a) REFLEX PHASE: Following inhalation concentrations of greater than 3 ppm, patients develop shallow, rapid breathing due to a vagal reflex action that can cause decreased vital capacity and volume producing mild hypoxemia and mild respiratory acidosis. During this phase, patients can experience pain in the eyes and throat, chest tightness, shortness of breath, wheezing, coughing, hypotension, bradycardia and possible dysrhythmias.
b) DELAYED (LATENCY PHASE) EFFECTS: Depending on the inhaled dose (ie, higher exposure doses usually result in a shorter symptom-free period) there can be a symptom free period of up to 48 hours. However, biochemical effects (ie, histologic changes) start immediately after exposure. Following the symptom-free period, symptoms of cough, chest tightness, dyspnea, tachypnea and pulmonary edema can develop. INHALATION DOSE: Inhalation dose of less than 50 ppm-min: no clinical pulmonary effects; 50 to 150 ppm-min: subclinical pulmonary reactions (edema unlikely); 150 ppm-min or above: pulmonary edema probable; 300 ppm-min or above: life-threatening pulmonary edema anticipated. PROGNOSTIC INDICATOR: Generally, the shorter the latency period, the worse the prognosis.
c) CLINICAL (TERMINAL PHASE) EFFECTS: Progressive dyspnea, crackles throughout the lung fields and cyanosis are present. Symptoms can include pulmonary edema, cough, choking sensation, tachypnea, and production of foaming bloody sputum. Secondary to severe pulmonary edema, cardiac failure has also occurred.

a) REST: A decrease in oxygen consumption (ie, decreased physical exertion/activity) may be a factor in reducing the risk of developing pulmonary edema.
b) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of positive pressure airway management and mechanical ventilation may be needed. Consider recommendations by ARDSnet for protective ventilation in patients with evidence of pulmonary edema.
c) EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO): There are no reports of ECMO use following phosgene exposure; however, a consult with a pulmonologist or intensivist should be considered in a patient with a 150 ppm-min or greater exposure, a direct spray to the face and/or chest to a high concentration of phosgene in a solvent without the use of protective gear; or a suspected significant exposure that cannot be confirmed by a badge reading. Ideally, the patient should be transferred during the latency phase to an ECMO center if clinical symptoms require a transfer to a higher level of care (ie, tertiary care center).

a) Cardiac failure may occur as a complication of severe pulmonary edema (Borak & Diller, 2001; Proctor & Hughes, 1978).

a) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), 50% of patients had diffuse chest pain at the time of admission. The time between exposure to admission ranged from 10 to 19 hours (Vaish et al, 2013).

a) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), 60% of patients were hypotensive at the time of admission. The time between exposure to admission ranged from 10 to 19 hours (Vaish et al, 2013).

a) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), all patients developed sinus tachycardia as shown on ECG. No other ECG abnormalities were reported (Vaish et al, 2013).

a) In a dog model, severe phosgene poisoning caused initial bradycardia followed by tachycardia and progressive hypotension (Patt et al, 1946).

a) Shortness of breath, tightness in the chest, a retrosternal or epigastric sensation of pressure, and/or coughing usually develop with exposure to greater than 3 ppm phosgene (Galdston et al, 1947; Borak & Diller, 2001; Mathur & Krishna, 1992; Diller, 1985a; Diller, 1985; Polednak & Hollis, 1985).
b) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), all patients initially experienced coughing and a choking-like sensation. This was followed by ocular symptoms (ie, redness, lacrimation) after 2 to 3 hours in 30% of patients and breathlessness in all cases (Vaish et al, 2013).
c) The symptoms may disappear with cessation of exposure, but reappear if sufficient exposure has occurred to cause pulmonary edema (Mathur & Krishna, 1992).

a) In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), 80% of patients were tachypneic and 60% had diffuse bilateral coarse crepitations at the time of admission. The time between exposure to admission ranged from 10 to 19 hours (Vaish et al, 2013).

