems reasonable to use this modality as a rescue therapy in patients failing more conventional ventilation strategies.

Inhaled β₂-adrenergic agonists are the first-line therapy for acute reversible bronchoconstriction resulting from asthma or chronic obstructive pulmonary disease and are recommended to improve oxygenation and ventilation in victims of smoke inhalation. Pathophysiologic changes induced by irritant gases in smoke are similar to those found in asthma, suggesting that β₂-adrenergic agonists would also improve airflow obstruction in smoke inhalation.^84,104 β₂-Adrenergic agonists also possess antiinflammatory properties, partially through interaction with β-adrenergic receptors on immune cells.^103,172 β₂-Adrenergic agonists also enhance resolution of alveolar edema by modulating the flow of sodium and potassium across cell membranes.^103,172 Limited data in an ovine model suggest that nebulized albuterol improves pulmonary function after smoke inhalation and burn injury.¹³⁰ Nebulized epinephrine improved oxygenation and decreased pulmonary vascular permeability in animal models but differs from albuterol in that it provides both α- and β-adrenergic agonist activity.^90,100 Although human data on the efficacy of β₂-adrenergic agonists in smoke inhalation injury are lacking, their role is well established in conditions with reversible bronchoconstriction, animal studies lend support for their use, and the potential benefits greatly outweigh the risks.^130,172 Accordingly, we recommend the use of nebulized albuterol in victims of smoke inhalation injury with evidence of bronchospasm.

Corticosteroids have been used for smoke inhalation in an attempt to limit inflammation and improve outcome. One argument for their use is for the treatment of lung injury induced by oxides of nitrogen. Pulmonary sequelae, including bronchiolitis obliterans, are known to occur after significant exposure to oxides of nitrogen, which are sometimes a prominent component of smoke.^77,93 The mixed xenobiotic exposure from smoke inhalation appears to further complicate the outcome. One early rat study showed a trend toward reduced mortality rates in animals given supraphysiologic doses (25–100 mg/kg) of methylprednisolone; however, other tested corticosteroids (hydrocortisone, dexamethasone, cortisone) failed to demonstrate similar improvement. Consequently, this study failed to effectively prove that corticosteroids reduce mortality rates after rat exposure to smoke.⁴⁹ Human studies have also failed to show an improvement in clinical outcome and trend toward worsening outcome.^{35,94,121,145} Thus, we do not recommend the routine use of corticosteroids for treatment of patients with smoke inhalation.

A significant amount of pulmonary injury after smoke inhalation is attributable to free radical damage. Smoke inhalation decreases systemic concentrations of the antioxidant vitamin E in sheep models, and treatment with nebulized vitamin E (α- and γ-tocopherol) attenuates smoke inhalation induced pulmonary injury in animal models.^{64,112,165,176} Similarly, both nebulized heparin and N-acetylcysteine (NAC) are used by some centers to limit pulmonary damage.¹⁰⁶ Heparin is a glycosaminoglycan with anticoagulant and antiinflammatory properties occasionally used both topically and intravenously in burn treatment. In an ovine model of combined cutaneous burn and smoke inhalation, nebulized heparin combined with recombinant human antithrombin reduced airway obstruction and improved gas exchange.⁵⁴ The mechanism is likely attributable to decreased airway inflammation and decreased fibrin deposition and, consequently, decreased cast formation in the airway.⁵⁴ Although literature regarding the use of inhaled anticoagulants show variable results, a systematic review of both animal and human clinical data found an association between inhaled anticoagulants and improved mortality from smoke inhalation-associated ARDS.^{48,76,106,107} The five human studies included were retrospective analyses of smoke-injured patients treated with nebulized heparin and NAC.¹⁰⁷ At the doses used (typically either 5,000 U or 10,000 U of heparin nebulized every 4 hours), patients did not experience changes in systemic coagulation parameters. However, an additional recent retrospective study demonstrated no difference in mortality or length of ICU stay among patients treated with heparin and NAC and a no treatment control group. In this study, the treatment group had a higher rate of pneumonia compared to the control group.⁸² Further data are needed to provide evidence regarding inhalational treatment with heparin, NAC, or both. Although human data are currently limited, with only animal studies and human retrospective data available, it would be reasonable to use nebulize heparin and NAC for the treatment of intubated patients with bronchoscopy confirmed smoke inhalation and associated ARDS.¹⁰⁷ Care should be taken to monitor for pneumonia, which, in one study, had a higher incidence in treated patients.

The initial treatment strategy for patients with CO poisoning should focus on optimizing oxygen delivery to the tissues. Oxygen can be administered by a high-flow tight-fitting mask, endotracheal tube, or hyperbaric oxygen therapy (HBO). Oxygen shortens the half-life of carboxyhemoglobin, the rate of which inversely correlates with the PO₂ of the patient.^135,170 Hyperbaric oxygen can achieve very high arterial oxygen concentrations, enhancing oxygen delivery to tissues and accelerating elimination of CO from blood and tissues.^69,135 Hyperbaric oxygen therapy is recommended as a modality for treatment in certain situations involving CO exposure; however, smoke inhalation injury is much more complex than poisoning solely with CO, such as that caused by a furnace leak.⁶⁵ In victims of smoke inhalation, other clinical requirements, such as maintaining a secure airway and the need for additional resuscitative measures to treat ARDS, cardiovascular instability, and metabolic derangements go beyond providing supplemental oxygen to treat CO poisoning. Optimal timing of HBO administration is often during the same period when intensive resuscitative efforts and focused ventilator management are required and could limit attention to these important therapies. Irritant-induced bronchospasm along with exudates and airway casts increase the risk of air trapping, potentially leading to HBO-induced barotrauma.^31,115 In addition, it is known that pulmonary toxicity results from elevated partial pressures of oxygen.¹⁵¹ Very little information is available to predict the effect of hyperoxygenation on pulmonary toxicity after smoke inhalation.^161,175 The decision to treat a smoke inhalation patient with HBO should take into account risks and other clinical requirements when determining the appropriate therapy because the therapeutic priority is meticulous supportive care and high-flow oxygen therapy. A judicious approach to the treatment of CO poisoning in smoke inhalation is administering 100% oxygen by a tightly fitting mask (or an endotracheal tube if intubated) as long as clinically appropriate (Chap. 122 and Antidotes in Depth: A40).^28,174

Cyanide is a common product of combustion, with toxic concentrations often measured in fire victims. Because rapid determination of blood cyanide concentrations is not readily available in the prehospital setting or in the emergency department, surrogate markers must be used to help establish the diagnosis. Cyanide poisoning should be suspected in patients involved in enclosed-space fires with evidence of smoke inhalation, particularly in the presence of altered mental status, hemodynamic instability or metabolic acidosis with an elevated lactate concentration.^56,142 Serum lactate concentrations correlate closely with blood cyanide concentrations. In a study of smoke inhalation victims, a blood lactate concentrations of 10 mmol/L was reported to be a sensitive indicator of cyanide toxicity as defined by a blood cyanide concentration above 40 micromol/L (1 mg/L).¹² However, in this study, 26% of fatalities occurred in patients with a blood cyanide concentration less than 40 micromol/L (1 mg/L), possibly because of the compounding effects of cyanide and other toxic products of combustion such as CO. Carboxyhemoglobin levels of more than 10% also correlated with elevated cyanide concentrations.¹² Studies also indicate that smoke inhalation victims with cardiac arrest, those who must be rescued from the environment, and those with soot on the face, oral cavity, neck or carbonaceous sputum are more likely to have elevated blood cyanide concentrations.^12,58 For patients with suspected cyanide poisoning, specific treatment of cyanide toxicity should be implemented while other life support measures are instituted. Systematic reviews of various cyanide antidotes conclude that it is possible to survive even cardiorespiratory arrest caused by cyanide poisoning if the patient is provided optimal supportive care and an appropriate antidote.¹²⁴

Cyanide antidotes function as an adjunct to basic critical care strategies that optimize oxygen delivery and utilization. The components of the classic cyanide antidote kit, amyl nitrite and sodium nitrite, hinder this strategy and therefore should not be routinely used in victims of smoke inhalation. Amyl nitrite and sodium nitrite produce methemoglobinemia, (Chap. 124 and Antidotes in Depth: A43). Unfortunately, methemoglobin is a dysfunctional type of hemoglobin that poorly utilizes oxygen, impairing delivery to the tissues.⁴⁴ Impairing oxygen-carrying capacity and oxygen delivery to tissues with nitrite-induced methemoglobinemia is a valid concern in the presence of tissue hypoxia from carboxyhemoglobinemia, lung injury, or other factors. Furthermore, rapid infusion of sodium nitrite causes hypotension secondary to vasodilation.⁶¹

Hydroxocobalamin is a vitamin B₁₂ (cyanocobalamin) precursor that works by chelating cyanide from the cytochrome system and acting as a nitric oxide scavenger. It comes as a red crystalline powder that must be reconstituted and then administered intravenously over 15 minutes.¹⁶² Animal studies focus on poisoning by cyanide salts over cyanide poisoning from smoke inhalation but demonstrate improvement in blood pressure parameters when hydroxocobalamin was compared with the combination of sodium thiosulfate and sodium nitrite, and improved mortality compared with either placebo or sodium thiosulfate alone.^14,15,20 There are no human studies providing head-to-head data on cyanide antidotes in smoke inhalation. Human studies are limited to retrospective or prospective case series that are poorly controlled. Authors of these articles typically report improved survival and few adverse events, but use either historic controls or typically lethal blood concentrations of cyanide as comparison groups, limiting the strength of the evidence.^21,22,57 Side effects of hydroxocobalamin administration include red or pink discoloration of the skin, red discoloration of the urine, and alteration in some laboratory parameters, including carboxyhemoglobin concentrations.^33,91 In addition, certain hemodialysis machines can be adversely affected by red discoloration or the plasma leading to a blood leak error warning.¹⁵⁵ Although the evidence for the use of hydroxocobalamin for patients with cyanide poisoning from smoke inhalation is limited, this antidote appears to be superior to sodium thiosulfate or supportive care alone.^14,15 Because nitrites have a more detrimental side effect profile and are likely detrimental to patients with concomitant CO poisoning, hydroxocobalamin is recommended as first-line therapy when cyanide poisoning is suspected in victims of smoke inhalation.

