eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - Lung-Damaging Agents, Phosgene

Joy C Wethern, DO, Resident Physician PGY3, Department of Emergency Medicine, Carl R Darnall Army Medical Center, Ft Hood, Texas
Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center

Updated: May 27, 2009

Introduction

Background

Phosgene is produced and utilized across numerous industries for legitimate chemical synthetic processes, but it has been used in the past as a chemical weapon by warring nations and extremist groups. It has the potential to function as a weapon of mass destruction by any group with simple chemical synthetic capabilities or with the means to sabotage an existing industrial phosgene source. Its primary mode of action is as an irritant pulmonary toxin that produces delayed-onset noncardiogenic pulmonary edema.

Phosgene is also known as carbonyl chloride and has the chemical structure COCl₂. The British chemist John Davy first synthesized phosgene in 1812 by combining chlorine gas and carbon monoxide with activated charcoal as a catalyst (CO + Cl₂ ® COCl₂). Although it is typically colorless as a gas, phosgene may appear as a white cloud under conditions of concentrated release due to slow hydrolysis with airborne water vapor. Phosgene has a boiling point of 8°C (47°F) and exists as a gas at room temperature. Below the boiling point, it exists as a colorless fuming liquid. Vaporization is still significant at lower temperatures, making inhalational exposure possible even in cold conditions. Phosgene is usually transported as a compressed liquefied gas, and direct contact with this form of the substance may produce frostbite injuries.

Although phosgene is nonflammable, it is a strongly reactive substance and demonstrates electrophilic properties. It reacts with alkalis, ammonia, amines, copper, and aluminum. It can also attack plastics and rubber materials. Because phosgene is poorly soluble in water, it reacts minimally with oropharyngeal and conducting airway tissues and as a result can penetrate deeply into the lung, where it exerts its effects at the alveolar-capillary membrane.

The odor of newly mown hay characterizes phosgene gas exposures, but this olfactory warning signal may not be appreciated by all individuals. Since the odor detection threshold concentration is approximately 0.5-1.5 ppm, which is at least 5 times the permissive exposure limit of 0.1 ppm¹ set by the National Institute for Occupational Safety and Health (NIOSH) and the American Conference of Government Industrial Hygienists (ACGIH), significant exposure may occur before any unusual scent is perceived. This odor detection threshold approaches the NIOSH-defined immediately dangerous to life and health (IDLH) level of 2 ppm¹ . As a result, the odor of new mown hay is an insufficient warning signal for dangerously high phosgene levels. Other pulmonary irritant gases such as chlorine are so noxious that exposed persons flee the immediate area of release, but persons exposed to phosgene may inadvertently remain in a highly contaminated area, unaware that they are in any danger.

Because phosgene is 4 times denser than air, it tends to remain close to the ground and to collect in low-lying areas. This distribution of contamination should be considered when planning evacuation routes in the event of a phosgene release. Children may be at risk for higher exposure levels as a result of increased gas distribution closer to the ground. Children may also be at higher risk for severe exposure to this irritant gas due to their larger minute volume-to-weight ratios and their larger lung surface area–to–body weight ratios.

Phosgene is used in the synthesis of plastics, pharmaceutical agents, isocyanates, polyurethanes, dyes, and pesticides. Industries in the United States produce over 1 billion pounds of phosgene per year. Unfortunately, industrial accidents involving phosgene are not uncommon. On March 6, 2000, a phosgene gas leak from a Thai plastics factory killed 1 person and injured 814 others. A laboratory accident involving inadvertent phosgene release in Fuzhou, China, on June 16, 2004, killed 1 person and injured more than 260 others. A phosgene-containing pipe rupture on September 8, 1994, in Yeochon, Korea, resulted in multiple injuries and 3 deaths.

Small-scale exposures to phosgene have also occurred, as phosgene is a product of thermal decomposition of chlorinated hydrocarbons. Such agents include refrigeration coolants, dry cleaning fluids (carbon tetrachloride), metal degreasing agents (trichloroethylene), and paint strippers (methylene chloride). When these chlorinated hydrocarbons are exposed to a heat source such as welding, a fire, or heat gun application, phosgene may be liberated. Several case reports document phosgene-induced pulmonary injury via these routes of exposure.

The Germans used phosgene first as a weapon in World War I, although this gas was also used in an offensive capability by French, American, and British forces. The initial World War I deployment of phosgene occurred when the Germans released approximately 4000 cylinders of gas against the British near Ypres on December 19, 1915. In this conflict, phosgene was often combined with chlorine in liquid-filled shells, so it is difficult to state the number of casualties and deaths attributable solely to phosgene. Because trench warfare typified much of World War I, heavier-than-air gases such as phosgene readily inflicted casualties in these low-lying areas. Between the world wars, phosgene was assigned the military designation CG and was classified as a nonpersistent agent because of its rapid evaporation. In military publications, it has been referred to as a choking agent, pulmonary agent, or irritant gas.

