Phosgene Toxicity

Background

Phosgene (COCl₂) is a highly toxic gas or liquid that is classified as a pulmonary irritant. Synonyms for phosgene include carbonic dichloride, carbon oxychloride, carbonyl dichloride, chloroformyl chloride, d-stoff, and green cross. The military symbol for phosgene is CG, and its United Nations/Department of Transportation number is UN#1076. The American Chemical Society's Chemical Abstracts Service (CAS) registry number for phosgene is #75-44-5. Phosgene's structure is depicted in the image below.

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Phosgene structure.

Sir Humphrey Davy first synthesized phosgene in 1812 by passing carbon monoxide and chloride through charcoal. During World War I, it was used in combination with chlorine gas for combat purposes by the German army. This combination allowed phosgene emission to be hastened in cold weather. The German army switched to mustard gas in 1917 because of the development of effective gas masks. More effective agents and improved personal protective equipment make phosgene an unlikely agent to be used in future battles.

Present day exposure occurs during the manufacture of aniline dyes, polycarbonate resins, coal tar, pesticides, isocyanates, polyurethane, and pharmaceuticals. Phosgene exposure also occurs in the uranium enrichment process and during the bleaching of sand for glass production. Exposures related to the heating or combustion of chlorinated organic compounds, such as carbon tetrachloride, chloroform, and methylene chloride, also occur.^[1] These products are found in common household solvents, paint removers, and dry cleaning fluids.^[2] Occupational exposure can occur when welders heat metals treated with these chemicals and in organic chemistry laboratories that use chloroform.^{[3, 4]} Similarly, vehicle crashes involving trains or trucks transporting phosgene (or chlorinated hydrocarbons, such as methylene chloride, that could combust to form phosgene) could expose numerous individuals to this toxin.^[1]

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Pathophysiology

Phosgene is a colorless gas with the odor of newly mown hay or green corn. Olfactory fatigue may occur with a large exposure. Exposure to concentrations of 3 ppm may not cause noticeable symptoms for 12-24 hours. Exposures to 50 ppm may be rapidly fatal. While an odor threshold of 1.5 ppm has been reported in some humans, this does not protect against toxic inhalation effects.^{[5, 6, 7]}

Phosgene is considered to have poor warning properties and, hence, may reach the lower airways before it is noticed. It is 4 times heavier than air and is a gas above 47°F (8°C). Because of hydrolysis from atmospheric water, it appears as a white cloud in an outside environment.

There are 2 mechanisms of injury, hydrolysis and acylation.^[8] In hydrolysis, damage caused by phosgene is due to the presence of a highly reactive carbonyl group attached to 2 chloride atoms. The gas dissolves slowly in water, but when this occurs, it hydrolyses to form carbon dioxide and hydrochloric acid. This slow dissolution allows phosgene to enter the pulmonary system without significant damage to the upper airways. However, in the lower airways and alveoli, the tissue undergoes necrosis and inflammation. After the first few hours of exposure, the carbonyl group attacks the surface of the alveolar capillaries, causing leakage of serum into the alveolar septa. The tissue fills with fluid, causing hypoxia and apnea. Massive amounts of fluid (up to 1 L/h) leak out of the circulation, leading to a noncardiogenic pulmonary edema, with associated hypoxemia and volume depletion.

Acylation involves the reaction of phosgene with nucleophilic moieties causing denaturation of proteins, changes in cell membranes, and disruption of enzymes. The permeability of the blood-air barrier is altered, leading to interstitial edema, and the inflammatory cascade is activated. This primarily occurs in the bronchioli and alveoli since they are not protected by a mucous layer.

Researchers in the past decade have discovered 2 important facts that may lead to improved therapy. First, phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes. Second, phosgene combines with glutathione to form diglutathionyl dithiocarbonate. When the glutathione stores become depleted, phosgene binds to the cellular macromolecules, causing cell necrosis in the renal and hepatic tissues.

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Epidemiology

Frequency

United States

Clinically significant phosgene exposure occurs infrequently. Sporadic exposures in recent years are related to industrial accidents or isolated.^[9]

International

In view of currently available war gases, which are much more lethal than phosgene, and improved respiratory protection, phosgene is no longer considered a significant threat.

Mortality/Morbidity

The Occupational Safety and Health Administration permissible exposure limit (OSHA PEL) for the workplace is 0.1 ppm (0.4 mg/m) as an 8-hour time weighted average. The level immediately dangerous to life or health (IDLH) is 2 ppm. Even a short exposure to 50 ppm may result in rapid fatality.