In the prehospital setting or if unable to obtain a rapid lactate concentration, for patients involved in an enclosed-space fire with signs of inhalation injury and the presence or altered mental status or hemodynamic instability (systolic blood pressure of 90 mm Hg or less), it is reasonable to administer hydroxocobalamin. If a rapid lactate concentration is available, hydroxocobalamin is recommended for to such patients with a lactate concentration greater than or equal to 10 mmol/L. Few data are available to guide clinicians for patients who have evidence of smoke inhalation and the lactate concentration is elevated but less than 10 mmol/L. For patients with an elevated lactate concentration less than 10 mmol/L with altered mental status or hemodynamic instability, it is reasonable to administer hydroxocobalamin. For patients who are hemodynamically stable and without significantly altered mental status and who have an elevated lactate less than 10 mmol/L, it is reasonable to monitor these patients closely while performing resuscitation and considering other causes of the elevated lactate concentration.^3,57,63,101 The initial dose of hydroxocobalamin is 70 mg/kg(5 g in an adult) intravenously, with the option of subsequent dosing of 70 mg/kg (5 g in an adult) intravenously for signs of continued cyanide toxicity or if in cardiac arrest (Chap. 123 and Antidotes in Depth: A41 and A42). ⁷⁸ It is reasonable to use sodium thiosulfate as adjunctive therapy, but it should not be given concomitantly through the same IV line.¹³⁸

Victims of fires have respiratory compromise and other pathology not directly related to smoke inhalation, such as trauma or other underlying medical problems. Trauma from falls or explosions must be suspected and treatment started simultaneously with treatment of burns and inhalation injury. Comatose patients should be evaluated for other causes of their status and should receive naloxone, thiamine, and hypertonic dextrose as indicated. Inhaled xenobiotics, such as CO directly, cause altered mental status, but drug and ethanol intoxication also contribute significantly to fire fatalities and injuries. Blood ethanol concentrations in fire victims correlate with elevated levels of CO and concentrations of cyanide, suggesting that intoxication impairs escape and prolongs toxic smoke exposure.^8,19,118 Intracranial pathology should be considered and noncontrast head CT scans obtained as clinically indicated.

Xenobiotics often injure the skin or mucous membranes in addition to the respiratory mucosa.⁴¹ The duration of contact of a xenobiotic with tissue is an important factor in determining the extent of chemical injury to the skin and eyes. Rapid removal of soot from the skin or eyes helps to prevent continued injury. The eyes should be evaluated for corneal burns caused by thermal or irritant chemical injury. Patients with signs of ophthalmic irritation should have their eyes irrigated, and dermal decontamination performed as necessary to prevent burns from toxin-laden soot adherent to the skin (Special Considerations: SC2).

SUMMARY

• Smoke inhalation contributes significantly to the morbidity and mortality of fire victims.

• Smoke inhalation is a complex syndrome involving diverse toxicologic injuries. A spectrum of damage occurs, ranging from rapid upper airway occlusion to delayed ARDS.

• The end result of respiratory tract toxicity is tissue hypoxia.

• Goals of treatment should focus on maximizing oxygen delivery while avoiding unnecessary therapies that may hinder oxygenation.

• Early airway management should be implemented for patients with airway compromise. High-flow oxygen will help reverse tissue hypoxia, and fluid resuscitation should be instituted to improve cardiovascular status if indicated.

• Definitive antidotes and procedures for cyanide and carbon monoxide are available in select cases and should be used when appropriate to help stabilize the patient.

REFERENCES

CASE STUDY 13

INTRODUCTION

The respiratory system is responsible for gas exchange, elimination of certain xenobiotics, insensible water loss, temperature regulation, and minor metabolic processes. The principal function of the respiratory system is gas exchange, which occurs in the more 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 be exposed to 11,500 L of air. There are a number of protective mechanisms within the respiratory system to prevent exposure to xenobiotics, but these mechanisms can be overwhelmed. The principles of respiratory system function are covered extensively in Chap. 28.

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 act at unique points in this distribution pathway to limit or impair tissue oxygenation. For example, whereas opioids and neuromuscular blockers induce hypoventilation, carbon monoxide and methemoglobin inducers prevent loading and unloading of oxygen onto and off 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 results in tissue hypoxia.

HISTORY AND EPIDEMIOLOGY

Unlike most xenobiotic exposures, simple asphyxiant and pulmonary irritant poisonings frequently occur on a mass scale due to the magnitude of these exposures. For example, the large-scale emission of carbon dioxide (CO₂) from Lake Nyos, a carbonated volcanic crater lake in Cameroon, West Africa, resulted in nearly 2,000 human deaths and many more livestock deaths (Chap. 2).⁸In 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.¹²⁸ Exposure to compressed liquefied gases, which expand several hundredfold on depressurization or warming, accounts for a substantial number of workplace injuries.¹¹⁴

Irritant gases similarly 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. 126). Atmospheric sulfur dioxide and oxides of nitrogen are the primary components of photochemical smog. During the London Fog incident in 1952, 4,000 deaths occurred, primarily from respiratory causes.¹⁰² Similar smog incidents continue to occur around the globe. Relatedly, the diverse irritants found in fire smoke are a major cause of death after smoke inhalation.¹¹³

Unexpected release of other irritant inhalants leads to large-scale poisoning. In 1984, an inadvertent release of methyl isocyanate (MIC) in Bhopal, India, resulted in immediate and persistent respiratory symptoms in approximately 200,000 local inhabitants, with approximately 2,500 deaths.⁸²

Isolated exposures to individuals occur as well, often in workplaces, and more frequently in contained spaces (eg, indoors). Simple asphyxiation as a painless and relatively undetectable method for committing suicide and, paradoxically, for euphoric and erotic experiences, are found in books, on the Internet, and in the medical literature.^39,45,108

SIMPLE ASPHYXIANTS

Simple asphyxiants work primarily by displacing oxygen from ambient air, unlike chemical asphyxiants, which cause cellular hypoxia and are discussed in Chaps. 122 to 124. 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% (nitrogen 78%), 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 is insufficient to allow adequate oxygen saturation in certain individuals, and supplemental oxygen becomes necessary. As barometric pressure decreases, exposure to simple asphyxiant gases further reduces the oxygen partial pressure to life-threatening levels. Conversely, underwater divers reduce their FiO₂ to below 21% by adding an inert gas, such as helium, to their breathing mixture to avoid oxygen toxicity, yet they maintain adequate oxygenation. This occurs because the elevated barometric pressure increases the partial pressure of oxygen to normal amounts despite the addition of an asphyxiant. 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 large volumes of 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 121–1). 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 occur.²⁸ Postmortem findings are generally minimal, hampering the cause of death determination without historical evidence or advanced laboratory testing.

Exposure to simple asphyxiants does not impair CO₂ exchange, 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.⁷⁵ In these circumstances, victims frequently succumb to hypoxemia without ever developing the expected warning symptoms. In the case of CO₂ inhalation, hypercapnia occurs very rapidly, which itself produces 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 often the inert gas used by divers to replace nitrogen to prevent nitrogen narcosis at depth (see Nitrogen). Even using gas mixtures of 50% helium, divers have 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 of the inhaled air, 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.⁵⁴ This displaces oxygen from the environment and causes asphyxia. Helium is also used in lung imaging studies and pulmonary function testing. Similarly, the low viscosity of helium 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 results in either asphyxiation or freezing injuries, or both.⁵⁴ 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.⁵⁴ 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 effects because the FiO₂, and thus their oxygen content, essentially is normal. Methane, also known as “natural gas” and “swamp gas,” is present in high ambient concentrations in bogs of decaying organic matter. In addition, compressed natural gas is used as an alternative automotive fuel and poses an asphyxiation hazard if leaked internally. 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 or oxygen deficiency. 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. 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 uncommonly causes respiratory symptoms and pulmonary dysfunction.⁶² However, methane itself is not 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 the explanation for these symptoms (see Oxides of Nitrogen).

Ethane (C₂H₆) is an odorless 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. 81).¹¹⁰

Fire-eater’s lung (FEL) is a unique form of hydrocarbon pneumonitis caused by aspiration of flammable petrochemical products. Fire-eater’s lung occurs after inhalational exposure to the chemicals used to “breathe fire” or “eat fire” during performances. The hydrocarbons are typically low viscosity and disperse throughout bronchioles fairly easily leading to severe lipoid pneumonitis and pneumonia in addition to a systemic inflammatory response. Pulmonary infiltrates occur in as many as 83% of patients studied.³⁷

Carbon Dioxide

Although not a simple asphyxiant gas by definition because it produces physiologic effects, CO₂ closely resembles simple asphyxiants from a toxicologic viewpoint. It is used in laboratories as a painless form of animal euthanasia and as a means of large-scale euthanasia of diseased livestock.⁹⁴ Carbon dioxide gas has many practical industrial uses, such as production of carbonation in soft drinks. Because it is nonflammable, CO₂ is used as a shielding gas during welding and in commercial fire suppression systems because it safely displace oxygen from the local environment.⁴⁴ Dry ice, the frozen form of CO₂, is extremely cold (–141.3°F {–78.5°C}) and undergoes conversion from solid to gas without liquefaction, a process known as sublimation. Poisoning occurs when dry ice is allowed to sublimate in a closed space,¹⁹ such as the cabin of a car or in a cold storage room at 39.2°F (4°C).^32,44 Furthermore, inadvertent connection of respirable gas hoses to CO₂ and other nonrespirable sources is reported in both industrial and medical settings,^63,115 with resultant worker and patient fatalities. This occurrence is uncommon because of mandated 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.⁷⁵ For this reason, exogenous CO₂, 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 CO₂ occurs, which further stimulates respiration thereby further increasing the uptake of ambient CO₂.²⁷ Accordingly, closed anesthesia systems use scrubbers containing sodium hydroxide (NaOH) to chemically eliminate exhaled CO₂. 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 CO₂, develops hypercapnia, and typically presents with gradual somnolence. This is linked to respiratory failure, as in the case of emphysema or opioid poisoning, or at times is iatrogenic, occurring during permissive hypercapnia.²⁷ Even in experimental models in which a normal FiO₂ is maintained, massive CO₂ inhalation produces CNS and respiratory system manifestations within seconds.^53,61 This occurs because CO₂ is not solely a simple asphyxiant but also possesses protean physiological effects.

Nitrogen Gas

Although nitrogen, like CO₂, produces clinical effects independently of hypoxemia, most poisonings are characterized by the manifestations of a simple asphyxiant. 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 occurs after rapid evaporation of the supercooled liquid.^66,67

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^55,80 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.⁸³ More severely poisoned patients manifest the spectrum of depressed mental status.⁷⁰ Systemic absorption is not rapid, however, and prolonged, high-concentration 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 is sometimes called rapture of the deep (l’ivresse des grandes profondeurs) and causes many deaths in the subaquatic environment. The underlying mechanism of nitrogen narcosis is unknown, but the simple structure and relatively high lipophilicity of nitrogen suggest a mechanism similar to that of the anesthetic gases.¹¹² 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 liquid nitrogen is extremely cold and ingestion of liquid nitrogen similarly produces a freezing injury of the gastrointestinal (GI) tract.¹³⁰

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. 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. Hyperbaric oxygen therapy offers no benefit.

PULMONARY IRRITANTS

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 121–2).