Since World War I, phosgene has rarely been used by traditional militaries, but the extremist cult Aum Shinrikyo used this agent to attack the Japanese journalist Shouko Egawa in 1994. Egawa had been reporting on the cult's activities, and the cult retaliated against her by introducing phosgene into her Yokohama apartment through the mail slot while she slept.

Pathophysiology

Phosgene interacts with biological molecules through 2 primary reactions: hydrolysis to hydrochloric acid and acylation reactions. Because phosgene is poorly soluble in water, the hydrolysis reaction (COCl₂ + H₂ O ® CO₂ + 2 HCl) contributes far less to the typical clinical presentation, but this reaction is likely responsible for the mucous membrane irritant effects observed when persons are exposed to phosgene in high concentrations. The acylation reactions occur with amino, hydroxyl, and sulfhydryl groups on biological molecules, which attack the highly electrophilic carbon molecule in phosgene. These reactions can result in membrane structural changes, protein denaturation, and depletion of lung glutathione. Acylation reactions may be particularly important with phospholipids such as phosphatidylcholine, which is a major constituent of pulmonary surfactant and lung tissue membranes.

Studies in animal models have shown that exposure to phosgene vastly increases alveolar leukotrienes, which are thought to be important mediators of phosgene toxicity to the alveolar-capillary interface. Phosgene exposure also increases lipid peroxidation and free radical formation. These processes may lead to increased arachidonic acid release and thus provide more substrate for lipoxygenase (ie, more leukotriene production). Proinflammatory cytokines, such as interleukin-6, are also found to be substantially higher 4-8 hours after phosgene exposure.² Na/K-ATPase dysfunction, resulting in increased oxidative stress and depletion of antioxidants, has also been demonstrated in mice exposed to phosgene.³

In addition, studies have shown that postexposure phosphodiesterase activity increases, leading to decreased levels of cyclic AMP. Normal cAMP levels are believed to be important for maintenance of tight junctions between pulmonary endothelial cells and thus for prevention of vascular leakage into the interstitium.

On a physiological level, the most important clinical effect of phosgene toxicity is the development of noncardiogenic pulmonary edema resulting from increased pulmonary vascular permeability due to the damaged alveolar-capillary interface. Similar to other pathologic processes resulting in noncardiogenic pulmonary edema, this state is characterized by heavy, wet lungs that have low compliance. Oxygenation and ventilation both suffer, and the work of breathing is dramatically increased. Often positive end expiratory pressure (PEEP) is required to stent open alveoli that would otherwise collapse and result in significant ventilation/perfusion (V/Q) mismatch. Arterial blood gases after severe phosgene exposure demonstrate low PaO₂, decreased oxygen saturation, and often a respiratory acidosis due to impaired gas exchange. Pulmonary function tests show a markedly decreased vital capacity and an overall restrictive pattern.

Clinical

History

Time to onset of symptoms after phosgene exposure is a critical historical detail.

• Head, ears, eyes, nose, and throat (HEENT) (immediate if high concentrations of phosgene; typically lasts 3-30 min)
  • Lacrimation
  • Conjunctival irritation/burning
  • Burning sensation in mouth/throat
  • Throat swelling/changes in phonation - May reflect laryngeal edema due to irritant effects of phosgene hydrolysis (hydrochloric acid formation) at vocal cords
• Respiratory (usually 4-24 h postexposure)
  • Cough - Initially dry, then increasing frothy white/yellow sputum
  • Chest tightness, chest pain, or substernal burning
  • Dyspnea - Present at rest but much worse on exertion
  • If patient is a smoker, metallic or unpleasant taste to cigarettes

Physical

• HEENT
  • Pharyngeal erythema
  • Conjunctivitis
  • Altered phonation
• Respiratory
  • Crackles on auscultation - Herald the onset of pulmonary edema
  • Cyanosis - Late finding
  • Thin, frothy white/yellow secretions
  • Wheezing
  • Tachypnea
  • Stridor
  • Accessory muscle use for respiratory effort
• Cardiac
  • Tachycardia
  • Hypotension - Late finding secondary to inflammation-mediated fluid diversion out of vascular system and into lung interstitium

Causes

Phosgene exposure may result from a weapon of mass destruction release by extremist groups, traditional military conflict involving chemical munitions, industrial sabotage, industrial accident, fire exposure, or small-scale accidental exposure involving the heating of chlorinated hydrocarbons. Any weapon of mass destruction release will likely produce large numbers of casualties presenting simultaneously with similar symptoms, but a large industrial accident could result in similar patient arrival patterns.