Another means to assess exposure and potential complications is using the inhaled dose instead of concentration alone. An inhaled dose of greater than 25 ppm-min leads to subclinical biochemical lung alterations, greater than 150 ppm-min causes overt alveolar edema, greater than 300 ppm-min is possibly lethal, and the level with 50% mortality is about 500 ppm-min.^{[5, 6, 7]}

• During World War I, from December 1915 to August 1916, casualties from phosgene exposure occurred in 4.1% of gas-exposed troops. Fatality from phosgene exposure occurred in 0.7% of gas-exposed troops. Total casualties from chemical gas exposure occurred in 1.2 million troops and caused 100,000 deaths. Phosgene accounted for an estimated 80% of these cases.
• According to OSHA, millions of kilograms of phosgene are produced annually, with 10,000 workers at risk of exposure. This does not include the large number of people that may have mild-to-moderate exposures in their homes from using solvents (eg, methylene chloride) with heat guns to remove paint.
• Morbidity and mortality are related to the degree of pulmonary insult and subsequent hypoxemia. Delayed diagnosis may result from delayed signs and symptoms. Underlying medical conditions contribute to the patient's ability to withstand the hypoxic insult.

Race

No evidence has demonstrated that outcome of phosgene toxicity is dependent on race.

Sex

No sex predilection exists. Historically, most exposures have occurred in men because of their military roles. Women were exposed during World War I from developing and testing gas masks at the home front.

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History

Diagnosis of phosgene toxicity depends largely on history of exposure.^[9] Consider phosgene toxicity in patients involved in the manufacture of dyes, resins, coal tar, and pesticides. Query patients regarding occupation and any exposure to chemicals, especially around sources of heat.^[10] In the work setting and at home, phosgene can be produced by the combustion of methylene chloride (paint remover) or trichloroethylene (a degreasing solvent). Patients typically have an asymptomatic period of 30 minutes to 72 hours, but most significant exposures have a latent period less than 24 hours. The duration and concentration of exposure determine the time to symptom onset.

Pulmonary

• Cough (initially nonproductive, later frothy white-to-yellow sputum) or hemoptysis
• Dyspnea (exertional early on, subsequently becomes resting dyspnea)
• Chest tightness or discomfort (may be pleuritic but frequently is described as retrosternal burning)

Head, ears, eyes, nose, and throat

• Mucosal irritation - More common with intense exposure
• Eye irritation and tearing
• Nasal irritation (irritation and burning of the nasal passages) - Occurs with phosgene concentrations higher than 3 ppm, but, with lower respiratory tract disease, may occur at even lower concentrations
• Throat irritation extending to the retrosternal area - Common with exposures more than 5 ppm and may be described as a burning sensation
• Sudden death secondary to laryngospasm with large exposures

Cardiovascular (caused by volume depletion or hypoxemia)

• Lightheadedness, palpitations
• Angina

Other

• Headache (thought to be secondary to the hypoxemia and the inflammatory response initiated in the pulmonary parenchyma)
• Anorexia, nausea, and vomiting
• Flat metallic taste when smoking cigarettes or overall altered taste sensation
• Weakness
• Anxiety and sense of impending doom (likely from the hypoxemia and tachycardia)
• Skin burning if the patient has been sweating or if clothing is wet (caused by the breakdown to hydrochloric acid)

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Physical

Physical examination is useful with patients with active symptoms. Patients who relate a recent exposure may be in the latent phase and have no specific findings related to the exposure.

Pulmonary

• Tachypnea and bronchorrhea
• Wheezes, crackles, or rales on auscultation
• Cyanosis
• Apnea (late finding)

Head, ears, eyes, nose, and throat

Upper airway findings are not good prognostic indicators because significant injury may occur to the lower airways without upper airway involvement.

• Conjunctival injection and lacrimation
• Oropharyngeal hyperemia and salivation
• Nasal mucosa hyperemia associated with rhinorrhea

Cardiovascular

• Tachycardia
• Hypotension

Skin

• Cyanosis from pulmonary injury and resultant hypoxemia
• Chemical burns from liquefied phosgene (Although it also is considered a frostbite hazard in the compressed liquid form)

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Causes

The major risks are occupational exposure and close proximity to an industrial incident.^[11]

• Present day exposures described in literature are caused by the combustion products from chlorinated chemicals (eg, methylene chloride, trichloroethylene).^[1]
• Welding metals recently treated with degreasers, such as trichloroethylene, may produce phosgene.^{[3, 4, 12]} Solvents used for degreasing purposes should be stored more than 200 feet from a welding arc, as the exposure to UV light can create phosgene by photodegradation.
• Use of methylene chloride, a commonly used chemical paint remover, near a heat source allows the release of phosgene.
• Carbon monoxide is released in vivo as a metabolic product of methylene chloride.
• Phosgene is a breakdown product of chloroform that is stored for more than 6 months, even if the chloroform is stabilized with amylene.