Pathophysiology

In the lung, irritant chemicals damage both the more prevalent type I pneumocytes and the surfactant-producing type II pneumocytes. 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.⁷⁹ 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 results in rapid cytoskeletal shortening, creating spaces between endothelial cells and allowing fluid movement into the alveolar spaces.¹¹⁹ Other gases, such as oxygen and ozone, induce pulmonary damage primarily through free radical-mediated oxidative stress on the cellular membranes.¹³ 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 chemical weapon, 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.^88,99 Phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes and other cytokines such as TNF-α.⁹⁹ Leukotrienes are important chemotactic factors for neutrophils, which accumulate, liberate oxidants, and produce ARDS. Experimentally, ARDS is prevented in rabbits by tomelukast, a leukotriene receptor antagonist, and by methylprednisolone, which blocks leukotriene synthesis, both of which are beneficial postexposure.⁵¹ 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 rates in mice when administered shortly after phosgene exposure.¹⁰⁰ 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.¹⁰¹ However, nebulized NAC has not proven successful in the majority of published case material despite some success in basic science research and is not recommended at this time.⁴⁶ Intravenous (IV) administration of NAC to patients with mild to moderate ARDS, none of whom had irritant-induced pulmonary damage, improved systemic oxygenation and reduced their need for ventilatory support.¹¹⁶ However, progression to respiratory failure was not altered. There are no human studies evaluating exposure to chemical irritants and the management of ARDS in patients after a chemical irritant exposure is extrapolated from the ARDS literature. Advanced interventions for reducing the morbidity and mortality associated with non–toxin-induced ARDS such as lung protective strategies, high-frequency ventilation, and prone positioning, widely used in patients with trauma- or sepsis-induced ARDS, have not undergone evaluation in patient with toxin-induced ARDS.¹⁷ Given the pathophysiological and clinical similarities¹⁰⁷ and despite the lack of evidence, it seems reasonable to apply these strategies to patients with inhalational injuries.

Free radicals are highly reactive molecular derivatives, typically from oxygen or nitrogen that 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. 10). Products of lipid peroxidation and cellular damage initiate neutrophilic influx, presumably in an immunologic response to 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.¹³⁶ 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 1 hour after smoke inhalation, a form of oxidant lung injury, did not improve lung edema or pulmonary gas exchange.⁷⁷

Clinical Manifestations

Regardless of the mechanism by which the mucosa is damaged, the clinical presentations of patients exposed to irritant gases are similar.¹⁰⁷ 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 present with nasal or oropharyngeal pain in addition to drooling, mucosal edema, cough, or stridor. Conjunctival irritation or chemosis, as well as skin irritation, are often noted because concomitant ocular and cutaneous exposure to the gases usually is unavoidable. Gases that are less rapidly irritating do not typically provide an adequate signal of their presence and therefore do 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 are subsequently 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 generally agree with the clinical data.¹⁵ However, exceptions to this relationship of a gas and its predicted toxicity are common. For example, in situations in which escape from ongoing exposure is prevented, patients develop lower respiratory tract injury after prolonged exposure to acutely irritating gases. Alternatively, rapid onset of upper respiratory irritation occurs in patients after exposure to concentrated gases that are generally associated with delayed signs and symptoms. Exposure to exceedingly high concentrations of any irritant gas produces hypoxemia analogous to that resulting from exposure to a simple asphyxiant.

The most characteristic and serious clinical manifestation of irritant gas exposure is ARDS.⁹⁶ Acute respiratory distress syndrome 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.¹²² Acute respiratory distress syndrome is a nonspecific syndrome resulting from diverse physiologic insults such as sepsis or trauma. Patients with ARDS 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.⁴ The definition created three mutually exclusive strata of ARDS based on the degree of hypoxemia (Table 121–3). Some essential changes of the new definition include acute was defined as 1 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 radiographic criteria were 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 cleanser. The odor and irritancy are characteristic and serve as an effective warning signals of 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 develop tracheobronchial or pulmonary inflammation. Experimental inhalation of nebulized high-dose ammonia causes ARDS within 2 minutes of exposure.⁵⁸ 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.¹⁶ Chronic inhalation of low concentrations of NH₃ or repetitive exposure to high concentrations of ammonia causes pulmonary fibrosis.¹²

Chloramines

This series of chlorinated nitrogenous compounds (Fig. 121–1) 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 cleansing powers.⁸¹ Interestingly, the addition of bleach to septic systems results in liberation of the chloramines after the reaction of bleach with urinary nitrogenous compounds.⁸¹ 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 often do not prompt immediate escape, resulting in prolonged or recurrent exposure with pulmonary and ocular symptoms predominating.²⁰ Exposure to trichloramine occurs at indoor swimming pools and is responsible for inducing permeability changes in the pulmonary epithelium, the consequences of which are not yet understood.²⁵

Hydrogen chloride (HCl)

The largest and most important use of HCl gas is in the production of hydrochloric acid. Dissolution of HCl gas in lung water after inhalation similarly produces hydrochloric acid.⁹² Pyrolysis of polyvinyl chloride (PVC), a plastic commonly used in pipe fabrication, generates HCl and is an occupational hazard for firefighters.¹¹³ By adsorbing to respirable carbonaceous particles generated in the fire, HCl is deposited in the alveoli and produces pulmonary toxicity.

Hydrogen fluoride (HF)

Hydrogen fluoride and its aqueous form, hydrofluoric acid, are used in the gasoline, glassware, building renovation, and semiconductor industries. Gaseous HF is also liberated, paradoxically by extreme heat, during the release of hydrofluorocarbons from fire suppression systems.¹³⁵ 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 result in irritant symptoms,^41,132 and large exposures cause bronchial and pulmonary parenchymal destruction.¹³² Inhalation results in ARDS, but death usually is related to systemic fluoride poisoning independent of the route of exposure caused by hypocalcemia and hyperkalemia (Chap. 104).^30,135

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 is also generated by the inadvertent mixing of certain 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.⁹⁵ In addition to the effect of acid generation upon dissolution, sulfur dioxide causes oxidative damage to the lungs.¹⁰⁴ Large acute exposure to either xenobiotic produces the expected acute irritant response of both the upper and lower respiratory tracts,²¹ and pulmonary dysfunction (see Asthma and Reactive Airways Dysfunction Syndrome) in some persists for several years.¹⁰⁴

Intermediate Water-Soluble Xenobiotics

Chlorine (Cl₂)

Chlorine gas is a valuable oxidizer with various industrial uses, and occupational exposure is common. Chlorine gas was used as a chemical weapon by both the French and the Germans in World War I (Chap. 126). 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. 121–2).⁸⁵ 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, results in the release of chlorine gas. As such, inappropriate mixing of cleaning products is the cause of most nonoccupational exposures.⁸⁵ Rarely, patients intentionally generate chlorine gas in this manner for purportedly “pleasurable” purposes.⁹³ Chlorine gas is generated when aging swimming pool chlorination tablets, such as calcium hypochlorite [Ca(OCl)₂] or trichloro-s-triazinetrione (TST), decompose¹³⁴ or are inadvertently introduced to a swimming pool while swimmers are present.^6,126 Inadvertent mixture of Ca(OCl)₂ and TST results in excessive chlorine gas generation, which is also explosive. Acute chlorine toxicity occurs when there is a failure of the system of compressed chlorine gas which is used for direct chlorination of public swimming pools⁶ or for drinking water systems. Occasional mass poisoning has occurred during scientific, industrial, or transportation incidents.⁵⁶

The odor threshold for chlorine is low, but distinguishing toxic from permissible air concentrations is difficult until toxicity manifests. The intermediate solubility characteristics of chlorine result in only mild initial symptoms after moderate exposure and allow 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 or recurrent and patients with exposure to moderate concentrations often manifest increased bronchial responsiveness^1,42 (see Reactive Airways Dysfunction Syndrome).

Hydrogen sulfide (H₂S)

Hydrogen sulfide exposures occur most frequently in the waste management, petroleum, and natural gas industries,³⁸ although poisoning occurs in asphalt, synthetic rubber, and nylon industry workers as well. Hydrogen sulfide exposure also rarely occurs in hospital workers using acid cleaners to unclog drains clogged with plaster of Paris sludge. The generation of H₂S by mixing household chemicals in a closed automobile, a trend referred to as “detergent suicide,” produces a potential threat to the responders.² Hydrogen sulfide 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 cyanide¹²⁷ (Chap. 123).

Hydrogen sulfide 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,¹ 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.¹¹⁸ The rapidity of death in patients exposed to high H₂S concentrations makes it difficult to conclude whether simple asphyxiation or cytochrome oxidase inhibition is causal in most cases. Neither the postmortem H₂S nor thiosulfate concentrations are reliable for determining cause of death.⁷

Phosgene (carbonyl chloride {COCl₂})

During World War I, phosgene was an important chemical weapon that produced countless deaths (Chap. 126).³⁶ 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.

Exposure to phosgene initially produces limited manifestations, but results in acute mucosal irritation after intense exposure. In fact, the pleasant odor of fresh hay, rather than prompting escape, disturbingly promotes prolonged breathing of the toxic gas. The most consequential clinical effect related to phosgene exposure is delayed ARDS.¹⁰ The accumulation of a significant alveolar burden of phosgene due to the lack of a noxious warning property of the gas, explains why the clinical effects generally are severe. Because the onset is typically delayed up to 24 hours, prolonged observation of patients thought to be phosgene-poisoned is warranted. The mechanism of phosgene toxicity occurs by the dissolution of the gas into the fluid of the epithelial lining with resultant liberation of hydrochloric acid and reactive oxygen species (ROS).¹⁰

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 irritants and oxidants is difficult but is therapeutically relevant.

Oxygen (O₂)

Oxygen toxicity is uncommon in the workplace but, ironically, is common in hospitalized patients. Although prolonged, high concentration exposures to O₂ produce CNS and retinal toxicity, pulmonary damage is more common.¹¹¹ Several clinical studies indicate that humans can tolerate 100% O₂ at sea level for up to 48 hours without significant acute pulmonary damage.^18,29 Under hyperbaric conditions (2.0 atmospheres absolute), such as during compressed-air diving or while inside a pressurized hyperbaric chamber, oxygen toxicity develops within 3 to 6 hours.²³ Acute respiratory distress syndrome occurs in approximately 5% of patients administered hyperbaric oxygen for therapeutic purposes.¹¹¹ Delayed pulmonary fibrosis, presumably from healing of subclinical injury, develops in patients breathing lower concentrations of O₂ at sea level for shorter periods.