a) Phosgene is an irritant gas; the degree of pulmonary irritation can relate to the concentration and length of exposure (Clayton & Clayton, 1982), but the degree of initial symptoms of irritancy is not considered a good indicator of prognosis (Diller, 1985a; Diller, 1985).
b) Phosgene gas has low water solubility and thus can be deeply inhaled into the lung before an individual is aware of significant exposure. Upper respiratory tract irritation (e.g., cough, dyspnea, chest) is most common with exposure to greater than 3 ppm, and may be absent with short or long term exposure to lower concentrations (e.g. 2 ppm for 80 min) which can cause delayed pulmonary edema (Diller, 1985a; Diller, 1985).

a) INHALATION EXPOSURE/PULMONARY EFFECTS: Based on the inhaled dose (not the exposure concentration), severe pulmonary toxicity (including pulmonary edema) may occur. Although signs and symptoms of inhalation exposure can be divided into 3 phases (ie, reflex, latency, terminal), patients may NOT develop each distinct phase of exposure or the phases may be clinically unrecognizable (Vaish et al, 2013; Gutch et al, 2012; Borak & Diller, 2001; Proctor & Hughes, 1978).
b) REFLEX PHASE: Following inhalation concentrations of greater than 3 ppm, patients develop shallow, rapid breathing due to a vagal reflex action that can cause decreased vital capacity and volume producing mild hypoxemia and mild respiratory acidosis. During this phase, patients can experience pain in the eyes and throat, chest tightness, shortness of breath, wheezing, coughing, hypotension, bradycardia and possible dysrhythmias (Vaish et al, 2013; Borak & Diller, 2001; Proctor & Hughes, 1978).
c) DELAYED (LATENCY PHASE) EFFECTS: Depending on the inhaled dose (ie, higher exposure doses usually result in a shorter symptom-free period), there can be a symptom free period of up to 48 hours. However, biochemical effects (ie, histologic changes) start immediately after exposure. Following the symptom-free period, symptoms of cough, chest tightness, dyspnea, tachypnea and pulmonary edema can develop (Grainge & Rice, 2010; Borak & Diller, 2001).
d) CLINICAL (TERMINAL PHASE) EFFECTS: Progressive dyspnea, crackles throughout the lung fields and cyanosis are present. Symptoms can include pulmonary edema, cough, choking sensation, tachypnea, and production of foaming bloody sputum. Secondary to severe pulmonary edema, cardiac failure has also occurred. There may be chest x-ray evidence of diffuse opacities, and blood gas abnormalities; rales and rhonchi may be present, with or without an abnormal chest x-ray (Vaish et al, 2013; Borak & Diller, 2001; Proctor & Hughes, 1978).
e) PROGNOSIS: It is generally felt that if the victim survives 24 to 48 hours, the prognosis will be favorable (Borak & Diller, 2001; Russell et al, 2006; Clayton & Clayton, 1982; Proctor & Hughes, 1978), however survival is probably more directly related to the extent of pulmonary injury and gas exchange impairment.
f) CASE REPORT: A 20-year-old man inadvertently inhaled phosgene gas (dose inhaled unknown) from a leaking nearby pipeline and experienced an immediate burning sensation in his mouth and throat. Symptoms quickly progressed to acute noncardiogenic pulmonary edema. He was admitted with severe dyspnea, wheezing, tachycardia (130 bpm), hypotension (BP 90/60 mm Hg), tachypnea (respiratory rate 40/min) and audible rales and rhonchi over the entire chest. A chest x-ray showed bilateral fluffy infiltrates consistent with noncardiogenic pulmonary edema. An arterial blood gas (pH 7.16, pO2 47 mm Hg, pCO2 30 mm Hg and HCO3 10.4 mmol/L) was significant for severe metabolic acidosis. He was treated aggressively with mechanical ventilation, vasopressor support and received N-acetylcysteine via nebulization. Within 3 days of exposure, ventilatory support was withdrawn and 2 days later the patient was weaned from vasopressors. The patient fully recovered and was discharged on day 7 (Gutch et al, 2012).

a) PULMONARY EFFECTS: Following an exposure of 150 to 400 ppm-min, shallow, rapid breathing can result in mild hypoxemia and mild respiratory acidosis. Patients with severe hypoxia and hypotension may develop hepatic or renal injury or anoxic brain injury (Borak & Diller, 2001).

a) Secondary bacterial pneumonitis has been reported following acute phosgene gas exposure (Borak & Diller, 2001).