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Laboratory Studies

ABG demonstrates the degree of hypoxemia. A partial pressure of oxygen (pO₂) as low as 23 mm Hg on 8 L/min of oxygen by face mask has been reported. Typical presenting pO₂ levels are 50-60 mm Hg while breathing room air. The carboxyhemoglobin level is important for cases involving exposure to methylene chloride or when carbon monoxide exposure is suspected. Methemoglobinemia may suggest other causes.

CBC may be obtained as a baseline level or if pneumonia is high on the differential diagnosis list. An elevated WBC count is not specific because it may result from hypoxemic stress or an infectious process. CBC may reveal hemoconcentration late in the disease process.

Electrolytes may be obtained as baseline studies because of the anticipated large fluid shifts that occur.

Cardiac enzymes (eg, creatine kinase-MB [CK-MB], troponin T, troponin I) may be obtained if cardiogenic pulmonary edema is high on the differential.

Continue pulse oximetry and cardiac monitoring in patients suspected of phosgene toxicity.

Investigation on a blood test that measures exposure to phosgene is being pursued. Most likely, this test will be used in laboratory settings.

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Imaging Studies

Chest x-ray

Initial findings may be normal; however, as the disease progresses, the chest x-ray (CXR) may demonstrate bilateral, diffuse interstitial infiltrates, as in the images below.

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The chest radiograph of a 42-year-old woman chemical worker 2 hours postexposure to phosgene. Dyspnea progressed rapidly over the second hour; PO2 was....

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An anteroposterior (AP) portable chest radiograph of a male patient, who developed phosgene-induced adult respiratory distress syndrome. Notice the bi....

Heart and pulmonary vessel sizes are usually normal unless the patient has baseline cardiomegaly.

CXR findings may precede the clinical presentation.

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Procedures

• Perform endotracheal (ET) intubation and mechanical ventilation based on the degree of respiratory failure and overall clinical picture. Lower tidal volumes and increased PEEP may result in improved oxygenation and reduced mortality.

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Prehospital Care

To avoid further exposures, hazardous materials (Hazmat) prehospital providers should always ensure that the environment is safe.^[8] A self-contained breathing apparatus (SCBA) should be worn at the exposure site.^[13] Remove the patient's clothes to prevent further contamination. If the eyes and skin are exposed, begin irrigation on site.

In the field, standard management of ABCs usually is sufficient. Severe exposures may require ET intubation and suctioning. If a significant bronchospastic component is present, bronchodilators may be used with caution.^{[8, 14]}

Past wartime experience has demonstrated that, in a mass casualty situation, phosgene exposures should be classified as immediate because of the impending need for intubation and positive end-expiratory pressure (PEEP) to maintain distal airway opening.^[15]

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Emergency Department Care

Always consider the need for decontamination in any toxic exposure to minimize the risk of poisoning hospital personnel. Inhalational exposure of phosgene should not occur unless in the proximity of the gas. If external decontamination has not been performed in the field, use personal protective equipment, as necessary, including dermal, eye, and facial protection. A decontamination shower unit may be used.^{[8, 13]}

Initiate humidified oxygen supplementation. Intubation with continuous positive airway pressure (CPAP) ventilation and pressure support is usually required to improve oxygenation. Frequent suctioning may improve conditions.

Bronchodilators may improve existing bronchospasm. In animal studies, beneficial effect has been shown with the administration of numerous drugs, including leukotriene antagonists, ibuprofen, colchicine, cyclophosphamide, terbutaline, aminophylline, and N -acetylcysteine.^{[16, 17]} Nebulized sodium bicarbonate treatment theoretically may be beneficial; however, consider it as second line after the drugs noted above.

Avoid excessive fluid administration. Pulmonary artery catheter monitoring may be required to maintain appropriate fluid balance while treating hypotension caused by fluid shifts.

In severe cases, extracorporeal membrane oxygenation (ECMO) may be considered refractory to supportive care.

Minimize fluid administration except when it is needed to correct hypotension. Avoid diuretics because the patient typically is volume-depleted from fluid shifts.

Avoid exertion during treatment and for several weeks after recovery.

Prophylactic antibiotics have been recommended by some authors based on the findings of pneumonia and bronchitis in virtually all autopsy specimens.

Corticosteroid administration postexposure has been recommended to reduce the degree of pulmonary edema by reducing the inflammatory response. Some sources recommend administration begin within 15 minutes or as soon as possible after exposure.

No specific antidote or effective elimination process exists. During both world wars, the Germans and Russians believed that hexamethylene tetramine was the antidote. Subsequent studies have shown some preexposure benefit but no definite postexposure benefit.