Phosgene toxicity may occur in 3 phases. The first is an immediate irritant reaction likely caused by the hydrolysis of phosgene to hydrochloric acid on mucous membranes, which results in conjunctivitis, lacrimation, and oropharyngeal burning sensations. This symptom complex occurs only in the presence of high concentration (>3-4 ppm) exposures but does not have any prognostic value for the timing and severity of later respiratory symptoms. The most important finding to identify during this stage is a laryngeal irritant reaction causing laryngospasm, which may lead to sudden death. The irritant symptoms last only a few minutes and then resolve as long as further exposure to phosgene ceases.

One of the hallmarks of phosgene toxicity is an unpredictable asymptomatic latent phase before the development of noncardiogenic pulmonary edema. Typically, the latent phase lasts 3-24 hours, but it may be as short as 30 minutes or as long as 48 hours after phosgene exposure. The duration of the latent phase is an extremely important prognostic factor for the severity of the ensuing pulmonary edema. Patients with a latent phase of less than 4 hours have a poor prognosis. Increased physical activity may shorten the duration of the latent phase and worsen the overall clinical course. Unfortunately, there are no reliable historical or physical examination findings during the latent phase to predict its duration.

Differential Diagnoses

Workup

Laboratory Studies

• No combinations of laboratory or radiographic studies have been shown to discriminate reliably, which asymptomatic (latent phase) patients exposed to phosgene will develop life-threatening pulmonary edema.
• Pulse oximetry measurements remain normal during the latent phase, but it is useful for following progression over several hours of observation. Increase triage priority and level of intervention if oxygen saturation begins to decline, as hypoxemia heralds onset of pulmonary edema.
• Arterial blood gas measurements are normal during the latent phase but are useful for following progression of manifest illness after the onset of pulmonary edema. Also, arterial blood gas measurements may be useful for making adjustments in respiratory care therapy (ventilator settings). Acidosis typically occurs, initially as a respiratory acidosis, but later becomes a mixed acidosis due to anaerobic metabolism in the wake of profound tissue hypoxia.
• CBC may reflect hemoconcentration due to third spacing of fluid into lungs once pulmonary edema has occurred, but this test is of little value prognostically.
• A 2009 study noted that levels of secreted phospholipase A2 (sPLA-IIA) found on bronchial alveolar lavage increased markedly after phosgene exposure, peaking at 6 hours, and correlated well with severity of lung injury in the study population. While not specific for phosgene exposure, measurement of sPLA-IIA in bronchial lavage is a potential future measurement for the progression of lung injury from phosgene exposure.⁴

Imaging Studies

• Chest radiograph
  • In patients without preexisting cardiac disease, the heart silhouette should be normal.
  • Chest radiograph may help exclude other possibilities in the differential diagnosis (pneumothorax, pneumonia, hemothorax, pleural effusion).
  • Early changes after phosgene exposure include hyperinflation and hilar enlargement.
  • Later changes are typical for noncardiogenic pulmonary edema: fluffy "batwing" perihilar interstitial infiltrates.
  • Radiographic findings may evolve rapidly over the first few hours after phosgene exposure and clear over several days as clinical improvement occurs.
  • Using a low-energy exposure technique (50-80 kV) may facilitate early identification of evolving pulmonary edema (as early as halfway through the latent period).

Anteroposterior portable chest radiograph in a male patient who developed phosgene-induced adult respiratory distress syndrome. Notice the bilateral infiltrates and ground-glass appearance Image courtesy of Fred P. Harchelroad, MD, and Ferdinando L. Mirarchi, DO.

Treatment

Prehospital Care

No specific antidote exists for phosgene poisoning, but supportive care options are numerous.