a) Patients who survive exposure with pulmonary edema may have persistent complaints of exertional dyspnea and reduced exercise capacity and abnormal pulmonary function tests for months. In general, chronic respiratory effects following an acute inhalation exposure are usually more common in smokers or in patients with underlying or preexisting lung disease (Borak & Diller, 2001)

a) Following acute inhalational exposure to phosgene only at an arsenal during WWII, 4 of 6 patients had evidence of acute pulmonary edema and acute emphysema. Three of the 4 patients were exposed after inadvertently inhaling phosgene (dose unknown) while working with the substance and one victim was sprayed in the face with liquid phosgene (Galdston et al, 1947).

a) SUBJECTIVE EFFECTS: Headache, anxiety, and nausea may be reported (American Chemical Council, 2014).

a) Following acute inhalational exposure to phosgene, patients have experienced fatigue (Galdston et al, 1947).

a) SUBJECTIVE EFFECTS: Headache may be reported. (American Chemical Council, 2014).

a) SUBJECTIVE EFFECTS: Headache, anxiety, and nausea may be reported (American Chemical Council, 2014).

a) CASE SERIES: In a series of 10 patients inadvertently exposed (dose inhaled unknown) to phosgene gas, 50% of patients had 2 to 3 episodes of vomiting at the time of admission. The time between exposure to admission ranged from 10 to 19 hours (Vaish et al, 2013).

a) Respiratory acidosis has been reported but is inconsistent (Diller, 1985a; Diller, 1985; Snyder et al, 1992; Snyder et al, 1992a). Respiratory alkalosis has also been reported (Wells, 1985).

a) Metabolic and mixed metabolic and respiratory acidosis has been reported but is an inconsistent finding (Diller, 1985a; Diller, 1985) (Wells, 1985). Blood pH may be normal (Wells, 1985).
b) CASE REPORT: A 20-year-old man inadvertently inhaled phosgene and experienced an immediate burning sensation in his mouth and throat. Symptoms quickly progressed to acute noncardiogenic pulmonary edema. He was admitted with severe dyspnea, wheezing, tachycardia (130 bpm), hypotension (BP 90/60 mm Hg), tachypnea (respiratory rate 40/min) and audible rales and rhonchi over the entire chest. A chest x-ray showed bilateral fluffy infiltrates consistent with noncardiogenic pulmonary edema. An arterial blood gas (pH 7.16, pO2 47 mm Hg, pCO2 30 mm Hg and HCO3 10.4 mmol/L) was significant for severe metabolic acidosis. He was treated aggressively with mechanical ventilation, vasopressor support and received N-acetylcysteine via nebulization. Within 3 days of exposure, ventilatory support was withdrawn and 2 days later the patient was weaned from vasopressors. The patient fully recovered and was discharged on day 7 (Gutch et al, 2012).
c) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), arterial blood gases showed type 1 respiratory failure with metabolic acidosis in 60% of the patients. PCO2 and sodium bicarbonate levels were normal. The time between phosgene exposure and hospital admission ranged from 10 to 19 hours (Vaish et al, 2013).

a) HEMOCONCENTRATION: Capillary leakage of plasma may be significant, resulting in marked hemoconcentration and various metabolic disorders (Diller, 1985a; Diller, 1985).

a) Exposure to very high concentrations (greater than 200 ppm) may cause hemolysis within the pulmonary vasculature (Borak & Diller, 2001). Leukocytosis and intravascular coagulopathy have also been reported following inhalation of phosgene gas (dose inhaled unknown) (Vaish et al, 2013; Borak & Diller, 2001).

a) Direct contact with the liquefied material can cause severe dermal irritation and burns (Borak & Diller, 2001; Proctor & Hughes, 1978).

a) Liquefied phosgene can be a frostbite hazard (Vaish et al, 2013).

a) In animal studies, pulmonary influenza virus infection was more severe and prolonged following inhalation of phosgene gas that produced edema (Borak & Diller, 2001).

a) SUPPRESSED NATURAL KILLER CELL (NK) activity in whole lung homogenates from phosgene exposed rats (0.5 or 1 ppm for 4 hrs) for up to 4 days post exposure has been reported (Burleson & Keyes, 1989).