Although it appears paradoxical that O₂, an essential molecule, is 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. This same potent oxidizing activity allows O₂ to remove electrons from other compounds generating the reactive oxygen intermediate.⁹⁷

Generation of ROS, including superoxide (O₂^–.), hydroxyl radical (OH·), hydrogen peroxide (HOOH), singlet oxygen (O·), and nitric oxide (NO), produces cellular necrosis, increases pulmonary capillary permeability, and induces apoptosis.⁹⁷ Nitric oxide, produced by inducible NO synthase (iNOS) in the setting of oxidative stress, is directly cytotoxic or it can combine with superoxide anions to form the more reactive oxidant peroxynitrite (ONOO^–).⁵⁷ Experimental prevention of these effects by administration of either parenteral NAC,¹²⁹ a chemical antioxidant, or superoxide dismutase, an enzymatic antioxidant,⁶⁸ suggests that the mechanism of toxicity relates to the oxidant, or electrophilic, effects of these ROS (Chap. 10). 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. The potential role of liquid ventilation of the lung with perfluorocarbons to prevent or treat pulmonary oxygen toxicity remains under investigation but not highly promising.⁴⁰

Oxides of nitrogen (NO_x)

Oxides of nitrogen are a series of variably oxidized nitrogenous compounds. The most important substances included in this series are the stable free radicals nitrogen dioxide (NO₂) and NO, as well as nitrogen tetroxide (dinitrogen tetroxide {N₂O₄}), nitrogen trioxide (N₂O₃), and nitrous oxide (N₂O). The oxides of nitrogen are of limited concern in industrial operations, although they are generated during welding and brazing.²⁴ Nitrogen oxide, 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.⁴⁸ Nitrogen oxide toxicity also occurs when propane-driven ice-cleaning machines are used in indoor ice skating rinks with poor ventilation, thereby allowing accumulation of the generated NO_2,⁷² or after exposure to high NO₂ concentrations in closed space fires, such as in submarines.⁷⁸ Nitrogen oxide 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.³¹ In the absence of ventilation, high concentrations of NO₂ accumulate in the silo such that an individual entering the silo is rapidly asphyxiated from the depletion of oxygen.⁴⁹ Additionally, substantial quantities of NO₂ remaining after incomplete ventilation are associated with delayed-onset pulmonary toxicity characteristic of silo filler’s disease. Chronic indoor exposure to NO₂, generated during cooking or outdoor exposure to photochemical smog, of which the oxides of nitrogen are a component, predisposes individuals to the development or exacerbation of chronic lung diseases.⁶²

The various oxides of nitrogen 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.⁹⁰ 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.⁵² Antioxidants afford significant protection to environmental oxidant exposure including NO₂, indicating an important role of free radicals in the toxicology of these xenobiotics.⁶⁹

Nitric oxide, an endogenous compound important as a neurotransmitter and vasorelaxant, is used clinically exogenously for inhalational therapy to treat pulmonary hypertension and ARDS.⁴³ 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, although its use in premature infants with respiratory distress syndrome is well accepted.⁴³ Nitric oxide is less soluble in the fluid lining the epithelial surfaces than are the other oxides of nitrogen and produces irritant effects after large exposures.¹²⁴ 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^–. This radical selectively interacts with tyrosine to produce nitrotyrosine, which subsequently serves as a marker for oxidant damage. Nitric oxide is absorbed from the lung and is rapidly bound by hemoglobin to form nitrosylhemoglobin, and methemoglobin may also be produced.

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 is at times above regulatory limit, although a specific relationship with the development of clinical effects in airline crew members is elusive.¹³³ Ozone is an important component of photochemical smog and, as such, contributes to chronic lung disease. 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 oxidizers 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.¹³ Ozonation and free radical damage to the lipid component of the membrane initiate an inflammatory cascade. Reactive nitrogen species are also implicated because NO synthase knockout mice are relatively protected from ozone-induced inflammation and tissue injury.³⁴ Increased permeability of the pulmonary epithelium results in alveolar filling from the transudation of proteins and fluids characteristic of ARDS.

Miscellaneous Pulmonary Irritants

Methylisocyanate

Methylisocyanate (MIC) (Fig. 121–3) 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.⁸² Methylisocyanate is a significantly more potent respiratory irritant than the other regularly used isocyanate derivatives such as TDI.

Riot control agents: capsaicin, chlorobenzylidene malononitrile, and chloroacetophenone

Historically, riot control agents (Fig. 126–5), commonly called Mace, consisted primarily of chloroacetophenone (CN) or chlorobenzylidene malononitrile (CS).⁹ 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.⁹ 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 are described (see Asthma and Reactive Airways Dysfunction Syndrome). Closed-space or close-range exposure, as well as physical exertion during exposure, is associated with significant ocular toxicity, dermal burns, laryngospasm, ARDS, or death.¹²⁰ 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 pneumonitis and death.

Capsaicin interacts with the vanilloid receptor-1 (VR1), which was recently renamed the transient receptor potential vanilloid-1 (TRPV1).¹¹⁷ 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).

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 (Chap. 100).⁵⁹ Cadmium oxide (CdO) is generated during the burning of cadmium metal in an oxygen-containing environment, as occurs during smelting or welding (Chap. 88). The refining of nickel using carbon monoxide (Mond process) produces nickel carbonyl [Ni(CO)₄], a volatile pulmonary oxidant (Chap. 96).¹⁰³ Inhalation of volatilized elemental mercury occurs during the vacuuming of mercury spills or home extracting of precious metals (Chap. 95).⁸⁷ Although at high concentrations many of these metal exposures produce warning symptoms, severe toxicity may occur even in the absence of warning symptoms. The mechanism of toxicity typically relates to overwhelming oxidant stress with a pronounced inflammatory response as measured by serum cytokine (eg, TNF-α) concentrations, consistent with the role of metals in redox reactions (Chap. 10). 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.³ 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 it is reasonable to administer corticosteroids.⁶⁰ Chelation therapy has no documented benefit for treatment of patients with ARDS but is indicated based on conventional indications.

MANAGEMENT

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 new treatment modalities are available,¹⁷ supportive care remains a cornerstone of therapy. Supplemental oxygen, bronchodilators, and airway suctioning should be used for standard indications. Nitrovasodilators and diuretics have no role in the management of patients with ARDS, although light sedation is recommended as an anxiolytic.¹⁰⁵ Corticosteroid therapy, designed to reduce the inflammatory host defense response, frequently improves surrogate markers of pulmonary damage,¹²² such as oxygenation status, but generally offers little outcome enhancement in patients with ARDS.⁹¹ Clinical data on the efficacy of corticosteroids used in human beings exposed to pulmonary irritants are limited and inconclusive.²⁶ Importantly, most studies of ARDS involve predominantly septic or traumatized patients, with few patients having 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.²² Most available research evaluates parenterally administered corticosteroids, although animal models demonstrate a beneficial effect of nebulized beclomethasone or budesonide after acute chlorine poisoning.^26,50,131 Nebulized budesonide compared to IV betamethasone had similar effects.²⁶ However, a human pretreatment model of inhaled budesonide fails to document a substantive alteration of the effects of ozone inhalation.⁸⁶ 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, with additional study, they are thought by some to be beneficial. Overall, there is little reason to suspect any specific benefit of corticosteroids in most poisoned patients. However, because many studies demonstrate little identifiable risk and some potential benefit, corticosteroid use is reasonable whether inhaled or intravenous, and based largely on institutional practices for the management of patients with ARDS.

The clinical similarities among patients with irritant gas exposure and other etiologies of ARDS suggest that similar management principles are reasonable to apply. 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. Prone positioning during ventilation; PEEP; early neuromuscular blockade; and low-volume, low-pressure, lung protective strategies are successful in enhancing the oxygenation of patients with ARDS of various causes but are not necessarily successful in improving outcome.¹⁷ Lower tidal volume mechanical ventilation using 6 mL/kg and plateau pressures of 30 cm H₂O attenuated the inflammatory response and resulted in a lower mortality rate and less need for mechanical ventilation than traditional volume ventilation with 12 mL/kg.⁸⁴ It is reasonable to reduce the inspired concentration of oxygen to below 50% as rapidly as possible because patients poisoned by irritant gases have enhanced susceptibility to oxygen toxicity as a result of depletion of endogenous antioxidant barriers.¹⁰⁹

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 because of concern of an exothermic reaction in the process of neutralization, 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 is beneficial in patients poisoned by acid-forming irritant gases.¹²³ The vast majority of these cases involve chlorine gas exposure, and most patients received other symptomatic therapies as well.^5,74 Although there appears to be no specific benefit for patients exposed to chloramine, nebulized bicarbonate therapy appears to be safe and is reasonable to administer. 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 1 second (FEV₁) at 120 and 240 minutes in the group that received nebulized sodium bicarbonate.⁵ The sodium bicarbonate solution should be used in a sufficiently dilute form 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 ∼2% solution for nebulization).

Whether nebulized sodium bicarbonate therapy alters the natural course of irritant-induced pulmonary damage remains uncertain. The fact that many irritant gases produce concomitant oxidant injury suggests otherwise. 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, we recommend against their use at this time (Antidotes in Depth: A5).

Antioxidants

Antioxidants include reducing agents such as ascorbic acid,³⁵ N-acetylcysteine, free radical scavengers such as vitamin E, and enzymes such as superoxide dismutase. Studies in humans identify both increased⁹⁸ and decreased¹¹ 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 in humans. The rapid onset of the self-perpetuating destructive effects initiated by redox reactions hinders the success of 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 and not yet ready to be recommended.

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, is suggested to limit systemic fluoride absorption, and is reasonable to administer. By binding fluoride ion locally, nebulized calcium prevents fluoride-induced cellular and systemic toxicity. Systemic calcium salts should be administered as needed to correct hypocalcemia (Chap. 104 and Antidotes in Depth: A32).

Current therapy for inhalation of capsaicin or of any tear gas, is primarily supportive. Extracorporeal membrane oxygenation was used in children to maintain oxygenation in the presence of severe pulmonary toxicity resulting from capsaicin exposure. There are no antidotes currently available.

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. Patients with nonchemically induced ARDS have exfoliated tissue, and presumably persistent xenobiotic, effectively lavaged from the bronchopulmonary tree with this method. Perfluorocarbons improve oxygenation and have an antiinflammatory effect, as demonstrated by reduced oxidant lung injury after liquid ventilation in animals. Although perfluorocarbons have interesting potential to be a highly useful therapy in the future, the limited availability, high cost, and lack of demonstrated efficacy of this therapy make it reasonable only if readily available.^40,64

OTHER INHALED PULMONARY XENOBIOTICS

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 and subacute syndromes are discussed here.

Inorganic Dust Exposure

Silicosis, which is pulmonary diseases associated with inhalation of crystalline silica (SiO₂), or quartz, is representative of a range of lung diseases associated with inorganic silica dust inhalation.^71,89 The aftermath of the World Trade Center attack and building collapse resulted in substantial acute silica exposure to residents and rescuers. Exposure-related effects include several acute and delayed-onset pulmonary consequences, such as cough, asthma, chronic obstructive pulmonary disease, and sarcoidlike lung changes.^73,89 More typically, silica exposure 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 silica dust exposure produces acute silicosis in a few weeks and even death within 2 years. The mechanism of toxicity relates to the relentless inflammatory response generated by the pulmonary macrophages.⁶⁵ 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 was curtailed over the past two decades because of cases of severe pulmonary injury. Much of the toxicity of talc is related to free silica or asbestos contamination. Improvement after acute massive exposure is sometimes 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 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 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.¹²⁵ 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; 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 is typically normal but also reveals 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. It is reasonable to administer corticosteroids and recommended to avoid 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.⁴⁷ 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. In addition, patients experience headache, a metallic taste, myalgias, and chills. Direct pulmonary toxicity 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 weld 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.³³ Serum and urine metal concentrations typically are not elevated after the acute event, although they are also found to be chronically elevated following 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.⁴⁷ 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 are detected in bronchoalveolar lavage fluid. ⁷⁰ However, because symptoms often 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, produce direct toxic effects on the pulmonary parenchyma.