• Rescuer safety is paramount. Little risk exists of secondary exposure or contamination from patients who have been exposed only to phosgene gas, but any patient exposed to liquid phosgene requires decontamination to protect prehospital and in-hospital care providers and resources. Knowing the ambient temperature is important. If the environment where exposure occurred is warmer than the boiling point of phosgene (47°F), then it is likely that exposure was only to the gas form, and extensive decontamination should not be required. The patient should be removed from further exposure to the gas (taken upwind of the exposure source).
• To care for patients with liquid phosgene exposure, prehospital or HAZMAT personnel should be attired in at least level B protection (full face mask with either supplied air respirator or preferably self-contained breathing apparatus (SCBA), butyl rubber gloves, chemical protective suit, chemical resistant protective overboots). NIOSH recommends this level of protection for known phosgene concentrations in excess of 1 ppm or any situation with unknown phosgene levels. Decontamination of patients exposed to liquid phosgene should start with clothing removal and bagging/tagging of contaminated apparel. Patients should use soap and water to wash their hair and all body surfaces, with care to avoid unnecessary hypothermic stress. Warm water, warm blankets, and dry uncontaminated clothing are essential. Also see CBRNE - Chemical Decontamination.
• Because of the latency of symptom onset, all patients with suspected phosgene exposure should be transported to a medical facility for evaluation.
• Priorities for care remain airway, breathing, and circulation. If patients are being treated and transported shortly after the exposure incident, it is unlikely that that they will be severely symptomatic due the latent period associated with phosgene. If the patient reports dyspnea or chest tightness, begin therapy with supplemental oxygen. Enforce rest (litter evacuation, not walking) since any exertion shortens the latent period and worsens toxicity. Keep patients calm, warm, and quiet to minimize the work of breathing.
• Any patient with ocular exposure to phosgene should begin eye flushes with copious amounts of saline or plain water for at least 15 minutes. This treatment should be started in the prehospital setting. Contact lenses should be removed.

Emergency Department Care

• Triage
  • Triage is a relatively simple matter when only a few patients are involved, but in the event of a CBRNE attack or large-scale industrial accident, triage becomes much more difficult since any one medical facility would rapidly be overwhelmed by large patient volumes.
  • The numbers of "worried well" who have not actually been exposed are likely to be large in any CBRNE event, but they create a particular problem for triage of phosgene exposures because the "worried well" and the "soon to be sick" who are in the latent phase before pulmonary edema may appear identical on presentation.
  • Asymptomatic patients require a minimum of 6 hours of observation, and many authors recommend 12-24 hours of observation before discharge. Patients who are eligible for discharge after this observation time should be asymptomatic with a clear lung ausculatory examination, normal respiratory rate, normal oxygen saturation, and normal chest radiograph.
  • While triage is always a dynamic process, this statement is particularly true for the triage of phosgene-exposed persons, who require frequent reassessment and retriage (every 1-2 h). Some authors recommend repeating vital signs and lung ausculatory examinations every 30 minutes. The first physical sign of pulmonary edema, crackles on the ausculatory examination, typically appears at half the time of the greatest symptomatic involvement (ie, a patient who develops crackles at 3 h postexposure can be expected to be severely ill at 6 h postexposure).
  • Triage depends on the availability of high-level critical care and ventilators for patients with severe pulmonary edema. If the number of patients who require ventilators outstrips the number of available ventilators, then patients who present with symptomatic pulmonary edema would likely be triaged as expectant.
  • When a true mass casualty situation exists, one triage scheme that has been recommended for phosgene exposed persons is as follows:
    • Minimal: Asymptomatic patients - Observe, retriage every 2 hours
    • Delayed: Symptoms of dyspnea without any signs on physical examination (normal vital signs, normal oxygen saturation) - Observe, retriage every hour
    • Immediate (if critical care resources are available): Signs of pulmonary edema (crackles on lung ausculatory examination, vital sign abnormalities, chest radiograph infiltrate)
    • Expectant: Patients with pulmonary edema accompanied by hypotension or cyanosis
• Ensure patients have been decontaminated in the prehospital setting. If patients exposed to liquid phosgene present for care before decontamination, ensure that they are decontaminated outside of the emergency department by staff members in appropriate protective equipment (level B or higher).
• Focus on airway, breathing, and circulation. For a stridorous patient who appears to have phosgene-induced laryngospasm, proceed rapidly to pharmacologically facilitated endotracheal intubation. If orotracheal intubation is impossible, be prepared for a surgical airway. Intubated patients may have copious airway secretions that require frequent suctioning. For patients not in need of emergent intubation, provide supplemental oxygen if they have symptoms of dyspnea and/or signs of tachypnea, hypoxia, or crackles on lung ausculatory examination.
• Enforce rest for all patients exposed to phosgene to minimize work of breathing since exertion shortens the latent period and worsens the clinical course.
• For patients with pulmonary edema and worsening respiratory status (hypoxemia, hypercapnia, increased work of breathing), provide airway support with positive pressure ventilation. Initially alert patients may do well with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), but if their clinical status declines further, they may require intubation and mechanical ventilation for support. Frequently high inspired concentrations of oxygen and high positive end-expiratory pressure (PEEP) settings are required to treat the severe hypoxemia associated with phosgene-induced noncardiogenic pulmonary edema. This therapeutic measure is intended to recruit collapsed alveoli to participate in gas exchange, thereby decreasing V/Q mismatch and improving oxygenation. However, patients will require careful monitoring of cardiovascular status because high PEEP settings may depress cardiac output by decreasing venous return.
• For patients with significant wheezing or preexisting reactive airway disease and bronchospasm, treat with standard doses of inhaled bronchodilators and inhaled anticholinergic agents such as albuterol and ipratropium bromide.
• For patients with ocular exposures to phosgene, continue the irrigation begun in the prehospital setting for a total time of at least 15 minutes. Test the patient's visual acuity and perform a slit lamp examination. Topical anesthetics may be required to attenuate blepharospasm and permit an adequate examination. Stain the corneas with fluorescein to check for any corneal epithelial defects. Refer the patient to an ophthalmologist.

