377 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from

Lung Damaging Agents (Choking Agents)

GENERAL lung damaging materials injury such as those in smoke or products of combustion may Introduction cause toxic inhalational injury following the Lung damaging agents are chemical agents, generation of particulate aerosols. which produce a toxic inhalational injury – Military dispersion of phosgene during they attack lung tissue and primarily cause World War I followed the explosion of liquid pulmonary oedema. Whether produced for filled shells with subsequent rapid military or industrial use, these chemical evaporation and formation of a white cloud agents pose a very real threat to military due to its slight solubility in an aqueous personnel. environment. It spontaneously converted to a The term choking agents has been colourless, low-lying gas four times as dense traditionally applied to the use of certain as air. Because of its relatively low boiling lung damaging agents as chemical weapons, point (7.5ºC), phosgene was often mixed with and includes phosgene (CG), diphosgene other substances. Chlorine was released from (DP), chlorine (CL), and chloropicrin (PS). pressurised cylinders to form a pungent Phosgene accounted for 80% of all chemical greenish-yellow gas that was heavier than air. fatalities in World War I, but at least 14 different respiratory agents were used, as well Detection as obscurants (smokes), harassing agents Although field-detection equipment for (chloracetone), and vesicants (mustard) that classical choking agents is currently could cause pulmonary injury. employed by some nations, and various Today, only a handful of such pulmonary commercial industrial detectors are available toxicants still exist in stockpiles around the for the wider of lung damaging agents, there world. Several however, such as chlorine and are no automatic detectors in service. The phosgene, are currently produced in large characteristic odour of some lung damaging quantities for industrial purposes; other toxic agents may be unreliable as a sure means of

industrial chemicals which may cause toxic detection. For example, in low concentration http://militaryhealth.bmj.com/ inhalational injury include ammonia, phosgene has a smell resembling new mown isocyanates, mineral acids etc. hay, but the odour may be faint or lost after Other lung damaging materials – although accommodation. There is also considerable not likely to be used as CW agents - are still variation in the sense of smell between likely to be encountered on the battlefield. individuals. Perfluoroisobutylene (PFIB) is a toxic Similarly the eye irritation, coughing, pyrolysis product of tetrafluoroethylene sneezing, hoarseness, and other central polymers encountered in military materiel respiratory effects seen after exposure to high (e.g., Teflon®, found in the interior of many concentrations of some pulmonary toxicants are also unreliable indicators of exposure, as

military vehicles). The oxides of nitrogen on September 29, 2021 by guest. Protected copyright. (NOx) are components of blast weapons or these may be transient or entirely absent at may be toxic decomposition products. lower but still potentially lethal Smokes (e.g. HC) contain toxic compounds concentrations. This is particularly true in that cause the same effects as phosgene. the case of phosgene. Similar substances encountered in fires, e.g. PFIB, isocyanates, phosgene, and HCl may Protection also produce lung damage. Chemical fire The activated charcoal in the canister of the extinguishers containing carbon dioxide chemical protective mask adsorbs phosgene, should not be used in confined spaces to and in-service respirators afford full extinguish thermite or magnesium types of protection from this and other choking incendiaries - carbon tetrachloride in contact agents. However, only limited or temporary with flame or hot metal produces a mixture protection against toxic products of of phosgene, chlorine, carbon monoxide and combustion or smoke can be assumed, and hydrochloric acid. may be complicated in addition by the presence of oxygen-depleted air. Physical and Chemical Properties Decontamination Choking agents are usually true gases in field No decontamination is required following environments, and stored and transported as exposure to classic choking agents or other a liquid under pressure. Other less volatile lung damaging agents in gas or vapour form. 378 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from