The management of patients with metal fume fever is supportive and includes analgesics and antipyretics. There is no specific antidote, and chelation therapy we recommend against unless otherwise indicated. For example, patients with ARDS after metal fume inhalation most likely 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.⁴⁷ Patients develop self-limited influenzalike symptoms several hours after exposure to the fumes. As with metal fumes, very large exposures to polymer fumes 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 up to 25% of all newly diagnosed asthma in adults.¹²¹ Casual exposure to one of the 250 or more known sensitizers (Table 121–4) is usually associated with a latency period of weeks or months of exposure before symptom onset.⁷⁶ After symptoms begin, however, they recur consistently after reexposure to the inciting trigger agent. Occupational asthma with latency is either IgE dependent, in which case it is identical to allergic asthma, or IgE independent.¹²¹ The IgE-dependent form is most commonly associated with high-molecular-weight compounds (>5,000 Da) or with certain haptenic low-molecular-weight agents (eg, acetic anhydride). The low-molecular-weight compounds (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 is difficult to avoid in either case, reassignment or an outright occupational change is occasionally required. Treatment for exacerbations is comparable to standard asthma therapy and should include bronchodilators and corticosteroids as appropriate.

Acute exposure to irritant gas results 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 likely unrecognized. Although asthma typically is associated with massive inhalational exposure, as occurred with irritant dust exposure after the World Trade Center collapse,⁷³ occasional patients are susceptible to low-level exposure. Reactive airways dysfunction syndrome is often compared to occupational asthma because both disorders are chemically induced and most frequently occur after chemical exposure in the workplace. 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.¹⁰⁶ In addition, the airflow improvement with β₂-adrenergic agonist therapy is significantly better in patients with occupational asthma. Bronchial biopsy performed in patients with RADS generally reveals a chronic inflammatory response.¹⁴ Reactive airways dysfunction syndrome also has a neurogenic etiology, as opposed to an immunologic origin as in patients with occupational asthma, which differentiates 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). The role of corticosteroids is undefined, but animal models suggest an antiinflammatory benefit, and they are recommended as for any other patient with acute bronchospasm. Recovery often takes 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.

SUMMARY

• 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, a situation in which the ambient atmosphere has a diminished oxygen concentration.

• Parenchymal irritation occurs after exposure to acid-forming or free radical–generating gases and severe toxicity manifesting such as ARDS occur.

  Reactive airways dysfunction syndrome and occupational asthma are clinically similar diseases that are described in patients after inhalational exposure. Whereas asthma is typically immunologic in origin, RADS is irritant in origin.

• Treatment of all such exposures centers on symptomatic and supportive care, which includes both interventional and pharmacologic interventions. There is little support for corticosteroids, but if used for a short course of therapy, there is limited risk of harm.

REFERENCES

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

Carbon monoxide (CO) is formed during the incomplete combustion of virtually any carbon-containing compound. Because it is an odorless, colorless, and tasteless gas, it is remarkably difficult to detect in the environment even when present at high ambient concentrations and is a leading cause of poisoning morbidity and mortality in the United States. Based on US national death certificate data, there were 439 annual deaths from unintentional non-fire exposure to CO from 1999 to 2004.²⁷ The groups with the highest risk were male gender and elderly age, possibly because of occupational exposure and inability to discern CO symptoms, respectively. The CO-related mortality rate has remained essentially unchanged over the years despite increased CO detector use.^22,26,28 More than half of these cases (64%) occurred in homes with faulty furnaces, usually in the fall or winter months. Many clusters were associated with power failures during catastrophic weather, such as ice storms, blizzards, and hurricanes.^24,25 Analysis of the Centers for Disease Control and Prevention wide-ranging online data for epidemiologic research (WONDER) database showed total non–fire-related CO poisoning deaths decreased from 1,967 in 1999 to 1,319 in 2014.⁸⁸ Of these non–fire-related deaths, unintentional cases continue at a rate of approximately 450 annually from 1999 to 2015.^29,187

Just as important as mortality rates are the greater number of survivors from CO poisoning. Despite increased awareness for CO poisoning, there were still an average of 20,636 nonfatal, unintentional, non–fire-related CO exposures treated annually in the United States.²⁸ More than 40% of cases occurred in the winter, with almost 75% occurring in residences. However, exclusion of intentional and fire-related cases severely underestimates the extent of the problem. Based on firsthand hospital data, a minimum of 50,000 patients with CO poisoning present to US emergency departments (EDs) each year, up to half resulting in hospitalization.^96,111 More recent data using probable and suspected cases suggest that there were more than 230,000 ED visits in 2007 alone that were unintentional and related to non-fire CO poisoning.¹¹²

The bigger problem with CO poisoning is the associated morbidity that survivors risk even after acute treatment. The most serious complication is persistent or delayed neurologic sequelae (DNS) or delayed neurocognitive sequelae, which occurs in up to 50% of patients with symptomatic acute poisonings.^81,174,226 At 1 year after exposure, of the 1,643 patients not treated with HBO 42% had cognitive sequellae at 6 weeks, 30% at 6 months and 18% at 12 months. Of the 75 treated with HBO 24% had cognitive sequellae at 6 weeks, 17% at 6 months and 14% at 12 months.²²⁸ There is still no highly reliable method of predicting who will have a poor outcome, requiring the threshold for HBO therapy for CO poisoning and follow-up be particularly low.

Potential sources of CO abound in our society, often resulting in unintentional poisoning²⁸ (Table 122–1). Although CO is found naturally in the body as a byproduct of hemoglobin degradation by heme oxygenase found in the liver and spleen,⁴⁷ it is readily available for inhalation from the incomplete combustion of virtually any carbonaceous fuel. Alternatively, absorption (dermal, ingestion, or inhalation) of methylene chloride results in CO toxicity after hepatic metabolism (Chap. 105).¹⁵⁶ Despite catalytic converters and other emission controls, more than 50% of unintentional CO deaths are still caused by motor vehicle exhaust.^45,151 The introduction of catalytic converters with emissions controls is associated with a decrease in suicide attempts and deaths using automobile exhaust.⁹¹ Occupants of motor vehicles are not the only victims of exhaust gases; CO poisoning is also reported in occupants of the beds of pickup trucks and on boats.^22,95,130 Workers are at risk from use of propane-powered equipment indoors such as ice skating rink resurfacers^21,52 and forklifts.^66,104 For optimal performance, propane-powered forklifts are typically adjusted to produce less than 10,000 ppm of CO in exhaust but in fact average more than 30,000 ppm, which could lead to unsafe concentrations in an enclosed warehouse within 1 hour.⁶⁷

In the past 10 years, nonvehicular sources of CO have increasingly accounted for the majority of unintentional poisonings.¹⁵¹ More than one-third of the deaths from unintentional CO poisoning occur in winter months (December, January, and February) in the US.²⁹ Predominantly, these involve the burning of charcoal, wood, or natural gas for heating and cooking.⁹² Furnaces that burn natural gas (methane or propane) for heating are often implicated, especially when the flue is blocked.^100,101 Gas kitchen stoves are also an important source of CO in indigent populations with marginal heating systems.¹⁰¹ In fact, the use of gas stoves for supplemental heat is predictive of CO poisoning in patients who present to the ED with headache and dizziness.¹⁰⁰

Absence of fuel-burning devices is not necessarily protective for CO poisoning. In multifamily homes, CO can diffuse through drywall, which is actually quite porous.⁸⁹ During ice storms, blizzards, hurricanes, and other natural disasters with power loss, the indoor use of gasoline-powered generators^115,218 and charcoal-burning grills, the latter particularly in immigrant populations, leads to epidemic CO poisoning outbreaks.^23,25,234

Fires are another important source of CO exposure, contributing substantially to the approximate 5,613 smoke inhalation deaths each year.⁴⁵ Carbon monoxide is considered to be the most common hazard to smoke inhalation victims.^72,186 These cases are further compounded by the high incidence of hydrogen cyanide poisoning (Chap. 123).⁸⁴

TOXICOKINETICS

Carbon monoxide is readily absorbed after inhalation. The Coburn-Forster-Kane (CFK) model allows approximate prediction of carboxyhemoglobin (COHb) levels based on exposure history.^46,48 A simplification of the model allows for estimation of the equilibrium based on the ambient concentration of CO in ppm: COHb (%) = 100/{1 + (643/ppm CO)}.²¹⁴ This assumes that the individual weighs 70 kg and is not anemic. With exponential uptake, it takes more than 4 hours for equilibrium to be attained. Therefore, within minutes of high CO exposures, the arterial COHb level actually overshoots predicted estimates before equilibration.^9,15 Endogenous production of CO is not factored in because its contribution to COHb is only 2%.

After its absorption, CO is carried in the blood, primarily bound to hemoglobin. The Haldane ratio states that hemoglobin has approximately a 200 to 250 times greater affinity for CO than for oxygen. Therefore, CO is primarily confined to the blood compartment, but eventually up to 15% of total CO body content is taken up by tissue, primarily bound to myoglobin.⁴⁶ Therefore, the dissolved CO concentration in the plasma better reflects the ultimate potential for poisoning because it is available for diffusion into all tissue compartments, including the muscle and brain.¹³⁵

Elimination of CO, like absorption, from the blood is modeled mathematically using the CFK model. The equation predicts a half-life of 252 minutes. In actual volunteer studies, means of 249 and 320 minutes breathing room air are reported.¹⁷¹ With 100% oxygen, these half-lives can be reduced significantly to means ranging 47 to 80 minutes in studies of volunteers who attain COHb levels of 10% to 12%.^171,195 Patients poisoned with CO showed actual mean half-lives ranging from 74 to 131 minutes when treated with 100% oxygen.^226,227

Methylene chloride, a paint stripper, is another source of CO. It is readily absorbed through the skin or by ingestion or inhalation and is metabolized in the liver to CO.¹⁹¹ Carboxyhyemoglobin levels peak 8 hours or later and range from 10% to 50%.^134,177 Because of ongoing production of CO, the apparent COHb half-life is prolonged to 13 hours in these patients.¹⁷⁶ Carboxyhyemoglobin levels after methylene chloride exposure are proportional to the concentration and duration of exposure.¹⁷⁶

PATHOPHYSIOLOGY

The most obvious deleterious effect of CO is binding to hemoglobin, rendering it incapable of delivering oxygen to the cells. Therefore, despite adequate partial pressures of oxygen in blood (PO₂), there is decreased arterial oxygen content. Further insult occurs because CO causes a leftward shift of the oxyhemoglobin dissociation curve, thus decreasing the offloading of oxygen from hemoglobin to tissue (Fig. 28–2).¹⁸⁰ This results in part from a decrease in erythrocyte 2,3-bisphosphoglycerate (2,3-BPG) concentration. The net effect of all these processes is the decreased ability of oxygen to be delivered to tissue.