Consultations

• Notify the local/state health department.
• If decontamination needs surpass hospital capabilities, request help from the local hazardous materials team.
• Discuss management with the regional poison control center.
• Notify law enforcement if industrial sabotage or an intentional release of phosgene is suspected. The Federal Bureau of Investigation (FBI) is the lead agent for investigating possible terrorist actions and weapons of mass destruction events.
• Internet sources for more information include the following: Centers for Disease Control and Prevention, Chemical Emergencies; and National Response Center (for reporting chemical spills).

Medication

Most of the data regarding medication use in phosgene poisoning are derived either from anecdotal experience in case reports or from studies involving animal models. Case reports are plagued by the absence of a control group and frequently by the lack of any documentation regarding level of phosgene exposure. Animal studies are useful for elucidating pathophysiological mechanisms and providing initial measures of treatment efficacy, but the applicability of such studies to the treatment of human phosgene toxicity is unknown. Human phosgene toxicity cases occur in too sporadic and sudden a fashion to allow randomized clinical trials, and clearly intentional exposure of human subjects to phosgene would be unethical.

Multiple authors agree on the need for aerosolized bronchodilator therapy for patients with reactive airway disease or asthma diagnoses prior to phosgene exposure and for patients who are actively wheezing.

Diuretics were recommended for many years, but most recent authors seem disinclined to recommend their use and note that they may actually be harmful in phosgene toxicity. Volume overload is not a feature of phosgene-related noncardiogenic pulmonary edema. In fact, patients are often hypotensive and intravascularly dry, since they are losing fluid from the vascular space into the lung interstitium due to the breakdown of the alveolar-capillary interface. Positive pressure ventilation may further depress venous return and decrease cardiac preload and may require vigorous support with isotonic crystalloid.

Recommendations for steroid use in phosgene toxicity vary widely. No data support the use of steroids to treat human phosgene exposure, but one animal study demonstrated that intravenous methylprednisolone 30 mg/kg completely blocked pulmonary edema and the associated increased leukotriene synthesis in phosgene-exposed rabbits. Two caveats about this study are that this protocol involved pretreatment with methylprednisolone before phosgene exposure rather than the postexposure scenario, which practicing clinicians face, and that this study was not designed to test whether the methylprednisolone actually resulted in a survival benefit.

Medical management guidelines for phosgene exposure from the CDC through the Agency for Toxic Substances and Disease Registry (ATSDR)⁵ recommend starting intravenous corticosteroids in cases of severe exposure even if the patient is asymptomatic. Some authors recommend both inhaled and systemic steroids for all phosgene-exposed patients, while others recommend steroids only if the patient has a prior diagnosis of reactive airway disease. Dosing recommendations from authors who advocate steroids suggest methylprednisolone 1 g IV on the day of exposure, followed by a taper over the following several days.

Prophylactic antibiotics are not recommended in phosgene-induced pulmonary edema. Antibiotic therapy should be reserved for patients who have clinical findings consistent with pneumonia such as a sputum culture with a likely culprit organism.

A variety of studies have been completed in rabbits and mice using postexposure administration of intratracheal isoproterenol, parenteral ibuprofen, intratracheal N -acetylcysteine, parenteral aminophylline, subcutaneous terbutaline, colchicine, and parental leukotriene receptor blockers. While many of these agents and delivery routes show promise in terms of decreased pulmonary edema, increased levels of reduced glutathione, decreased production of lipid peroxidation products, decreased leukotriene production, and maintenance of tissue cAMP levels, these favorable laboratory end points have not necessarily been tied to clinical end points of improved survival. None of these agents has Food and Drug Administration (FDA) approval for treatment of noncardiogenic pulmonary edema associated with toxic inhalations.

Systemic corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune system to diverse stimuli.