a) INITIAL CARE: Remove patient(s) from exposure and monitor for respiratory distress. Monitor vital signs. Begin oxygen therapy after phosgene inhalation, if the victim shows signs of hypoxemia or respiratory distress or has a pulse oximetry reading of less than 94%. Assist ventilation as needed. Reassure the patient, by providing a calm environment.
b) IRRITANT EFFECTS: Treatment is symptomatic and supportive. Oxygen (humidified is preferred) therapy should be used in patients with dyspnea, wheezing, or pulse oximetry reading of SaO2 of less than 94%. If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
c) PULMONARY EFFECTS: Monitor patients for 24 hours after exposure because of the possibility of delayed pulmonary edema. Early use of positive pressure airway management and mechanical ventilation may be needed in patients with severe toxicity. The following agents have been suggested as early PROPHYLACTIC treatment of pulmonary effects to block the inflammatory cascade that occurs following a significant exposure; clinical studies have not been conducted. The following suggestions are based on an estimated phosgene exposure.
d) REST: A decrease in oxygen consumption (ie, decreased physical exertion/activity) may be a factor in reducing the risk of developing pulmonary edema (American Chemical Council, 2014; Grainge & Rice, 2010)
e) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of positive pressure airway management and mechanical ventilation may be needed. Consider recommendations by ARDSnet for protective ventilation in patients with evidence of pulmonary edema (Grainge & Rice, 2010).
f) EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO): There are no reports of ECMO use following phosgene exposure; however, a consult with a pulmonologist or intensivist should be considered in a patient with a 150 ppm-min or greater exposure, a direct spray to the face and/or chest to a high concentration of phosgene in a solvent without the use of protective gear; or a suspected significant exposure that cannot be confirmed by a badge reading. Ideally, the patient should be transferred during the latency phase to an ECMO center if clinical symptoms require a transfer to a higher level of care (ie, tertiary care center) (American Chemical Council, 2014).

a) More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791

a) Aerosolized: Maximal dosage based on the specific corticosteroid; and/or
b) Intravenous: 250 mg methylprednisolone or equivalent

a) Aerosolized: Maximal dosage based on the specific corticosteroid; and/or
b) Intravenous: 1 g methylprednisolone

a) It has been proposed that the administration of N-acetylcysteine (NAC) (not an approved FDA indication) during the asymptomatic (latency) phase may prevent phosgene-induced pulmonary edema (Grainge & Rice, 2010; Gutch et al, 2012; Borak & Diller, 2001a). It is postulated that NAC can trap phosgene and convert it to a less harmful metabolite and its antioxidant properties may have a role in the decrease in direct toxicity to pulmonary parenchyma (Gutch et al, 2012). Although it may have a role in treating phosgene inhalation injury, there is limited clinical information (Rodgers & Condurache, 2010).

a) In cases of phosgene exposure of 150 ppm-min or greater, treatment with NAC (20 mL of a 20% solution via nebulizer) should be considered (American Chemical Council, 2014).

a) CASE REPORT: A 20-year-old man inadvertently inhaled phosgene (dose inhaled unknown) and rapidly developed acute noncardiogenic pulmonary edema. He was admitted with severe dyspnea, wheezing, tachycardia, hypotension, tachypnea (respiratory rate 40/min) and audible rales and rhonchi over the entire chest. A chest x-ray was significant for bilateral fluffy infiltrates consistent with noncardiogenic pulmonary edema. The patient also developed severe metabolic acidosis and respiratory failure. He was treated aggressively with mechanical ventilation and vasopressor support. The patient also received N-acetylcysteine via nebulization at a dose of 1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution every 2 to 6 hours. Within 3 days of exposure, ventilatory support was withdrawn and 2 days later the patient was weaned from vasopressors. The patient recovered uneventfully and was discharged on day 7 (Gutch et al, 2012).
b) CASE SERIES: In a series of 10 patients inadvertently exposed to phosgene gas (dose inhaled unknown), the time between exposure and hospital admission ranged from 10 to 19 hours. The predominant symptoms at the time of admission were breathlessness, chest pain and vomiting. An initial chest x-ray showed evidence of acute respiratory distress syndrome in 6 patients and the remaining 4 were normal. All patients were treated with N-acetylcysteine (1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution via nebulization every 2 to 6 hours) and IV corticosteroids. Other therapies included vasopressors or antibiotic therapy in patients as indicated. Of the 10 patients, 4 died despite treatment. Each of these patients had a positive chest x-ray on admission and all were on ventilator support for more than 4 days. At 6 month follow-up, the remaining patients were symptom free with no permanent sequelae (Vaish et al, 2013).