Carbon monoxide toxicity cannot be attributed solely to COHb-mediated hypoxia. Neither clinical effects nor the phenomena of delayed neurologic deficits is completely predicted by the extent of binding between hemoglobin and CO.^90,209 Furthermore, such a model fails to explain why even minimal levels of COHb (4%–5%) occasionally result in cognitive impairment. An early study showed that dogs breathing 13% CO died within 1 hour and had COHb levels of 54% to 90%. However, exchange transfusion of this same blood into healthy dogs to reach similar COHb levels caused no untoward effects.⁷³ Hemorrhaging the dogs to comparable degrees of anemia also produced no adverse effects. The appropriate conclusion was that inherent to CO toxicity is its delivery to target organs such as the brain and heart and that although COHb is easily measured, it rarely has a significant contribution to clinical toxicity. For CO to reach tissue, it has to be dissolved in the plasma rather than bound to hemoglobin.^79,80

Carbon monoxide interferes with cellular respiration by binding to mitochondrial cytochrome oxidase. Initial studies show that this binding is especially exaggerated under conditions of hypoxia and hypotension. In vitro rat models demonstrate that this oxidative stress causes mitochondrial damage with protein oxidation and lipid peroxidation, particularly in the hippocampus and corpus striatum.¹⁹⁶ In vivo models reveal that CO poisoning causes cell loss in the frontal cortex, which is associated with decrements in learning and memory.¹⁷² Although no comparable brain studies exist in humans, the peripheral lymphocytes and monocytes of CO-poisoned patients show cytochrome oxidase inhibition accompanied by increased lipid peroxidation.^71,146 In a small clinical series of CO-poisoned patients, normalization of this cytochrome activity lagged behind and seemed to agree better with symptom severity than COHb levels.¹⁴⁷

Inactivation of cytochrome oxidase is only an initial part of the cascade of inflammatory events that results in ischemic reperfusion injury to the brain after CO poisoning (Fig. A40–1). During recovery from the initial poisoning, white blood cells are attracted to and adhere to the damaged brain microvasculature.^201-203 This attraction is partly attributable to endothelial changes from initial cytochrome oxidase dysfunction, mediated primarily through the free radical nitric oxide (NO).^201,207 Carbon monoxide displaces NO from platelets that in turn form peroxynitrites, which are even stronger inactivators of cytochrome oxidase.²⁰⁷ Multiple animal studies demonstrate that NO is ultimately responsible for much of the endothelial damage from CO and that NO synthase inhibitors can prevent toxicity.^205,207 The NO formation promotes platelet–neutrophil aggregates that in turn lead to neutrophil adhesion to the brain microvasculature.²⁰² Myelin peroxidase activation in the area further promotes neutrophil adhesion with degranulation and release of proteases that convert xanthine dehydrogenase to xanthine oxidase, an enzyme that promotes formation of oxygen free radicals.²⁰⁰ Also, mouse studies suggest that circulating microparticles play a proinflammatory role in activation of neutrophils.²³⁷ The end result of this process is delayed lipid peroxidation of the neurons, and the extent of destruction correlates with decrements in learning in rodents.²⁰⁰ Rats depleted of xanthine oxidase through a tungsten modified diet show no changes in myelin basic protein and cognitive function after CO poisoning.⁹⁸

Simultaneously, with all this perivascular oxidative stress in the brain, there is activation of excitatory amino acids, which ultimately is responsible for the subsequent neuronal cell loss.²⁰⁷ In fact, in rat brains, glutamate concentrations increase after CO poisoning. Glutamate is an excitatory amino acid that binds at N-methyl-D-aspartate (NMDA) receptors and causes intracellular calcium release, resulting in delayed neuronal cell death (Chap. 13). Blockade of NMDA receptors prevents the neuronal death and learning deficits that accompany serious CO poisoning in mice.¹¹³ Increases in the glutamate concentrations in rat brain in the first hour after severe CO poisoning are followed by a later increase in hydroxyl radicals.¹⁷² Ultimately, at 1 to 3 weeks, the animals show histologic evidence of both neuronal necrosis and apoptosis in the frontal cortex, globus pallidus, and cerebellum that are accompanied by deficits in learning and memory.

Carbon monoxide neuronal cell death is partly attributable to apoptosis. In bovine pulmonary artery cells, CO exposure is accompanied by activation of caspase-1, a protease implicated in delayed cell death.²⁰⁶ Confirmatory evidence was provided in the same study because both caspase-1 and NO synthase inhibitors blocked apoptosis. The end result of all these cellular processes is brain injury, particularly in the basal ganglia and hippocampus.²²¹ In some studies, this is accompanied by learning impairment.²⁰² Thus, animal models correlate well with what ultimately occurs in victims of serious CO poisoning, namely, persistent or delayed deficits in learning and memory associated with structural changes in the brain.

Myoglobin, another heme protein, binds CO with an affinity about 60 times greater than it binds oxygen.⁴⁹ About 10% to 15% of the total body store of CO is extravascular, primarily binding to myoglobin.^15,46 A dog model demonstrates that this binding is enhanced under hypoxic conditions.⁴⁹ This binding partially explains the myocardial impairment that occurs in both animal studies and low concentration exposures in patients with ischemic heart disease. The combination of COHb formation, which decreases oxygen-carrying capacity, and reduced myoglobin in the heart, which decreases oxygen extraction, contributes to the preterminal dysrhythmias that occurs in poisoned animals.

Several studies suggest that CO effects on the cardiovascular system are necessary for ischemic reperfusion injury of the brain. Hypotension is an essential component and results from a combination of myocardial depression and vasodilation. Carbon monoxide, perhaps because of its similarity to NO, activates guanylate cyclase, which in turn relaxes vascular smooth muscle. Also, CO further displaces NO from platelets, resulting in additional vasodilation.²⁰⁵ These factors contribute to the hypotension that occurs in animal experiments with exposure to high concentrations of CO.⁷³ Such an episode of hypotension leads to syncope, portending a worse clinical outcome.⁴⁰ In rhesus monkeys, cerebral white matter lesions correlate better with decreases in blood pressure than with COHb level.⁷⁸ Lipid peroxidation of the brain in rats develops 1 hour after a CO exposure that has produced syncope and hypotension.¹⁹⁹ This delay is comparable to the time that is necessary to produce mitochondrial destruction from oxidative stress in rats exposed to CO. In a feline model, central nervous system (CNS) damage from CO is reproduced only when hypoxia is accompanied by an interval of ischemia, confirming the ischemia reperfusion model.¹⁵⁹

Endogenous CO behaves like NO, binding to guanylate cyclase and thereby increasing cyclic guanosine monophosphate (cGMP) concentrations.¹¹⁴ Although low endogenous concentrations are physiologic, excessive concentrations of CO from exogenous sources are problematic because CO persists much longer than NO. Carbon monoxide appears to be a neuronal messenger by virtue of the fact that as a gas, it can diffuse and signal adjacent cells.¹⁴¹

CLINICAL MANIFESTATIONS

Acute Exposure

The earliest symptoms associated with CO poisoning are often nonspecific and readily confused with other illnesses, typically a viral syndrome²²³ (Table 122–2). The initial symptom reported by volunteers within 4 hours of exposure to 200 ppm CO (producing COHb levels of 15%–20%) is headache; shorter exposures at 500 ppm also produce nausea.¹⁹² The incidence of CO poisoning in symptomatic patients presenting to EDs in the winter with an influenzalike illness ranges from 3% to 24% in some series.^61,101 The typical presenting complaints include headache, dizziness, and nausea, and the most frequent exposures occur during the winter, explaining why influenza is the most common misdiagnosis.⁶¹ The most common symptom, headache, is usually described as dull, frontal, and continuous. Carbon monoxide poisoning is also frequently misdiagnosed as food poisoning, gastroenteritis, and even colic in infants. Similar to adults, children tend to develop nonspecific symptoms, complicating diagnosis.

Continued exposure to CO leads to symptoms attributable to oxygen deficiency in the heart. Low-concentration exposures, leading to COHb levels of 2% to 4%, in volunteers with stable angina result in decreased exercise tolerance as well as signs and symptoms of myocardial ischemia.² At higher levels (COHb of 6%), there is a greater frequency of premature ventricular contractions during exercise. Myocardial infarction and dysrhythmias are described in victims of CO poisoning, and acute mortality from CO is usually a result of ventricular dysrhythmias.^2,3 Prolonged exposure to CO or high COHb levels are associated with temporary myocardial stunning, manifested as global hypokinesia or Takotsubo cardiomyopathy lasting usually less than 24.^116,118 In some cases stunning, with decreased left ventricular ejection fraction, can last several days and is associated with increased concentrations of β-type natriuretic peptide, lactate, and troponin.¹³² Troponin elevations often occur even in the absence of any coronary artery disease or even electrocardiographic (ECG) or echocardiographic changes.^31,55

These patients have an increased propensity for cardiac mortality, with almost one-third dying within 8 years after serious CO poisoning.¹⁰² A nationwide population based cohort study in Taiwan found an increased incidence of dysrhythmias, mostly paroxysmal tachycardia and ventricular fibrillation, in decade after CO poisoning of 8,381 subjects.¹³¹ Although serious CO exposures are associated with increased long-term mortality beyond 90 days, there was no association with increased cardiac death.⁸⁷

The CNS is the organ system that is most sensitive to CO poisoning. Acutely, otherwise healthy patients may manifest headache, dizziness, and ataxia at COHb levels as low as 15% to 20%, with higher levels or longer exposures causing syncope, seizures, or coma.²²³ Focal neurologic findings suggest a cerebrovascular accident. Some cases have diffuse frontal slow-wave activity on electroencephalogram. Within 1 day of exposures that result in coma, many patients show decreased density in the central white matter and globus pallidus on computed tomography (CT) (Fig. 122–1) or magnetic resonance imaging (MRI).¹³⁷ Autopsies show involvement of other areas, including the cerebral cortex, hippocampus, cerebellum, and substantia nigra.¹²⁹

Metabolic changes reflect the toxic effects of CO better than any particular COHb level. Patients with mild CO poisoning develop respiratory alkalosis in an attempt to compensate for the reduction in oxygen-carrying capacity and delivery. More substantial exposures result in metabolic acidosis with lactate production that accompanies tissue hypoxia.¹⁸⁹ Even in the absence of hypotension, lactate was an independent predictor of worse mental status and inpatient complications.^30,60,150 The importance of metabolic acidosis was highlighted in a retrospective series of 48 CO-poisoned patients, in whom hydrogen ion concentration was a better predictor of poor recovery during initial hospitalization than was COHb level.²¹⁶

Although the brain and heart are the most sensitive, other organs also manifest the effects of CO poisoning. One-fifth to one-third of patients with severe CO poisoning, particularly those requiring endotracheal intubation, develop pulmonary edema.⁸² This is caused by cardiac depression directly from CO or ARDS from associated smoke inhalation.^118,186 This does not appear to be a direct effect of CO on lung tissue because sheep with prolonged exposure to CO, resulting in COHb levels greater than 50%, showed no anatomic or physiologic changes in lung function.¹⁸⁵ Although myonecrosis and even compartment syndromes occur, patients rarely develop acute kidney injury (AKI). Retinal hemorrhages occur with exposures longer than 12 hours.¹²⁰ Cherry-red skin coloration occurs only after excessive exposure (2%–3% of cases referred to one hyperbaric center) and represents a combination of CO-induced vasodilation, concomitant tissue ischemia, and failure to extract oxygen from arterial blood.¹⁷⁸ Another classic but uncommon phenomenon is the development of cutaneous bullae after severe exposures. These bullae are thought to be caused by a combination of pressure necrosis and possibly direct CO effects in the epidermis.