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

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

Dosing

Adult

Day 1: 1000 mg IV
Days 2-3: 800 mg IV
Days 4-5: 700 mg IV
Day 6: Reduce dose quickly if chest radiograph remains clear

Pediatric

Not established

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; grapefruit juice increases prednisolone concentrations; methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma levels of each drug

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use
Depo-Medrol contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue; administration of Depo-Medrol by other than indicated routes, including the epidural route, has been associated with reports of serious medical events including arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, seizures, visual impairment including blindness, ocular and periocular inflammation, and residue or slough at injection site

Aerosolized bronchodilator therapy

Patients with hyperactive airways usually benefit from aerosolized bronchodilator therapy.

Albuterol (Proventil, Ventolin)

Relaxes bronchial smooth muscle by action on beta 2-receptors with little effect on cardiac muscle contractility.

Dosing

Adult

Nebulizer: Dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL normal saline; administer 2.5-5 mg q4-6h, diluted in 2-5 mL sterile saline or water

Pediatric

<5 years (nebulizer): Dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL normal saline and administer q4-6h in equally divided doses
>5 years (nebulizer): Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Follow-up

Further Inpatient Care

• Patients with phosgene-induced pulmonary edema should be admitted to a critical care setting. These include all phosgene-exposed persons with crackles on ausculatory examination, chest radiograph abnormalities consistent with pulmonary edema, hypoxemia, or tachypnea.
• Patients with pulmonary edema will require ongoing supplemental oxygen therapy and likely will require positive pressure ventilation, either noninvasively through CPAP or BiPAP or invasively through endotracheal intubation and mechanical ventilation. Intubated patients are likely to require frequent suctioning due to copious secretions.
• Patients with ongoing symptoms of dyspnea but no objective abnormalities on examination, radiograph, or vital signs should be hospitalized for observation until they declare themselves as either improving or worsening. Improving patients may be discharged, and worsening patients should be admitted to a critical care setting.

Further Outpatient Care

• Patients may be discharged after an appropriate observation period (6-12 h if the patient has a clear chest radiograph, 24 h in a setting without chest radiography capability) if they are asymptomatic, have normal vital signs, and have a clear ausculatory examination.
• Patients need good follow-up care instructions with precautions to return if they develop symptoms. A preprinted patient information sheet and discharge instructions are available from CDC/ATSDR.

Inpatient & Outpatient Medications

• Discharged patients require no medications since they are asymptomatic. Previously diagnosed asthmatic patients should continue to take their inhaled steroids and inhaled bronchodilators as prescribed.
• Inpatients should be considered for bronchodilator therapy and possibly for systemic steroids as described above. Diuretics should probably be avoided, and antibiotics should be used only in the presence of a documented infection.

Transfer

• Patients with phosgene-induced noncardiogenic pulmonary edema require hospitalization in a critical care setting. If a local hospital cannot provide such care, then transfer must be arranged by direct physician-to-physician contact with a critical care provider at another institution. Critical care capable transport should be used (ACLS ambulance or helicopter with capability for mechanical ventilation).
• En route deterioration should be anticipated since the pulmonary edema is often rapidly progressive. For patients who are already significantly ill, consideration should be given to pretransfer intubation, sedation, and mechanical ventilation.

Complications

• Patients who survive the first 48 hours after phosgene exposure have a generally excellent prognosis. Clinical and radiographic improvement often occurs in 3-5 days.
• Patients who remain significantly ill beyond 5 days should be evaluated for a concurrent disease process such as superimposed infection.
• No data suggest carcinogenicity or reproductive/developmental hazards in association with phosgene exposure.
• Many patients report ongoing exertional dyspnea for months or even years after phosgene exposure despite normalized chest radiographs. Some patients may develop reactive airway dysfunction syndrome (RADS), which is an irritant-induced reactive airway process. These patients may benefit from follow-up pulmonary function testing 2-3 months after phosgene exposure, possibly to include a methacholine challenge test.
• Chronic low level exposure to phosgene (<0.1 ppm) in a cohort of almost 800 workers at a uranium enrichment facility during World War II resulted in no documented increase in all-cause mortality or respiratory causes of mortality in 35 years of follow-up when matched with unexposed control workers at the same facility.

Prognosis

• Latent period duration of less than 4 hours suggests a severe course of illness but one that is still survivable with maximum critical care interventions.
• Most patients exposed to phosgene recover uneventfully and have an excellent long-term prognosis.