Following exposure to high concentrations of centrally acting irritants, sufficient agent may penetrate into the peripheral lung to cause pulmonary oedema. Similarly, high conc- entrations of peripherally-acting agents can release enough hydrochloric acid to cause significant central airway irritation and epithelial damage. Because chlorine is intermediate in its solubility and reactivity, chlorine-exposed soldiers in World War I usually exhibited both central airway damage and pulmonary oedema, even from moderate concentrations of the gas. Phosgene is only slightly soluble in water and aqueous solutions; once dissolved, it rapidly hydrolyses to form carbon dioxide and hydrochloric acid. The early-onset ocular, nasopharyngeal, and central airway irritation from high concentrations of phosgene appears to result from the release of Fig 26. Phosgene induced injury to pig lungs. hydrochloric acid during phosgene hydrolysis by water in the upper airways. Mechanism of Action Chemicals that are highly reactive and/or Toxicity highly soluble in aqueous solutions tend to The odour threshold for phosgene is about act in the conducting, or central 1.5 mg/m3, and phosgene irritates mucous compartment of the respiratory tract. membranes at 4 mg/m3. The LCt50 of Centrally-acting irritants such as sulphur phosgene is approximately 3200 mg.min.m-3, mustard, ammonia, and hydrochloric acid, which is half the LCt50 (6,000 mg.min.m-3) cause pronounced irritation of the epithelial of chlorine, the first gas used on a large scale cells lining the upper airway. Additionally, at in World War I. Phosgene is twice as toxic as low concentrations, centrally-acting chlorine; although it is less potent than compounds are essentially consumed by almost all of the subsequently developed deposition and reaction in the conducting chemical warfare agents, this should not lead airways before they reach the peripheral to an underestimation of its danger - deaths portion of the respiratory tract. have occurred after the inhalation of only a In contrast, most of the pulmonary agents, few breaths of high concentrations of http://militaryhealth.bmj.com/ such as phosgene, oxides of nitrogen, and phosgene. Perfluoroisobutylene (PFIB) is PFIB, are relatively insoluble and said to be ten times more toxic than nonreactive, readily penetrating to the level phosgene. of the respiratory bronchioles and the alveoli. There they undergo acylation reactions and are essentially consumed at that site, causing CLINICAL-PATHOLOGICAL the damage that may eventually lead to pulmonary oedema. EFFECTS Chemically induced, acute lung injury by these peripherally-acting agents involves a Pathology permeability defect in the blood-air barrier The outstanding feature of acute lung injury on September 29, 2021 by guest. Protected copyright. (the alveolar-capillary membrane); however, caused by lung damaging agents is massive the precise mechanisms of toxicity remain pulmonary oedema. This is preceded by largely unknown. Leakage of fluid from damage to the bronchiolar epithelium, capillaries into the pulmonary interstitium is development of patchy areas of emphysema, normally compensated by lymphatic partial atelectasis, and oedema of the drainage from the parenchyma, but as the perivascular connective tissue. The trachea fluid leakage increases, normal drainage and bronchi are usually normal in mechanisms become progressively over- appearance. This contrasts with the findings whelmed. After an asymptomatic or latent in chlorine and chloropicrin poisoning in period of 20 min to 24 h (depending on the which both structures may show serious exposed dose), fluid leakage into the damage to the epithelial lining with pulmonary interstitium decreases comp- desquamation. The lungs are large, liance producing a stiff lung and increasing oedematous and darkly congested. Oedema complaint of tight chest, shortness of breath, fluid, usually frothy, pours from the bronchi and dyspnoea. Fluid eventually invades the and may be seen escaping from the mouth alveoli and produces clinically evident and nostrils (Figure 26). With exposure to pulmonary oedema. very high concentrations, death may occur The distinction between centrally and within several hours; in most fatal cases peripherally acting agents is not strict. pulmonary oedema reaches a maximum in 379 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from

12h, followed by death in 24 to 48h. If the support, such patients are at high risk of casualty survives, resolution commences death. Complications include infection of within 48h and, in the absence of comp- damaged lungs and delayed deaths following licating infection, there may be little or no such respiratory infections. residual damage. Condition of Exposed Tissues Clinical Effects Pre-existing airway damage (such as that Exposure to high concentrations of lung caused by prior exposure to a lung damaging damaging agent may irritate moist mucous agent) may seriously compromise the membranes, depending on their reactivity respiratory system’s normal protection and and solubility in water. Transient burning clearance mechanisms. Cigarette smoking sensation in the eyes with lacrimation may may severely compromise airway function coexist with early onset cough and a with respect to both airway patency and substernal ache with a sensation of pressure. clearance mechanisms. Hyper-reactive Irritation of the larynx by very large airways (asthma in varying degrees) are seen concentrations of the agent may lead to in up to 15% of the adult population. sudden laryngeal spasm and death. Exposures to pulmonary intoxicants may Pulmonary oedema follows a clinically trigger bronchospasm in these individuals. latent period of variable length that depends This bronchospasm may delay the clearance primarily on the intensity of exposure (i.e., of the agent, interfering further with gas the Ct), but also partly on the physical transport. The development of an acute activity of the exposed individual. This is interstitial process (e.g. phosgene-related particularly true for phosgene. After the pulmonary oedema) may also trigger latent period, the patient experiences bronchospasm. Individuals with any of the worsening respiratory distress that at first is following characteristics should be unaccompanied by objectively verifiable considered likely to develop bronchospasm signs of pulmonary damage, but may as the result of a exposure to lung damaging progress relentlessly to pulmonary oedema agents: and death. - Prior history of asthma or hay fever (even The most prominent symptom following as a child). the clinical latent period is dyspnoea, - Prior history of eczema. perceived as shortness of breath, with or - Family history of asthma, hay fever, or without chest tightness, and in the initial eczema. stages there may be no objectively verifiable - History of chronic sinusitis or seasonal signs of pulmonary damage. These rhinitis. sensations reflect hypoxemia, increased

