Phosgene Toxicity Treatment & Management

Phosgene is a ubiquitous industrial product and exposures may occur at any time due to an accident, which is a more likely scenario than its use as a weapon. Emergency departments (EDs) should plan for such hazards in conjunction with local emergency planning committees/hazardous materials (HAZMAT) teams and to conduct appropriate training.

Prehospital and ED personnel should become educated about the hazards involved with liquid phosgene and should be trained in the appropriate personal protective equipment needed to work with phosgene-exposed patients. Prehospital personnel should be trained in the protection against exposure to phosgene gas at accident scenes.

Notify appropriate community authorities (HAZMAT, law enforcement, health department) of suspected phosgene exposure in a scenario where community health may be at risk.

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.

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

Management of phosgene toxicity is supportive. Bronchodilators are indicated for patients with evidence of bronchospasm. Corticosteroids (inhaled, systemic) have been recommended, but no solid evidence supports their efficacy. Prophylactic antibiotics and antifungals may be used because of the risk of superinfection. Pressor agents may be required to treat hypotension, bradycardia, and renal failure. Other agents (eg, leukotriene inhibitors, N -acetylcysteine, angiopoietin-1) have shown benefit in animal studies. ^{[2, 20]}

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.

Rescuer safety is paramount. ^[21] 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 and uphill from the exposure source).

To care for patients with liquid phosgene exposure, prehospital or HAZMAT personnel should be attired in at least level B protection, as follows:

• Full face mask with either supplied air respirator or preferably self-contained breathing apparatus (SCBA) ^[22]
• Butyl rubber gloves
• Chemical protective suit
• Chemical resistant protective overboots

The National Institute for Occupational Safety and Health (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. ^[23] Patients should use soap and water to wash their hair and all body surfaces, with care to avoid unnecessary hypothermic stress (especially in the very young and very old). Warm water, warm blankets, and dry uncontaminated clothing are essential. For more information on this topic, 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. Anticipate rapid in-transport deterioration of the patient with phosgene-induced pulmonary edema. Strongly consider pretransport intubation and mechanical ventilation.

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. 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.

If the patient reports dyspnea or chest tightness, begin therapy with supplemental oxygen. Severe exposures may require endotracheal intubation and suctioning. If a significant bronchospastic component is present, bronchodilators may be used with caution. ^{[21, 23]}

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.

Past wartime experience has demonstrated that in a mass casualty situation, patients with phosgene exposure should be triaged as requiring immediate care because of the impending need for intubation and PEEP to maintain distal airway opening. ^[24]

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 Chemical, Biological, Radiological, Nuclear, and Explosives (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.

Be wary of discharging asymptomatic patients during the latent phase after phosgene exposure. Patients who later develop severe pulmonary edema may be completely asymptomatic shortly after exposure.

Asymptomatic patients require a minimum of 8 hours of observation, and many authors recommend 12-24 hours of observation before discharge. Enforce rest of asymptomatic patients during the latent period, as exertion worsens the clinical course of phosgene toxicity.

Criteria for discharge after this observation time are as follows:

• No symptoms
• Clear lung ausculatory examination
• Normal respiratory rate
• Normal oxygen saturation
• Normal chest radiograph
• Good support system (physical, mental)
• Secure transportation

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. Reassess patients at frequent intervals—at least every 2 hours during the first 6 hours after exposure. Hourly reassessment would be preferred, and some authors recommend repeating vital signs and lung ausculatory examinations every 30 minutes.

Triage depends, in part, on the availability of high-level critical care and ventilators for patients with severe pulmonary edema. It is The possibility may arise that the number of victims may be greater than the number of immediately available ventilators. Upon knowledge of a phosgene attack having occurred, it is incumbent on local authorities (eg, medical, public health) to realize the potential for inadequate resources over time and secure additional resources through their local and state emergency management agencies, the Federal Emergency Management Agency (FEMA), and the Strategic National Stockpile (SNS). In the meantime, the exposed, asymptomatic victims, in order to preserve local resources, may be transferred, with appropriate personnel, to alternative venues where resources are more readily accessible, keeping and caring for the symptomatic victim in situ.

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

However, this triage scheme is, arguably, more an indication of poor planning than proper triage. To label a victim who has pulmonary edema, hypotension, and/or cyanosis as “expectant” is depriving that person of acute classic medical care because the local healthcare infrastructure is declaring there is virtually no hope of resources arriving in days, weeks, or months. This could be the case with a nuclear war or a 1918-like pandemic, but an intentional phosgene gas attack, while inflicting scores of casualties, is still a limited event encircled by untouched regional resources. Since phosgene toxicity has a latency period, there is time, albeit short and stressful, to marshal those resources expeditiously.

Ensure that 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 ED by staff members in appropriate protective equipment (level B or higher). A decontamination shower unit may be used. ^{[21, 22]}

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.

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.

In many cases, high inspired concentrations of oxygen and high 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 ventilation/perfusion 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.

Minimize fluid administration except when it is needed to correct hypotension. Pulmonary artery catheter monitoring may be required to maintain appropriate fluid balance while treating hypotension caused by fluid shifts. Avoid diuretics because the patient typically is volume-depleted from fluid shifts. Extracorporeal membrane oxygenation (ECMO) may be considered for patients with respiratory impairment refractory to supportive care.

Bronchodilators may improve existing bronchospasm. Prophylactic antibiotics have been recommended by some authors based on the findings of pneumonia and bronchitis in virtually all autopsy specimens. Corticosteroid administration postexposure remains controversial.

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. ^{[25, 26]} Nebulized sodium bicarbonate treatment theoretically may be beneficial; however, consider it as second line after the drugs noted above.

Tomelukast, a leukotriene receptor antagonist, prevents pulmonary edema in phosgene-exposed rabbits. Experimentally, ibuprofen has been shown to reduce phosgene-induced pulmonary edema. ^[27] In mouse studies, colchicine and cyclophosphamide have reduced neutrophil influx, lung injury, and mortality when administered 30 minutes following phosgene exposure. ^[28]

Intratracheal dibutyryl cyclic adenosine monophosphate (DBcAMP), a cyclic adenosine monophosphate (cAMP) analogue, inhibits the release of leukotrienes that contribute to the disease process. ^{[29, 30]} In phosgene-exposed rabbits, terbutaline and aminophylline (cAMP enhancers) limit the pulmonary capillary leakage. In addition, intratracheal N -acetylcysteine administered to rabbits 45 minutes postexposure reduces leukotriene formation and pulmonary edema. ^[31] Theoretically, nebulized N -acetylcysteine also should be effective.

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. Improvement typically occurs within 48-72 hours. ^[21] Improving patients may be discharged, and worsening patients should be admitted to a critical care setting for continued monitoring and supportive care.

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.

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 (advanced cardiac life support [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.

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 and a medical toxicologist.

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 Centers for Disease Control and Prevention (CDC) Chemical Emergencies Web page and the National Response Center (for reporting chemical spills).

Patients may be discharged after an appropriate observation period (8-12 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/Agency for Toxic Substances and Disease Registry (ATSDR ).

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.

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.