Patient Education

• Resources are available through the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (ATSDR).
• For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Chemical Warfare and Personal Protective Equipment.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize that phosgene is a ubiquitous industrial product and that exposures may occur at any time due to an accident, which is a more likely scenario than its use as a weapon. Failure to plan for such hazards in conjunction with local emergency planning committees/HAZMAT teams and to conduct appropriate training.
• Failure to educate prehospital and emergency department providers about the hazards involved with liquid phosgene and provide training regarding the appropriate personal protective equipment needed to work with phosgene-exposed patients.
• Reliance on presence of the characteristic odor of new mown hay to substantiate a suspected phosgene exposure. Some persons cannot detect the smell of this agent, and the threshold for olfactory detection is well above dangerous exposure levels.
• Early discharge of asymptomatic patients during the latent phase after phosgene exposure. Patients who later develop severe pulmonary edema may be completely asymptomatic shortly after exposure. All patients with possible exposure should be observed for a minimum of 6 hours for development of symptoms or signs of pulmonary edema.
• Failure to reassess patients at frequent intervals—at least every 2 hours during the first 6 hours after exposure. Hourly reassessment would be preferred.
• Failure to anticipate rapid in-transport deterioration of the patient with phosgene-induced pulmonary edema. Strongly consider pretransport intubation and mechanical ventilation.
• Failure to enforce rest of asymptomatic patients during the latent period. Exertion will worsen the clinical course of phosgene toxicity.
• Failure to notify appropriate community authorities (HAZMAT, law enforcement, health department) of suspected phosgene exposure in a scenario where community health may be at risk.

Special Concerns

• Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy or position of Naval Medical Center San Diego, the Department of the Navy, the Department of Defense, or the United States Government.

Multimedia

Media file 1: Anteroposterior portable chest radiograph in a male patient who developed phosgene-induced adult respiratory distress syndrome. Notice the bilateral infiltrates and ground-glass appearance Image courtesy of Fred P. Harchelroad, MD, and Ferdinando L. Mirarchi, DO.

Media file 2: Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/chemical.html.

Image available at http://img.medscape.com/pi/emed/ckb/emergency_medicine/756148-829124-832454-832540.pdf.

References

1. US Department of Labor, Occupational Safety and Health Administration. Safety and Health Topics: Phosgene. Revised October 10, 2003. Available at http://www.osha.gov/dts/chemicalsampling/data/CH_262200.html. Accessed May 27, 2009.

2. Sciuto AM, Clapp DL, Hess ZA, Moran TS. The temporal profile of cytokines in the bronchoalveolar lavage fluid in mice exposed to the industrial gas phosgene. Inhal Toxicol. Jun 2003;15(7):687-700. [Medline].

3. Qin XJ, Li YN, Liang X, Wang P, Hai CX. The dysfunction of ATPases due to impaired mitochondrial respiration in phosgene-induced pulmonary edema. Biochem Biophys Res Commun. Feb 29 2008;367(1):150-5. [Medline].

4. Chen HL, Hai CX, Liang X, Zhang XD, Liu R, Qin XJ. Correlation between sPLA2-IIA and phosgene-induced rat acute lung injury. Inhal Toxicol. Feb 2009;21(4):374-80. [Medline].

5. [Guideline] Agency for Toxic Substances and Disease Registry. Medical management guidelines for phosgene. Accessed March 29, 2006;[Full Text].

6. Borak J, Diller WF. Phosgene exposure: mechanisms of injury and treatment strategies. J Occup Environ Med. Feb 2001;43(2):110-9. [Medline].

7. Bradley BL, Unger KM. Phosgene inhalation: a case report. Tex Med. May 1982;78(5):51-3. [Medline].

8. Cucinell SA. Review of the toxicity of long-term phosgene exposure. Arch Environ Health. May 1974;28(5):272-5. [Medline].

9. Diller WF. Early diagnosis of phosgene overexposure. Toxicol Ind Health. Oct 1985;1(2):73-80. [Medline].

10. Diller WF. Late sequelae after phosgene poisoning: a literature review. Toxicol Ind Health. Oct 1985;1(2):129-36. [Medline].

11. Diller WF. Pathogenesis of phosgene poisoning. Toxicol Ind Health. Oct 1985;1(2):7-15. [Medline].

12. Diller WF. Therapeutic strategy in phosgene poisoning. Toxicol Ind Health. Oct 1985;1(2):93-9. [Medline].

13. Diller WF, Zante R. A literature review: therapy for phosgene poisoning. Toxicol Ind Health. Oct 1985;1(2):117-28. [Medline].

14. Everett ED, Overholt EL. Phosgene poisoning. JAMA. Jul 22 1968;205(4):243-5. [Medline].

15. Glass WI, Harris EA, Whitlock RM. Phosgene poisoning: case report. N Z Med J. Dec 1971;74(475):386-9. [Medline].

16. Guo YL, Kennedy TP, Michael JR, Sciuto AM, Ghio AJ, Adkinson NF Jr, et al. Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators. J Appl Physiol. Nov 1990;69(5):1615-22. [Medline].