NEUROCOGNITIVE SEQUELAE

The persistent or delayed effects of CO poisoning are varied and include dementia, amnestic syndromes, psychosis, parkinsonism, paralysis, chorea, cortical blindness, apraxia and agnosia, peripheral neuropathy, and incontinence.^133,233 If not diagnosed at initial poisoning, neurologic deterioration is delayed and preceded by a lucid period of 2 to 40 days after the initial poisoning.⁴⁰ In patients admitted to an intensive care unit (ICU) for severe CO poisoning and treated with 100% oxygen, 14% of survivors had permanent neurologic impairment.¹²³ In a Korean series of 2,360 CO-poisoned patients, 3% continued to show memory failure or parkinsonian features 1 year after exposure.⁴⁰ Another series of 63 seriously poisoned patients showed memory impairment in 43% and deterioration of personality in 33% at 3-year follow-up.¹⁸⁹ Children also develop behavioral and educational difficulties after severe poisoning.¹²⁸ However, patients older than 30 years of age are more susceptible to the development of delayed sequelae.^41,228 Most cases of delayed neurocognitive sequelae are associated with loss of consciousness (LOC) in the acute phase of toxicity.⁵¹

Neurocognitive sequelae probably involve lesions of the cerebral white matter.⁷⁵ Weeks after exposure, autopsies show necrosis of the white matter, globus pallidus, cerebellum, and hippocampus. Magnetic resonance imaging studies confirm the damage to the white matter and hippocampus.^70,137,223 Animal studies show that having a markedly elevated COHb level alone cannot cause similar white matter lesions but that there must also be an episode of hypotension.^78,159 The fact that the areas permanently damaged in serious CO poisoning cases are the areas with the poorest vascular supply in the brain is consistent with these findings.

CHRONIC EXPOSURE

Often, patients complain of persistent headaches and cognitive problems after long-term exposure to low concentrations of CO. Unfortunately, to date, there have been no controlled studies demonstrating that in the absence of a severe acute poisoning episode, this type of exposure results in any long-term sequelae. Warehouse workers who are chronically exposed to CO from propane combustion have intermittent problems with headache, nausea, and lightheadedness.⁶⁶ Fortunately, unless the individual had an episode of severe poisoning with acute deterioration, most workers achieve resolution of their symptoms.⁶⁷ One series of patients with chronic CO poisoning demonstrates a high incidence of headache and memory complaints in addition to motor slowing and memory problems on neuropsychologic testing.¹⁵³ Although many of the objective deficits improved with elimination of the exposure and HBO treatment, many continued to have posttraumatic stress and conversion disorders. Although it is uncertain whether chronic exposure to low concentrations of CO causes permanent damage, health care providers should be vigilant for symptomatic individuals to prevent continued or catastrophic outcomes.

DIAGNOSTIC TESTING

The most useful diagnostic test obtainable in a suspected CO poisoning is a COHb level. Normal levels of COHb range from 0% to 5%. Levels at the high end of this range occur in neonates and patients with hemolytic anemia because CO is a natural byproduct of the breakdown of protoporphyrin to bilirubin.³³ Of note, in blood samples from neonates, falsely high COHb levels up to 8% can occur because of interference of fetal hemoglobin with spectroscopy (Chap. 28).²²⁰ Carboxyhemoglobin levels average 6% in one-pack-per-day smokers but may range as high as 10%.¹⁹⁰ Although high COHb levels confirm exposure to CO, particular levels are not necessarily predictive of symptoms or outcome.^90,170

The usual method for measuring COHb is with a cooximeter, a device that spectrophotometrically reads the percentage of total hemoglobin saturated with CO. Traditionally, arterial blood was used for this determination; however, venous blood levels are accurate because there is little CO extraction from hemoglobin across the capillary bed.²¹⁴ Refrigerated heparinized samples yield accurate COHb levels for months and at room temperature for 28 days, making retrospective clinical and postmortem evaluations reliable.^86,125 The prior administration of hydroxocobalamin, commonly given for cyanide poisoning after smoke inhalation, negatively interferes with COHb levels on selected cooximeters, which could lead to false reassurance.^136,164

Bedside tests using ammonia or sodium hydroxide are unable to differentiate reliably various levels of COHb versus control participants.¹⁶¹ Because of the similarities in extinction coefficients, COHb is misinterpreted as oxyhemoglobin on most types of pulse oximetry (Chap. 28).⁸ Thus, the pulse oximetry reading is usually normal in the setting of even severe CO poisoning.⁸⁵ Some newer pulse oximeters, called pulse cooximeters, have the ability to measure COHb noninvasively.⁶ A study in 10 healthy volunteers who inhaled CO at 500 ppm until they reached a peak COHb level of 15% found good agreement between pulse cooximetry and cooximetry.⁷ Early models of a commercial bedside pulse cooximeter showed very poor agreement, mischaracterizing half the patients with levels over 15% as lower.²¹⁴ Subsequently, two other cohorts of ED patients, using a later model of the same device, found that it measured COHb well, with a bias of 0.6% to 3% and precision of 3.3%.^179,183 Because it tends to overestimate COHb, the authors recommend a normal upper limit of 6.6% as triggering intervention. Because the pulse cooximeter is noninvasive, it can be used for initial screening of ED patients for occult CO poisoning who present with nonspecific symptoms.³⁷ Likewise, the device is useful for field screening, especially with mass casualties. But because of potential errors with its use, we agree with the American College of Emergency Physicians (ACEP) recent clinical guideline on CO poisoning that recommended it not be used independently to diagnose CO toxicity and therefore cannot substitute for a standard blood COHb measurement.²³²

Breath-sampling methods are used for screening patients.^50,53,64 Cutoffs of 53 ppm in patients breathing air and 43 ppm in those breathing oxygen have a reliability of approximately 80% in predicting COHb levels above 10%.⁶⁹ Limited data from French prehospital screening show no correlation between severity of CO poisoning and exhaled CO concentrrations.¹⁰⁹ Therefore, because of its poor reliability, we do not recommend breath sampling for screening of hospitalized CO-poisoned patients.

Some clinical laboratories measure CO directly in blood samples rather than COHb. This technique involves assaying CO directly with infrared spectrophotometry after it is extracted from the blood sample with a manometer. Based on calculations rather than true experimental data, the assumption is made that for a patient with a normal hemoglobin, a CO level of 1 mmol/L corresponds to an 11% COHb concentration. A simpler method to measure serum CO content is to add a known solution of hemoglobin followed by sodium dithionite to form COHb. The resulting COHb is measured spectrophotometrically with the assumption that 1 mole of hemoglobin binds 4 moles of CO. Interestingly, in one study, serum CO ranged from 0.14 to 0.6 mg/L but was the same in smokers (average, 4.6% COHb) and nonsmokers (average, 1% COHb).²³⁰ At this time, further research is required to determine the clinical importance of serum CO content.

Additional laboratory tests are useful in severe poisoning cases. Metabolic acidosis with elevated lactate concentration is a more reliable index of severity than a measurement of the COHb concentration.¹⁸⁹ Unfortunately, even arterial pH does not correlate well with either initial neurologic examination or the COHb level, making it a poor criterion for deciding the need for HBO treatment.¹⁵² Specificity of lactate is low in smoke inhalation victims, in whom it is used to indicate concomitant cyanide poisoning (Chap. 123).

Continuous cardiac monitoring and a 12-lead ECG are essential to identify ischemia or dysrhythmias in symptomatic patients with preexisting coronary artery disease or severe exposure. Mild elevations of creatine phosphokinase are common (ranging 20–1,315 IU/L in one series of 65 cases), usually because of rhabdomyolysis rather than cardiac sources.¹⁸⁴ However, because CO causes myocardial infarction in the presence of normal coronaries,¹¹⁸ nonspecific increases in troponin concentrations may reflect diffuse cardiac myonecrosis rather than focal coronary artery disease.³⁴ Congestive heart failure or hypotension can be evaluated with a β-type natriuretic peptide or echocardiography (or both), looking for evidence of myocardial stunning.^33,118 Because of the potential for increased cardiovascular mortality,¹⁰² patients with ECG changes or elevated cardiac markers benefit from further cardiac testing, a stress test, or angiography.

The problem with using COHb levels to base treatment is that there is a wide variation in clinical manifestations across patients with identical COHb levels. Furthermore, particular COHb levels are not predictive of symptoms or final outcome.^142,157,189 In a large prospective study of CO poisoning, COHb levels did not correlate with LOC and were not predictive of delayed neurologic sequelae.¹⁷⁴ Admission COHb levels are inaccurate predictors of peak levels, and the use of nomograms to extrapolate to earlier levels is not validated. Their credibility is also suspect because of the great variability in COHb half-lives and differences in treatment with oxygen. To avert this problem, France equips prehospital personnel with cooximeters (model not stated), which, although imprecise do help them distinguish the severity of poisoining.¹⁰⁹

Because of the inherent unreliability of COHb levels in predicting outcome, researchers are searching for other surrogate markers. Rats have early increases in glutathione released from erythrocytes, a potential marker for CO oxidative stress that could ultimately lead to brain injury.²⁰⁸ Another promising marker is serum S100B, a structural protein in astroglia that is released from the brain after hypoxic stress. A series of 38 consecutive patients poisoned with CO showed that those who presented with normal neurologic findings and no LOC had normal S100B concentrations.¹⁷ Patients who presented with LOC and neurologic deficits all had elevated concentrations. Carbon monoxide poisoned rats treated with HBO did not develop elevated S100B concentrations unlike those treated with ambient oxygen therapy.¹⁶ Levels at the target organ, the brain, show that S100B in the cerebrospinal fluid (CSF) predicted extreme neurologic sequelae, that is, persistent vegetative state only.¹¹⁰ Enolase, a byproduct of neuronal destruction, has a longer half-life than S100B and independently predicts delayed neurologic sequelae.³² Although markers used for cerebral injury, specifically S100B and neuron-specific enolase, rise after CO poisoning, they have not be shown to be reliable enough to predict final outcome or need for treatment.^1,19,175 A recent pilot study concluded that almost 100 different plasma proteins—cytokines, chemokines, and other biomarkers—increase after CO poisoning in patients; their significance awaits more definitive studies.²⁰⁴

NEUROPSYCHOLOGIC TESTING

The extent of neurologic insult from CO can be assessed with a variety of tests. The most basic is documentation of the normal neurologic examination, including a quick mini mental status examination. A more sensitive indicator of the acute effects of CO on cortical function is a detailed neuropsychologic test battery developed specifically for CO patients.¹⁴⁵ The advantages of such testing, which usually takes about 30 minutes, are that it can reliably distinguish 79% of the time between CO-poisoned patients and control participants, and it shows improvement with appropriate HBO treatment.¹⁴⁵ Unfortunately, such testing shows a sensitivity of only 77% and a specificity of 80% for CO poisoning. The patient can show practice effects as well with repeated testing. Another study suggested that the degree of impairment CO patients had on a test of short-term rote and context-aided verbal memory correlated well with the number of HBO treatments needed.¹⁴⁴ The biggest problem with such neuropsychiatric testing is that it is uncertain whether the determined deficits found during the acute CO poisoning phase are at all predictive of the development of neurologic sequelae and therefore the necessity of HBO treatment.