ventilatory drive, and decreased lung Individuals with hyper-reactive airways will http://militaryhealth.bmj.com/ compliance, all of which result from the benefit from bronchodilator therapy and accumulation of fluid in the pulmonary possibly from steroids after exposure to a interstitium and peripheral airways. Fine lung damager.This statement, however, does crackles appear at the lung bases, but these not constitute an endorsement for routine may not be clearly audible unless steroid use in all toxic inhalational injuries. auscultation is conducted after a forced expiration. Later, auscultation reveals coarse Differential Diagnosis crackles and râles in all lung fields, and Phosgene is distinguished by its odour, its increasing quantities of thin, watery generalised mucous membrane irritation in secretions are noted. The build-up of fluid in high concentrations, dyspnoea, and the lungs has two clinically pertinent effects. pulmonary oedema of delayed onset. on September 29, 2021 by guest. Protected copyright. Riot-control agents produce tearing along 1. Developing pulmonary oedema interferes with burning and pain sensation with oxygen delivery to alveolar capillaries predominantly in the eyes, upper airways, and may lead to hypoxemia. If a sufficient mucous membranes and skin. This irritation percentage of haemoglobin is unoxygen- is typically more intense than that caused by ated, cyanosis will become apparent. phosgene and is unaccompanied by the 2. The sequestration of plasma-derived fluid distinctive odour of phosgene. in the lungs (up to one litre per hour) may Nerve agents induce the production of lead to hypovolemia and hypotension. watery secretions as well as respiratory Death results from respiratory failure, distress; however, their other characteristic hypoxemia, hypovolemia, or a comb- effects (e.g. muscle twitching, miosis) ination of these factors. Hypoxia and distinguish nerve agent toxicity from hypotension may progress particularly organohalide inhalation injury. rapidly and suggest a poor prognosis. Vesicants usually produce a delayed The development of symptoms and signs respiratory toxicity associated predominantly of pulmonary oedema within four hours of with the central, rather than the peripheral exposure is an especially accurate indicator airways. Vesicant inhalation severe enough to of a poor prognosis; in the absence of cause dyspnoea typically causes signs of immediately available intensive medical airway necrosis, often with pseudomembrane 380 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from formation and partial or complete upper TREATMENT OF TOXIC airway obstruction. Finally, pulmonary INHALATIONAL INJURY parenchymal damage following vesicant exposure usually manifests itself as Medical Management haemorrhage rather than pulmonary Terminate exposure as a vital first measure. oedema. This may be accomplished by physically removing the casualty from the hazard Clinical Investigations environment or by protecting with a properly Sophisticated laboratory studies are of fitting respirator. Decontamination of liquid limited value in the immediate care of an agent on clothing or skin terminates exposed, injured individual. The following exposure from that source. studies are of some predictive value in Execute the ABCs of resuscitation as required. determining the severity of exposure and the Establishing an airway is especially crucial in likely outcome. a patient exhibiting hoarseness or stridor; such individuals may face impending Chest Radiograph laryngeal spasm and require intubation. The presence of hyperinflation suggests toxic Establishing a clear airway also aids in injury of the smaller airways, which results in interpretation of auscultatory findings. Steps air being diffusely trapped in the alveoli. The to minimise the work of breathing must be presence of "batwing" infiltrates suggests taken. Because of the danger of hypotension pulmonary oedema secondary to toxic induced by pulmonary oedema or positive alveolar-capillary membrane damage. Atelec- airway pressure, accurate determination of tasis is often seen with more-central-toxic the casualty's circulatory status is vital, not inhalant exposures. As radiological changes just initially, but also at regularly repeated may lag behind clinical changes by hours to intervals and whenever indicated by the days, the chest radiograph may be of limited clinical situation. Carefully replace intra- value, particularly if normal. vascular volume as required to maintain hemodynamic stability. Arterial Blood Gases Enforce rest. Even minimal physical Hypoxia often results from exposure to lung exertion may shorten the clinical latent damaging materials such as chlorine. period and increase the severity of Measurement of the partial pressure of respiratory symptoms and signs in an oxygen (PO2) is a sensitive but non-specific organohalide casualty. Physical activity in a tool in this setting; both the central and symptomatic patient may precipitate acute peripheral effects of pulmonary intoxicants clinical deterioration and even death. Strict may produce hypoxia. Arterial blood gases limitation of activity (i.e. forced bed rest) and may show a low PaO2 or PaCO2, which are litter evacuation are mandatory for patients http://militaryhealth.bmj.com/ early, nonspecific warnings of increased suspected of having inhaled any agent that interstitial fluid in the lung. At 4 to 6h, might cause pulmonary oedema. This is true normal arterial blood gas values are a strong whether or not the patient has respiratory indication that a particular exposure has little symptoms and whether or not objective likelihood of producing a lethal effect. evidence of pulmonary oedema is present. Typically, carbon dioxide elevation is seen in Manage airway secretions and prevent/treat individuals with underlying hyper-reactive bronchospasm. Unless super-infection is airways; in this circumstance, it is thought present, secretions present in the airways of that bronchospasm is triggered by exposure phosgene casualties are usually copious and to the chemical.