Tomelukast, a leukotriene receptor antagonist, prevents pulmonary edema in phosgene-exposed rabbits. Experimentally, ibuprofen has been shown to reduce phosgene-induced pulmonary edema.^[18] Colchicine and cyclophosphamide reduce neutrophil influx when administered to mice 30 minutes following phosgene exposure. These drugs reduce lung injury and mortality in mice.^[19]

Intratracheal dibutyryl cyclic adenosine monophosphate (DBcAMP), a cyclic adenosine monophosphate (cAMP) analogue, inhibits the release of leukotrienes that contribute to the disease process.^{[20, 21]} In phosgene-exposed rabbits, terbutaline and aminophylline (cAMP enhancers) limit the pulmonary capillary leakage. Also, intratracheal N -acetylcysteine (NAC), administered to rabbits 45 minutes postexposure, reduces leukotriene formation and pulmonary edema.^[22] Theoretically, nebulized NAC also should be effective.

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Consultations

• Consult the regional poison control center and a medical toxicologist for additional useful information and patient care recommendations.
• Prolonged critical care management often is required for the pulmonary complications of phosgene exposure.

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Medication Summary

Management of phosgene toxicity is supportive. Oxygen, corticosteroids (inhaled, systemic), leukotriene inhibitors, IV fluids, and prophylactic antibiotics are recommended. The recommended steroid dose is much higher than the dose conventionally used in asthma. Prophylactic antibiotics and antifungals may be required because of the risk of superinfection. Pressor agents may be required to treat hypotension, bradycardia, and renal failure.

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Beclomethasone (Beclovent, Vanceril)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits bronchoconstriction mechanisms, producing direct smooth muscle relaxation; may decrease number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness.

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Methylprednisolone (Solu-Medrol)

• Dosing, Interactions, etc.

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

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Betamethasone (Celestone, Soluspan)

• Dosing, Interactions, etc.

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

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Class Summary

Reduce inflammatory response. Whether early administration of corticosteroids can prevent development of noncardiogenic pulmonary edema is unknown. The decision to administer corticosteroids must be made on clinical grounds.

Treatments lasting more than 1 week may require a taper to prevent abrupt steroid withdrawal.

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Dopamine (Intropin)

• Dosing, Interactions, etc.

Clinical Context:  Stimulates adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors that, in turn, produce renal and mesenteric vasodilation. Use low dose to protect renal function; use high dose to combat severe hypotension unresponsive to fluid administration.

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Class Summary

Used to treat hypotension, bradycardia, or renal failure.

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Zafirlukast (Accolate)

• Dosing, Interactions, etc.

Clinical Context:  No human studies have evaluated the efficacy and safety of zafirlukast in patients exposed to phosgene. Nevertheless, given the known effects of leukotriene stimulation by phosgene, the results from animal studies, and the drug's safety profile, should be considered first line.

In the presence of food, bioavailability of oral zafirlukast is decreased by 40%. Administer on an empty stomach.

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Class Summary

Reduce the inflammatory response elicited by the leukotriene cascade. Leukotriene antagonists are approved by the Food and Drug Administration (FDA) only for chronic asthma management.

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Further Inpatient Care

• Admit patient to an intensive care setting for continued monitoring and supportive care. Improvement typically occurs within 48-72 hours.^[8]

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Further Outpatient Care

• In a case of suspected exposure to phosgene, monitor the patient for a minimum of 8-12 hours because of the potential for delayed-onset pulmonary edema. (The patient must remain asymptomatic and have no chest x-ray changes or hypoxemia after observation to be released from the ED or inpatient ward.)
• Instruct patients discharged from the hospital after recovery from pulmonary edema to avoid exertion and any pulmonary toxins that may precipitate a recurrence. Also, instruct patients to avoid circumstances similar to their exposure and to warn others of the same dangers.

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Transfer

• Provide supplemental oxygen and/or bilevel positive airway pressure (BiPAP) and immediately transfer patients to an appropriate facility if they present to clinics or hospitals without endotracheal intubation capability, ventilator capability, or ICU monitoring.

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Deterrence/Prevention

• A standard field protective mask or gas particulate filter provides adequate protection.
• Personnel working with chlorinated hydrocarbon compounds should ensure adequate ventilation and avoid exposing the compounds and the vapors to heat or UV sources.^[13]

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Complications

• Recurrence of pulmonary edema because of exertion, re-exposure, or exposure to other pulmonary toxins
• Pneumonia
• Development of reactive airway dysfunction syndrome with bronchospasm and chronic airway inflammation

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Prognosis

• The prognosis of acute phosgene exposure is good with early intervention. Few significant long-term sequelae occur after recovery.
• Studies involving combat personnel and workers involved in the uranium enrichment process have shown increased morbidity and mortality with high level exposure because of the development of pneumonitis, chronic bronchitis, emphysema, and impaired pulmonary function.
• The degree of the patient's cyanosis provides a rough estimate of survivability. Historically, patients with a mouse grey cyanosis have a worse prognosis than those with a plum blue cyanosis (quantitative assessment of hypoxemia was not routinely available at the time of these historical observations). To estimate the time until respiratory failure, double the length of time from exposure to the development of crackles.

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