NEUROIMAGING

Acute changes on CT scans of the brain occur within 12 hours of CO exposure that resulted in LOC.^137,148 Symmetric low-density areas in the region of the globus pallidus, putamen, and caudate nuclei are frequently noted.¹⁰⁵ Changes in the globus pallidus and subcortical white matter early within the first day after poisoning are associated with poor outcomes¹⁶⁷ (Fig. 122–1). Alternatively, in one series of 18 patients, a negative CT within 1 week of admission was associated with favorable outcome.²¹³ The use of contrast enhances the early isodense changes not visible on initial CT scan²⁴⁰ but is not routinely performed.

Magnetic resonance imaging is superior to CT in detecting cerebral white matter basal ganglia lesions after CO poisoning.¹³⁷ One study found a much higher incidence of periventricular white matter changes on MRIs done within the first day after exposure. However, such changes had no correlation with COHb level or cognitive sequelae.¹⁶⁷ These periventricular changes are more common and probably more sensitive than globus pallidus lesions. Globus pallidus lesions were present on MRI in only one patient (1.4%) in a prospective study of CO-poisoned patients, half of whom had LOC.¹⁰⁵ Diffusion-weighted, or even diffusion tensor imaging MRI, has more promise in detecting changes in subcortical white matter within hours of serious CO poisoning.^10,197 Regardless, neuroimaging usually does not influence patient management and can be reserved for patients who show poor response or have an equivocal diagnosis.

The most promising area of neuroimaging after CO poisoning is the assessment of regional cerebral perfusion.^43,163 Single-photon emission CT (SPECT) gauges regional blood flow noninvasively using an iodine or technetium tracer. In one series of 13 patients with delayed neurologic sequelae (DNS), all cases showed patchy hypoperfusion throughout the cerebral cortex within 11 days of poisoning.⁴¹ These changes in perfusion occur as early as 1 day after poisoning and primarily involve watershed regions such as the temporoparietooccipital area.⁵⁸ Perfusion defects on SPECT scanning are associated with neuropsychological impairment months after serious CO poisoning.⁷⁰ In a recent series of CO-poisoned patients who required HBO, patients with DNS, rather than persistent neurologic sequelae, were more likely to show frontal hypoperfusion on SPECT scanning.^107,215 Unfortunately, because of the scant availability of the procedure and the lack of comprehensive studies, SPECT scanning is not the definitive tool at this time for determining prognosis or need for HBO. In addition, when imaging patients 1 to 2 years after poisoning, T2-weighted imaging on MRI is more sensitive than SPECT scanning.³⁸

Positron emission tomography (PET) can also be used to evaluate regional blood flow as well as oxygen metabolism in the brain after CO exposure. In one series of severely CO-poisoned patients, PET examination after HBO treatment showed increased oxygen extraction and decreased blood flow in the frontal and temporal cortices.⁵⁶ Of note, patients with permanent deficits persisted in showing these abnormalities on PET scanning. One delayed PET study demonstrated that increases in dopamine D₂ receptor binding in the caudate and putamen after CO poisoning were improved with bromocriptine, at which time neuropsychiatric symptoms resolved.²³⁹ Although PET scanning cannot be used to predict outcome, abnormalities that persist on the scan are associated with permanent neurologic sequelae. The same is true for proton magnetic resonance spectroscopy in which abnormalities within 1 week of exposure can predict DNS.¹²⁶

Electroencephalograms (EEGs) complement perfusion studies in the evaluation of CO-poisoned patients. Although initial studies demonstrate that many patients have regional EEG abnormalities after poisoning, it is unknown if these are predictive of persistent or delayed neurologic problems. Electroencephalograms mapping may be discrepant relative to SPECT scanning because EEG preferentially demonstrates subcortical lesions.

MANAGEMENT

The mainstay of treatment is initial attention to the airway. One hundred percent oxygen should be provided as soon as possible by either nonrebreather face mask or endotracheal tube. Although concerns have been raised regarding toxicity from excess oxygen, patients poisoned with CO can still have cellular hypoxia despite normal oxygen saturation.^14,85 It is important to remember that a nonrebreathing mask only delivers 70% to 90% oxygen; a positive-pressure mask or an endotracheal tube is necessary to achieve higher oxygen concentrations. The immediate effect of oxygen is to enhance the dissociation of COHb.¹⁸⁰ In volunteers, the half-life of COHb is reduced from a mean of 5 hours (range, 2–7 hours) when breathing room air (21% oxygen) to approximately 1 hour (range, 36–137 minutes) when breathing 100% oxygen at normal atmospheric pressure.¹⁷¹ Actual poisoned patients show a range in half-lives of 36 to 137 minutes (mean, 85 minutes) when breathing 100% oxygen; the longer elimination half-lives appear to be most often associated with long, low-level exposures.^155,227 With oxygenation and intensive care treatment, hospital mortality rates for serious exposures range from 1% to 30%. The duration of treatment is unclear, with a valid end point being the resolution of symptoms, usually accompanied by a COHb below 5%.

Continuous cardiac monitoring and intravenous (IV) access are necessary in any patient with systemic toxicity from CO poisoning. Hypotension should initially be treated with IV fluids, with the addition of inotropes for persistent myocardial depression. An evaluation for cardiac ischemia, including ECG and cardiac markers, is recommended in symptomatic patients at risk: prolonged exposure (>2 hours), altered mental status, or male gender.³¹ Echocardiography is reasonable in such cases; almost three-quarters of CO-poisoned patients with elevated troponins showed cardiomyopathy with global dysfunction or Takotsubo like changes.³³ Standard advanced cardiac life support protocols should be followed for the treatment of patients with life-threatening dysrhythmias. Patients with a depressed mental status should have a rapid blood glucose checked. Animal studies of CO poisoning suggest that hypoglycemia can be deleterious.¹⁶⁸ We recommend not giving sodium bicarbonate for correction of any acidemia unless profound because it will cause left shift of the oxyhemoglobin dissociation curve, further impairing tissue oxygenation.⁶²

Hyperbaric Oxygen

Hyperbaric oxygen (HBO) therapy is still the treatment of choice for patients with significant CO exposures.²¹⁰ But its most obvious effect is not the most important. One hundred percent oxygen at ambient pressure reduces the half-life of COHb from about 320 minutes to 85 minutes; at 2.5 atmospheres absolute (ATA), it is reduced to 20 minutes.^171,227 Actual CO-poisoned victims treated with HBO have COHb half-lives ranging from 4 to 86 minutes.¹⁵⁵ Hyperbaric oxygen also increases the amount of dissolved oxygen by about 10 times, which is sufficient alone to supply metabolic needs in the absence of hemoglobin (Chap. 28).¹² This is rarely an important clinical issue because most patients are already stabilized and have appreciably decreased COHb with ambient oxygen before preparation for an HBO treatment.

Therefore, HBO is more than just a modality to clear COHb more quickly than ambient oxygen (Antidotes in Depth: A40). More importantly, in rats after LOC from CO exposure, hyperbaric, but not normobaric, oxygen therapy prevents brain lipid peroxidation.¹⁶⁶ Hyperbaric oxygen therapy prevents ischemic reperfusion injury by a variety of mechanisms. First, in animal models, HBO accelerates regeneration of inactivated cytochrome oxidase, which is the initiating site for CO neuronal damage.¹² Unlike 100% oxygen at room pressure, in clinical trials, HBO was much more effective than room pressure oxygen at restoring mitochondrial function within peripheral white blood cells in CO-poisoned patients.⁵⁹ Hyperbaric oxygen also prevents β-integrin–mediated neutrophil adhesion to brain microvascular endothelium, a process essential for amplification of CNS damage from CO.¹⁷⁸ In vitro studies of rat astrocytes show protective effects of HBO versus 100% oxygen in preventing impairment of neurotrophic activity after CO poisoning.¹¹⁷ All these animal studies explain why HBO, but not 100% oxygen at atmospheric pressure, prevents delayed deficits in a learning and memory maze model.²⁰²

Clinical studies of the effectiveness of HBO in preventing neurologic damage from CO are not as convincing as basic science studies would suggest. In uncontrolled human clinical series, the incidence of persistent neuropsychiatric symptoms, including memory impairment, ranged from 12% to 43% in patients treated with 100% oxygen and was as low as 0% to 4% in patients treated with HBO.^{82,143,154,157}

Additionally, several controlled clinical trials have evaluated the efficacy of HBO in CO poisoning (Table 122–3). The first randomized study of CO poisoning included more than 300 patients and failed to show a benefit from HBO in patients who had no initial LOC.¹⁷⁴ Unfortunately, seriously ill patients were not randomized to surface pressure oxygen; they received either one or three treatments of HBO. Flaws in the study included significant delays to treatment and the use of suboptimal pressure, 2.0 ATA, well below the greater than 2.5 ATA typically used in positive animal and human studies. A smaller (n = 60) controlled study avoided some of these flaws and showed that HBO, at a maximum pressure of 2.8 ATA, decreased delayed neurologic sequelae at 3 to 4 weeks from 23% to 0% in CO-poisoned patients who presented without LOC.²¹¹ However, patients with syncope, a marker of serious poisoning, were excluded. A very small study (n = 26) of patients presenting with Glasgow Coma Scale (GCS) scores above 12 after CO poisoning included almost half with LOC.⁶³ Randomization to HBO versus 100% normobaric oxygen resulted in decreased EEG abnormalities and less reduction in blood flow reactivity to acetazolamide at 3 weeks. Unfortunately, all of these studies failed to definitively study all CO-poisoned patients, including those with syncope or coma.