watery. They may serve as an index to the on September 29, 2021 by guest. Protected copyright. degree of pulmonary oedema and do not Haematocrit require specific therapy apart from suction An increase in the hematocrit may reflect the and drainage. Antibiotics should be reserved hemoconcentration induced by transudation for those patients with an infectious process of fluid into the pulmonary parenchyma. documented by sputum gram-staining and culture. An elevation of the partial pressure Pulmonary Function Tests of carbon dioxide (PCO2) greater than 45 Peak expiratory flow rate may decrease soon mm Hg suggests that bronchospasm is the after a massive exposure. This non-specific most likely cause of hypercarbia, therefore test helps to assess the degree of airway bronchodilators should be used aggressively. damage and the effect of bronchodilator Bronchospasm may occur in individuals with therapy. Decreased lung compliance and reactive airways, and these patients should carbon dioxide diffusing capacity are receive beta-adrenergic bronchodilators. particularly sensitive indicators of interstitial Steroid therapy is also indicated for fluid volume in the lung, but are complex bronchospasm. Parenteral administration is tests for hospital use only. Ventilation/ the preferred route of steroid administration perfusion ratio (V/Q) scanning is very as inhaled routes may result in inadequate sensitive but is nonspecific and for hospital distribution to damaged airways. Methyl- use only. prednisolone, 700-1000 mg or its equivalent, may be given intravenously in divided doses 381 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from

during the first day and then tapered during has a degree of airway irritability or the duration of the clinical illness. The hypersensitivity, as exemplified by persons increased susceptibility to bacterial infection with asthma. These individuals are likely to during steroid therapy mandates careful display heightened sensitivity or even surveillance of the patient. No human bronchospasm, non-specifically after an studies have shown any benefit from steroids, inhalational exposure. The use of systemic thus steroids are not recommended in steroids would be indicated in this individuals without evidence of overt or population if their bronchospasm was not latent reactive airway disease. readily controlled with more routine Prevent/treat pulmonary oedema. Positive bronchodilators. If used in this setting, airway pressure provides some control over systemic steroids may be required for the clinical complications of pulmonary prolonged periods, particularly if super- oedema. Early use of a positive pressure infection should supervene. Inhaled steroids mask may be beneficial. Positive airway may be less effective than systemic steroids in pressure may exacerbate hypotension by circumstances of acute exposure, especially if decreasing thoracic venous return, later infected. Inhaled steroids appear most necessitating intravenous fluid admin- useful as an adjunct to the gradual reduction istration and perhaps judicious use of the or weaning or both from a systemic steroid pneumatic anti-shock garment. Pulmonary use. oedema noted after a toxic inhalant exposure should be treated similarly to adult Combined Injuries respiratory distress syndrome (ARDS) or Acute lung injury may complicate "noncardiac" pulmonary oedema. The early resuscitation and aggravate hypovolaemic application of PEEP is desirable, possibly shock associated with traumatic injury. In delaying or reducing the severity of such cases the latent period between pulmonary oedema. Diuretics are of limited exposure and the development of pulmonary value; however, if diuretics are used, it is oedema may also be shortened useful to monitor their effect by means of the pulmonary artery wedge pressure Triage measurement because excessive diuretics Patients seen within 12 h of exposure. A patient may predispose the patient to hypotension if with pulmonary oedema only is classified PEEP or positive-pressure ventilation is immediate if intensive pulmonary care is applied. immediately available. In general, a shorter Prevent/treat hypoxia. Oxygen therapy is latent period portends a more serious illness. definitely indicated and may require A delayed patient is dyspnoeic without supplemental positive airway pressure objective signs and should be observed

