Continuing Education Activity

Phosgene is a hydrophobic, gaseous pulmonary irritant with a ubiquitous presence in today's industrial landscape as a chemical intermediate. Its toxicity ranges from mild irritation to severe pulmonary edema, and no antidote or reversal agent exists at this time. Despite its widespread use, some regions poorly regulate its production, and concern exists for its potential as a weapon of bioterrorism, making it a topic of interest. Given its severe toxicity and high mortality, research is primarily limited to animal studies and case series. The article presents the background of phosgene, its pathophysiology, characteristic historical and physical features, and proposed management strategies required by inter-professional team members.

Objectives:

• Describe the pathophysiology of phosgene toxicity.
• Review current management strategies for phosgene toxicity.
• Identify key elements of history and physical that are characteristic of acute phosgene toxicity.
• Outline differential diagnoses and how to distinguish them from phosgene toxicity.

Introduction

Phosgene dates back over 200 years to its conception in the laboratory of Cornish chemist John Davy. During WWI, it was known as 'Choky Gas' or 'CG.'[1] Today it remains ubiquitous in the industrial landscape. Phosgene is a hydrophobic, volatile irritant that causes chemical pneumonitis and is a cause of acute respiratory distress syndrome (ARDS) that can be refractory.

Etiology

Current research is directed toward phosgene's potential as a bioterrorism weapon and 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 were to malfunction or become 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 detection by humans 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 pertaining to 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 found 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, which 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 and therefore 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 will 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 indicating predicted Toxicity by Inhalation Toxicity = Concentration x Time. Once inhaled, the concentration and duration of exposure predict the sequelae of events and the progression of the disease.

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 will be 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, there is liquid phosgene exposure to the face or oropharynx, or there are respiratory symptoms. Vital signs, serial examinations, and laboratory and imaging studies are used to 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 will likely be 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 on initial evaluation if not already performed by the emergency response system. 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] 

Low-dose morphine or benzodiazepines may be used for anxiolysis. Airway, breathing, and circulation should be assessed on 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 early use of noninvasive positive airway pressure (NIPPV) improves outcomes in those with and without pulmonary involvement.[18][19][20] 

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] 

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.

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 (e.g., acute decompensated congestive heart failure), or pulmonary hemorrhage.

History, physical examination, and laboratory analysis will differentiate acute cardiogenic pulmonary edema and pulmonary contusion. Consider infectious pneumonia in those with pyrexia, leukocytosis, and productive cough. Aspiration pneumonitis may be differentiated by various historical features and physical examination but will likely include management additions such as antibiotics.

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] Tomelukast, a leukotriene receptor antagonist, prevented progression to ARDS in one animal study.[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; however, it does not prevent progression to respiratory failure. Ibuprofen (IBU) is readily available and has shown positive outcomes when administered pre- and post-exposure, but 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. If the discussed criteria are not met after 8 hours, additional medical monitoring is warranted before discharge. 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 one to two 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.

Postoperative and Rehabilitation Care

Following hospitalization, recovery should include referral to occupational health and regular pulmonary function testing to monitor healing.

Consultations

Patients with measurable phosgene exposure, unknown exposure, or pulmonary findings should be observed and/or managed in a hospital setting. If the diagnostic evaluation is consistent with acute or impending hypoxic respiratory failure, then consultation with a critical care specialist is appropriate, as well as consideration regarding the potential benefit of ECMO. The step-down unit in intensive care is appropriate with stable diagnostics and trending improvement. Patients may be admitted to floor-level management after at least 6 hours of stable observation. If there are signs of ophthalmic injury, consult an ophthalmologist.

Deterrence and Patient Education

Phosgene is primarily an occupational exposure. Phosgene badges are used by workers in phosgene industries and may be the only indicator of exposure. Therefore the patient care team should inquire about one. Those exposed to phosgene should wear badges as close to the zone of inhalation as possible. They should only be used as estimates as they cannot reflect actual inhaled concentration. Thus, clinical judgment is paramount.

The Environmental Protection Agency (EPA) has measured air samples in California and identified concentrations not exceeding 31.8 parts per trillion (ppt) in the Los Angeles basin. The Occupational Safety and Health Administration, The National Institute for Occupational Safety and Health (NIOSH), and the American Conference of Governmental Industrial Hygienists (ACGIH) have recommended exposure limits no greater than 0.1 ppm. This is particularly useful in settings where phosgene badges are utilized. 

Pearls and Other Issues

Initiate NIPPV within 1 hour of evaluation of phosgene toxicity with pulmonary involvement.[18][20] Consider lung protective ventilation when managing phosgene ARDS to prevent iatrogenic trauma from mechanical ventilation and encourage healthy lung mechanics. In practice, maintain a high PEEP and low tidal volumes. Deep sedation and neuromuscular blockade can assist with ventilator compliance. 

Enhancing Healthcare Team Outcomes

Successful management will involve the coordination of nurses, emergency physicians and other clinicians, intensivists, pulmonologists, pharmacists, toxicologists, and nurses, operating as an interprofessional healthcare team. Coordination with nursing staff is critical to obtain timely analyses and identify any clinical deterioration. Nurses can monitor the patient, letting the clinicians know if they note any deterioration in the patient's status. While drug therapy plays a minor role in managing phosgene toxicity, pharmacists can provide the needed medications to manage the case and perform medication reconciliation.

Though insidious, phosgene pneumonitis can become emergent quickly, so timely gathering of critical data points by nursing staff can ensure providers are prepared for a failing airway. Intensivists will be involved with phosgene toxicity with associated respiratory failure and should be consulted early in the disease. Emergency clinicians should recognize progressive hypoxia and maintain ABCs while consulting toxicologists for accurate diagnosis and proper management. All interprofessional team members must exercise open communication and keep updated and accurate patient records, so that all caregivers have the same information on which to base clinical decisions. 

All interprofessional team members should be open to inclusivity concepts, both regarding the patients and fellow team members. This approach, combined with interprofessional care, will yield optimal patient results. [Level 5]

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Disclosure: Matthew Von Zimmerman declares no relevant financial relationships with ineligible companies.

Disclosure: Thomas Arnold declares no relevant financial relationships with ineligible companies.