17. Karalliedde L, Wheeler H, Maclehose R. Possible immediate and long-term health effects following exposure to chemical warfare agents. Public Health. Jul 2000;114(4):238-48. [Medline].

18. Kennedy TP, Michael JR, Hoidal JR. Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists protect against pulmonary edema caused by phosgene. J Appl Physiol. Dec 1989;67(6):2542-52. [Medline].

19. Lazarus AA, Devereaux A. Potential agents of chemical warfare. Worst-case scenario protection and decontamination methods. Postgrad Med. Nov 2002;112(5):133-40. [Medline].

20. Lim SC, Yang JY, Jang AS, Park YU, Kim YC, Choi IS, et al. Acute lung injury after phosgene inhalation. Korean J Intern Med. Jan 1996;11(1):87-92. [Medline].

21. Parrish JS, Bradshaw DA. Toxic inhalational injury: gas, vapor and vesicant exposure. Respir Care Clin N Am. Mar 2004;10(1):43-58. [Medline].

22. Peters PL. Phosgene medical information. J Ark Med Soc. Oct 1977;74(5):193-5. [Medline].

23. Polednak AP, Hollis DR. Mortality and causes of death among workers exposed to phosgene in 1943-45. Toxicol Ind Health. Oct 1985;1(2):137-51. [Medline].

24. Regan RA. Review of clinical experience in handling phosgene exposure cases. Toxicol Ind Health. Oct 1985;1(2):69-72. [Medline].

25. Sciuto AM, Hurt HH. Therapeutic treatments of phosgene-induced lung injury. Inhal Toxicol. Jul 2004;16(8):565-80. [Medline].

26. Sciuto AM, Moran TS, Narula A, Forster JS. Disruption of gas exchange in mice after exposure to the chemical threat agent phosgene. Mil Med. Sep 2001;166(9):809-14. [Medline].

27. Sidell FR. Triage of chemical casualties. In: Zajtchuk R, Bellamy RF, eds. Medical Aspects of Chemical and Biological Warfare. 1997:337-49.

28. Smart JK. History of chemical and biological warfare: an American perspective. In: Zajtchuk R, Bellamy RF, eds. Medical Aspects of Chemical and Biological Warfare. 1997;9-86.

29. Snyder RW, Mishel HS, Christensen GC. Pulmonary toxicity following exposure to methylene chloride and its combustion product, phosgene. Chest. Mar 1992;101(3):860-1. [Medline].

30. Snyder RW, Mishel HS, Christensen GC 3rd. Pulmonary toxicity following exposure to methylene chloride and its combustion product, phosgene. Chest. Dec 1992;102(6):1921. [Medline].

31. Urbanetti JS. Toxic inhalational injury. Medical Aspects of Chemical and Biological Warfare. 1997;247-270.

32. US Army Medical Research Institute of Chemical Defense. 3rd ed. Medical Management of Chemical Casualties Handbook. 1999.

33. Wang YT, Lee LK, Poh SC. Phosgene poisoning from a smoke grenade. Eur J Respir Dis. Feb 1987;70(2):126-8. [Medline].

34. Warden CR. Respiratory agents: irritant gases, riot control agents, incapacitants, and caustics. Crit Care Clin. Oct 2005;21(4):719-37, vi. [Medline].

35. Wells BA. Phosgene: a practitioner's viewpoint. Toxicol Ind Health. Oct 1985;1(2):81-92. [Medline].

36. Wyatt JP, Allister CA. Occupational phosgene poisoning: a case report and review. J Accid Emerg Med. Sep 1995;12(3):212-3. [Medline].

Keywords

phosgene, phosgene exposure, treatment, symptoms, causes, chemical weapon, CG, COCl₂, carbonyl chloride, WMD, weapons of mass destruction, chemical warfare, noncardiogenic pulmonary edema, toxic inhalation, lung-damaging agents, irritant pulmonary toxin, frostbite injuries

Contributor Information and Disclosures

Author

Joy C Wethern, DO, Resident Physician PGY3, Department of Emergency Medicine, Carl R Darnall Army Medical Center, Ft Hood, Texas
Joy C Wethern, DO is a member of the following medical societies: American College of Emergency Physicians and American Osteopathic Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center
Kermit D Huebner, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, Association of Military Surgeons of the US, Society for Academic Emergency Medicine, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Mark Keim, MD, Senior Science Advisor, Office of the Director, National Center for Environmental Health, Centers for Disease Control and Prevention
Mark Keim, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Robert G Darling, MD, FACEP, Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine
Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Association of Military Surgeons of the US
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Elizabeth A Gray, MD, John W Love, MD, and Jeffery L Arnold, MD, to the development and writing of this article.

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