a) N-acetylcysteine (NAC) administered intratracheally to rabbits 45 to 60 min after inhalational exposure to phosgene (1500 ppm/min) decreased pulmonary edema, production of leukotrienes and thiobarbituric acid reactive substances (interpreted as decreased lipid peroxidation), and maintained glutathione levels as compared to rabbits exposed only to phosgene. Assays were conducted in isolated perfused rabbit lungs and lung homogenates after in vivo phosgene exposure and NAC administration. (Sciuto et al, 1995)

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) SUMMARY
b) ANIMAL DATA

a) SUMMARY
b) ANIMA DATA

a) Further research is necessary before these agents can be recommended for the treatment of pulmonary edema in humans.

a) SUMMARY: Hexamethylenetetramine (HMT) was initially considered a specific antidote, but has been shown to be ineffective to treat acute phosgene exposure and is NOT recommended. It only appears to be effective if administered prophylactically (Gutch et al, 2012; Borak & Diller, 2001a).
b) Most human and animal studies have reported that hexamethylenetetramine (HMT) does not decrease phosgene lethality or pulmonary effects unless administered "prophylactically" before exposure (Diller, 1985b; Diller, 1985c) (Frosolono, 1985).

a) SUMMARY: In animal models, phosgene-induced pulmonary edema has been studied. Pretreatment with dibutyryl adenosine 3'5'-cyclic monophosphate (DBcAMP) plus isoproterenol were found to be effective in preventing an increase in lung weight and permeability caused by phosgene (Russell et al, 2006).
b) In the same study, several agents, when given in a pretreatment regimen, were helpful in preventing pulmonary edema in phosgene-exposed rabbits. These agents were: aminophylline, DBcAMP (dibutyryl adenosine 3,5-cyclic monophosphate), and a terbutaline/isoproterenol combination.
c) Using an in situ isolated perfused rabbit lung model, a constant intravenous infusion of isoproterenol 24 mcg/min (infused into the pulmonary artery) from 50 to 150 minutes after phosgene exposure plus an intratracheal 24 mcg bolus 50 to 60 minutes after exposure or an intratracheal bolus alone 50 to 60 minutes after exposure, significantly lowered pulmonary artery pressure, tracheal pressure and lung weight gain. Isoproterenol also significantly enhanced glutathione products or maintained protective levels (Sciuto & Hurt, 2004). Intrathecal administrations of isoproterenol (isoprenaline) at 8 mcg/kg 50 to 60 minutes after phosgene exposure in an isolated lung model also caused significant reduction in lung weight gain up to 150 minutes following exposure, as well as improvement in tracheal and pulmonary artery pressures (Grainge & Rice, 2010)

a) At present, there are no reports of the use of leucotriene antagonists in scientific literature for phosgene exposure (American Chemical Council, 2014).

a) In animal studies, acetylinic acid, colchicine, pentoxyfylline, hyperoxgenated solution, and elicosapentaenoic acid showed improvement in phosgene-induced acute lung injury, but there are no reports of human cases to support their use (American Chemical Council, 2014).

1) Phosgene

a) TWA: 0.1 ppm (0.4 mg/m(3))
b) STEL:
c) Ceiling: 0.2 ppm (0.8 mg/m(3)) [15-minute]
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

a) IDLH: 2 ppm
b) Note(s): Not Listed

a) 8-hour TWA:

a) 25 ppm for 30M -- Lung, thorax or respiration changes

a) 200 ppb for 6H/4W-I -- Structural or functional change in trachea or bronchi and changes in lung weight
b) 500 ppb for 6H/12W-I -- Structural or functional change in trachea or bronchi and changes in lung weight, weight loss or decreased weight gain
c) 250 ppb for 4H/17D-I -- Lung, thorax or respiration changes and changes in lung weight, dehydrogenases

1) However, the formation of hydrochloric acid as the sole mechanism of adverse pulmonary effects has been questioned (Diller, 1985).