Phosgene Toxicity

Etiology

Current research is directed toward phosgene's potential as a bioterrorism weapon in industrial settings where phosgene production is unregulated. Phosgene exists in the gaseous phase at room temperature but may be stored in the liquid phase below 8.2 degrees Celsius. Global estimates indicate more than 12 million metric tons of this chemical are produced annually.[2] 

Stratified by country, China produces 37% of the world's phosgene, followed by Europe (31%) and North America (20%). Recently, the Environmental Protection Agency (EPA) identified 123 sites in the United States that could expose millions of people to phosgene if the plant malfunctions or becomes a target of bioterrorism. Phosgene is denser than air, and thus, during exposure, it can be expected to accumulate in low-lying, poorly ventilated, or enclosed regions.[2][3] 

Characteristically, phosgene has a distinct odor. Reports have described it as musty or similar to freshly mowed grass or hay. However, only 10% of the population may appreciate this odor at concentrations reaching 2 ppm. The combination of its unassuming odor and poor human detection makes phosgene particularly dangerous.[4]

Epidemiology

Historically used in military settings, phosgene today is a chemical intermediate in dye production, pesticides, livestock feed chemicals, pharmaceuticals, and organic intermediates.[5] It may also be released as a byproduct during chemically induced paint decomposition or welding fumes.[6] 

Victims exposed to a large house fire or industrial fires are also at risk of phosgene poisoning due to the combustion of chlorinated products. There is a paucity of current epidemiologic data about phosgene toxicity. Reports are limited to anecdotes, case studies, simulations, and estimations.

Pathophysiology

Phosgene's lone carbonyl group makes it a highly reactive molecule.[7] Phosgene reacts with surfactant and other functional groups in the lower respiratory epithelium. Modern theories of phosgene toxicity propose that the carbonyl group reacts with primary amine, hydroxide, and mercapto groups, leading to cellular breakdown and reactive oxygen species, which deplete pulmonary glutathione stores.[7][8] 

The degradation of surfactant components leads to impaired respiratory mechanics and loss of the air-blood barrier, causing widespread atelectasis.[9][10] 

As phosgene's toxicity ensues, its degradation into HCl is also thought to worsen tissue insult. The combination of surfactant loss and a compromised air-blood barrier leads to pathognomonic noncardiogenic pulmonary edema, impairs gas exchange by increasing the diffusion distance for oxygen. As the blood-air barrier receives further insult, diffuse alveolar hemorrhage may occur. In severe cases, the fulminant interstitial edema may progress to acute respiratory distress syndrome (ARDS).[11]

Histopathology

Phosgene is a hydrophobic (low water solubility) molecule that resists degradation into HCl and CO2 in the upper airways. For this reason, phosgene migrates to the lower airway units, including the alveolar sacs and respiratory bronchioles, where histopathologic changes occur. These changes may include the destruction of the alveolar epithelial cells and capillary endothelium characterized by infiltration of the alveolus with inflammatory cells and proteinaceous fluid. Fibrin accumulation with alveolar macrophages may be present in patients who survive the initial insult.

Toxicokinetics

Phosgene exists in the gaseous phase at room temperature. The severity of the disease has been previously proposed to follow Haber's law, which indicates predicted Toxicity by Inhalation Toxicity = Concentration x Time. Once inhaled, the concentration and duration of exposure predict the events' sequelae and the disease's progression.

Symptom onset is inversely proportional to the concentration exposed; high concentrations of phosgene inhaled confer a more rapid onset of symptoms and a poorer prognosis. However, low doses of inhaled phosgene may present with few or no upper respiratory symptoms but may accumulate enough in the lower respiratory unit to cause delayed respiratory failure. The detection threshold in humans has been reported to be 0.125 ppm/ min. Concentrations exceeding 2 ppm/ min or more have been classified as immediately dangerous to life or health (IDLH) by the Centers for Disease Control and Prevention. At 1 - 3 ppm/ min, irritant effects may be expected. Below 50 ppm/ min, clinical pulmonary symptoms are not expected. Between 50- 150 ppm/ min, pulmonary irritation may be expected without manifest edema.[12] 

Exposures exceeding 150 ppm/ min should be expected to develop pulmonary edema.[13] Concentrations greater than 300 ppm/ min are likely to produce fatal pulmonary edema.[14]

History and Physical

At lower concentrations, patients may not report the characteristic odor of phosgene, though the odor is sharper and “suffocating” at higher concentrations. System review may reveal subjective findings such as headache, nausea, and fatigue. Irritant effects such as burning, lacrimation, eye redness, eye pain, pharyngitis, wheezing, and cough may be present.[3][15] 

Uniquely, tobacco smokers may report an aversion to tobacco smoke following exposure to phosgene. Pulmonary and cardiovascular findings may include wheezing, choking sensation, chest tightness, dyspnea, and chest pain.[16] Symptom onset commonly occurs within 2 to 24 hours; however, due to phosgene’s low water solubility, symptoms may be delayed past 24 hours. Case reports have documented delays of up to 72 hours and were provoked by exertion.

Vital signs most frequently reveal tachypnea, hypotension, and decreased pulse oximetry, though it may not be evident early in the clinical course. Physical exam may reveal a productive cough with pink, frothy sputum, pharyngeal edema, or erythema with inspiratory and expiratory rhonchi. Wheezing may be appreciated during the auscultation of lung fields. Patients in distress may appear cyanotic. Significant concentrations of inhaled phosgene have been reported to induce rapid onset laryngospasm.