administered via one of several available closely and re-triaged hourly. An http://militaryhealth.bmj.com/ devices for generating intermittent or asymptomatic patient with known exposure continuous positive pressure. Intubation should be classified minimal and observed with or without ventilatory assistance may be and re-triaged every two hours. If the patient required, and positive pressure may need to remains asymptomatic 24 h after exposure, be applied during at least the end-expiratory discharge the patient. If exposure is doubtful phase of the ventilator cycle. and the patient remains asymptomatic 12 h Prevent/treat hypotension. Sequestration of following putative exposure, consider plasma-derived fluid in the lungs may cause discharge. An expectant patient presents hypotension that may be exacerbated by with pulmonary oedema, cyanosis and positive airway pressure. Urgent intravenous hypotension. A casualty who presents with administration of either crystalloid or colloid these signs within 6 h of exposure generally on September 29, 2021 by guest. Protected copyright. (which in this situation appear equally will not survive; a casualty with the onset of effective) may need to be supplemented by these signs 4 h or longer after exposure may the judicious application of the pneumatic survive with immediate, intensive medical anti-shock garment. The use of vasopressors care. is a temporary measure until fluids can be Patients seen more than 12 h after exposure. A replaced. patient with pulmonary oedema is classified immediate provided he will receive Steroid Therapy intensive care within several hours. If Systemic steroid therapy has been con- cyanosis and hypotension are also present, sidered for use in certain toxic inhalational triage the patient as expectant.A delayed exposures. Human evidence of benefit from patient is dyspnoeic and should be observed steroids in phosgene exposure is scanty. closely and re-triaged every 2 h. If the There is some support in the literature for patient is recovering, discharge 24 h after steroid use in exposure to zinc/zinc oxide and exposure. An asymptomatic patient or oxides of nitrogen. However, there is no patient with resolving dyspnoea is classified other strong support in the literature for the minimal. If the patient is asymptomatic 24 treatment of other specific toxic inhalations h after exposure, he is fit for discharge. A with systemic steroids. patient with persistent hypotension despite A significant percentage of the population intensive medical care is expectant. 382 J R Army Med Corps: first published as 10.1136/jramc-148-04-07 on 1 December 2002. Downloaded from

Further Reading Chemical Warfare Service, Edgewood Arsenal, MD, and Diller WF. Pathogenesis of Phosgene Poisoning.Department the Department of Medicine, Johns Hopkins Hospital, of Occupational Health, BayerAG, D-5090 Leverkusen, Baltimore, MD, March 4, 1946. Federal Republic of Germany. Gilchrist HL. "The Residual Effects of Warfare Gases: Diller WF, Zante R. A Literature Review: Therapy for The Use of Phosgene Gas, with Report of Cases." the Phosgene Poisoning. Department of Occupational Health, Medical Bulletin of the Veterans' Administration, Vol 10, No Bayer AG, D-5090 Leverkusen and University of 1, July 1933. Dusseldorf, Federal Republic of Germany. Polednak AP, Hollis DR. "Mortality and Causes of Diller WF. "Late Sequelae After Phosgene Poisoning: A Death Among Workers Exposed to Phosgene in 1943- Literature Review." Toxicology and Industrial Health, Vol 1945." Toxicology and Industrial Health, Vol 1, No 2, 1, Mo 2, 1985. 1985. Diller WF. "Early Diagnosis of Phosgene Overexposure." Regan RA. "Review of clinical Experience in Handling Toxicology and Industrial Health. Vol 1, Mo 2, 1985. Phosgene Exposure Cases."Toxicology and Industrial Diller WF. Therapeutic Strategy in Phosgene Poisoning. Health, Vol 1, No 2, 1985. Department of Occupational Health, Bayer AG, D-5090 Seidelin R. the Inhalation of Phosgene in a Fire Leverkusen, Federal Republic of Germany. Extinguisher. Royal Air Force Hospital Nocton Hall, Galdston M. Hopson, et al. A Study of the Residual Effects May 6, 1960. of Phosgene Poisoning in Human Subjects: I. After Acute Wells BA. "Phosgene: A Practitioner's Viewpoint." Exposure. Clinical Research Section, Medical Division, Toxicology and Industrial Health, Vol 1, No 2, 1985. http://militaryhealth.bmj.com/ on September 29, 2021 by guest. Protected copyright.