Evaluation

Patients should be referred to a health care facility for evaluation and monitoring if phosgene exposures exceed 50 ppm/ min, inhaled concentration is unknown, liquid phosgene exposure to the face or oropharynx, or respiratory symptoms. Vital signs, serial examinations, and laboratory and imaging studies monitor the progression of acute hypoxemic respiratory failure caused by phosgene ALI. A complete blood count, chemistries, troponin, and brain natriuretic peptide (BNP) are also necessary.

Though not specific, case studies have reported leukocytosis, hypokalemia, and hyponatremia in patients exhibiting phosgene toxicity. Serum troponin and BNP may be used when the diagnosis is unclear and is likely normal. Arterial blood gas measurements and chest radiographs should be trended if there are indications of pulmonary involvement. Characteristic findings may include fluffy bilateral opacities and hilar congestion. ECG often reveals sinus tachycardia, although the fulminant disease may reveal signs of right heart strain.

Treatment / Management

Decontaminate the patient during the initial evaluation if the emergency response system has not already performed it. Liquid phosgene may prolong inhalation exposure if it remains present on the clothing. Garments should be removed and double-bagged. Encourage the patient to remain calm if the inhaled concentration is suspected to be greater than 150 ppm/ min, for excessive activity or distress may exacerbate pulmonary edema.[17] (B3)

Low-dose morphine or benzodiazepines may be used for anxiolysis. Airway, breathing, and circulation should be assessed during the initial evaluation. Patients should be started on noninvasive oxygen supplementation with pulse oximetry readings less than 92% or signs of respiratory distress. Recent animal studies have shown that noninvasive positive airway pressure (NIPPV) improves outcomes in those with and without pulmonary involvement.[18][19][20] (B3)

Early NIPPV is recommended or should be considered in patients with exposures exceeding 150 ppm/min, unknown exposure, or liquid phosgene exposure to the face. Endotracheal intubation may be required following inadequate support with NIPPV, inability to protect the airway, or other contraindications to noninvasive ventilation techniques. There is insufficient evidence to support the use of corticosteroids in treating phosgene ALI. Despite this, their use is left to the discretion of the attending clinician.[21][22] (B3)

Extracorporeal membrane oxygenation (ECMO) has produced positive outcomes in those requiring prolonged ventilatory support, pulmonary edema refractory to ventilatory techniques, or management requiring unsafe ventilator settings.[23] Inhaled beta-adrenergic agonists may be used to treat bronchospasm.(B3)

Differential Diagnosis

Phosgene ALI should be included in the differential for pathologies characterized by hypoxia with evidence of central vascular congestion with or without pulmonary infiltrates. Consider pulmonary contusion, infectious pneumonia, aspiration pneumonitis, cardiogenic pulmonary edema (eg, acute decompensated congestive heart failure), or pulmonary hemorrhage.

History, physical examination, and laboratory analysis differentiate acute cardiogenic pulmonary edema from contusion. Consider infectious pneumonia in those with pyrexia, leukocytosis, and a productive cough. Historical features and physical examination may differentiate aspiration pneumonitis, but management additions such as antibiotics are likely included.

Pertinent Studies and Ongoing Trials

Current research suggests prophylactic NIPPV may mitigate lung injury before clinical signs of pulmonary toxicity and may reduce mortality based on animal studies.[18][19] Ulinastatin is a serine protease inhibitor that has shown theoretical promise in animal studies by decreasing focused inflammatory markers in acute pneumonitis.[24] In 1 animal study, Tomelukast, a leukotriene receptor antagonist, prevented progression to ARDS.[11] 

Other anti-inflammatory medical therapies showing theoretical promise include nitrous oxide (NO) inhibitors, melatonin, and angiopoietin-1 (Ang1) inhibitors. Antioxidative strategies are also being investigated. Nebulized N-acetylcysteine (NAC) is being investigated for its potential as a glutathione (GSH) regenerator. However, studies are conflicting, and further research is needed to elucidate the proper timing of therapy. One study suggests pulmonary edema may render nebulized NAC inaccessible.[7] 

Intravenous NAC appears to improve systemic oxygenation but does not prevent progression to respiratory failure. Ibuprofen (IBU) is readily available and has shown positive outcomes when administered pre- and post-exposure. Still, the utility of pre-exposure use is not practical as most phosgene exposures are not anticipated. Supportive measures such as lung protective ventilation characterized by low tidal volume, high positive end-expiratory pressure, and high FiO2 are recommended for phosgene ALI.[20]

Prognosis

Patients with a known phosgene exposure of less than 50 mcg/ min are cleared from evaluation by a healthcare facility. Patients with exposures of 50 to 150 mcg/min, unknown exposure concentration, or respiratory symptoms should seek evaluation at a healthcare facility.[13]

After evaluation by a healthcare professional, patients with no signs of toxicity or pulmonary edema may be discharged with precautions after 8 hours of observation. Additional medical monitoring is warranted before discharge if the discussed criteria are not met after 8 hours. Severe injury is predicted by the onset of pulmonary edema within 2 to 6 hours. Patients who develop pulmonary edema should be considered for transfer to an ECMO facility, given the potential for refractory ARDS. Assuming survival from the initial insult, phosgene toxicity has a favorable prognosis, with a return to baseline expected within 1 to 2 years.

Complications

Patients who survive the initial insult have been reported to experience increased dyspnea on exertion and poor exercise tolerance for several months. A history of smoking worsens the prognosis of individuals with phosgene inhalation injury.