Chlorine gas is a pulmonary irritant with intermediate water solubility that causes acute damage in the upper and lower respiratory tract. Chlorine gas was first used as a chemical weapon at Ypres, France, in 1915. Of the 70,552 American soldiers poisoned with various gases in World War I, 1843 were exposed to chlorine gas.[1]
Chlorine is a greenish-yellow, noncombustible gas at room temperature and atmospheric pressure. Its intermediate water solubility accounts for the effect on the upper airway and lower respiratory tract.[2] Prolonged exposure to chlorine gas may occur because its moderate water solubility delays onset of upper airway symptoms for several minutes. In addition, the density of the gas is greater than that of air, causing it to remain near ground level and increasing exposure time. The odor threshold for chlorine is approximately 0.3-0.5 parts per million (ppm); however, distinguishing toxic air levels from permissible air levels may be difficult until irritative symptoms are present. As the concentration of chlorine gas exposure increases, the severity of symptoms and rapidity of onset increase. Concentrations above 400 ppm are often fatal.[3]
Chlorine is moderately soluble in water and reacts in combination to form hypochlorous (HOCl) and hydrochloric (HCl) acids. Elemental chlorine and its derivatives, hydrochloric and hypochlorous acids, may cause biological injury. The chemical reactions of chlorine combining with water and the subsequent derivative reactions with HOCl and HCl are as follows:
a1) Cl2 + H2 O ⇔ HCl (hydrochloric acid) + HOCL (hypochlorous acid) or
a2) Cl2 + H2 O ⇔ 2 HCl + [O-] (nascent oxygen)
b) HOCl ⇔ HCl + [O-]
Mechanism of activity
The mechanisms of the above biological activity are poorly understood and the predominant anatomic site of injury may vary, depending on the chemical species produced. Because of its intermediate water solubility and deeper penetration, elemental chlorine frequently causes acute damage throughout the respiratory tract.[2] Cellular injury is believed to result from the oxidation of functional groups in cell components, from reactions with tissue water to form hypochlorous and hydrochloric acid, and from the generation of free oxygen radicals. Although chlorine was at one time thought to cause direct tissue damage by generating free oxygen radicals,[4] this concept is now considered controversial.[5, 6]
Solubility effects
While chlorine gas is only moderately soluble in water, hydrochloric acid is highly soluble. The predominant targets of the acid are the epithelia of the ocular conjunctivae and upper respiratory mucus membranes.[7]
Hypochlorous acid is also highly water soluble with an injury pattern similar to hydrochloric acid. Hypochlorous acid may account for most of the toxic effects of elemental chlorine and hydrochloric acid to the human body.[8]
Early response to chlorine gas
Chlorine gas, when mixed with ammonia, reacts to form chloramine gas. In the presence of water, chloramines decompose to ammonia and hypochlorous acid or hydrochloric acid.[9] The early response to chlorine exposure depends on the (1) concentration of chlorine gas, (2) duration of exposure, (3) water content of the tissues exposed, and (4) individual susceptibility.[10]
Immediate effects
The immediate effects of chlorine gas toxicity include acute inflammation of the conjunctivae, nose, pharynx, larynx, trachea, and bronchi. Irritation of the airway mucosa leads to local edema secondary to active arterial and capillary hyperemia. Plasma exudation into the alveoli results in pulmonary congestion and edema.
Pathologic findings
Pathologic findings are nonspecific. They include pulmonary edema, pneumonia, hyaline membrane formation, multiple pulmonary thromboses, and ulcerative tracheobronchitis.[11]
The hallmark of pulmonary injury associated with chlorine toxicity is pulmonary edema, manifested clinically as hypoxia. Noncardiogenic pulmonary edema is thought to occur when there is a loss of pulmonary capillary integrity, and subsequent transudation of fluid into the alveolus. The onset can occur within minutes or hours, depending upon severity of exposure. Persistent hypoxemia is associated with a higher mortality rate.
The eye is rarely damaged severely by chlorine gas toxicity; however, burns and corneal abrasions have occurred. Acids formed by the chlorine gas reaction with the conjunctival mucous membranes are buffered, in part, by the tear film and the proteins present in tears. Consequently, acid burns to the eye typically cause epithelial and basement membrane damage but rarely damage deep endothelial cells. Acid burns to the periphery of the cornea and conjunctiva often heal uneventfully, while burns to the center of the cornea may lead to corneal ulcer formation and subsequent scarring.
In animal models of chlorine gas toxicity, immediate respiratory arrest occurs at 2000 ppm, with the lethal concentration for 50% of exposed animals in the range of 800-1000 ppm.[8] Bronchial constriction occurs in the 200-ppm range with evidence of effects on ciliary activity at exposure levels as low as 18 ppm. With acute exposures of 50 ppm and subacute inhalation as low as 9 ppm, chemical pneumonitis and bronchiolitis obliterans have been noted. Mild focal irritation of the nose and trachea without lower respiratory effects occur at 2 ppm.
The extent of tissue response varies with both the concentration of exposure as well as underlying tissue sensitivity. In one study of chlorine gas toxicity conducted on human volunteers, 4 hours of exposure to chlorine at 1 ppm produced significant decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow rate, as well as an increase in airway resistance.[12] Volunteers with hyperreactive airways were noted to experience an exaggerated airway response to exposure of 1 ppm chlorine gas.[13] While in another study, patients with rhinitis and advanced age demonstrated a significantly greater nasal mucosal congestive response to chlorine gas challenge than patients who did not have rhinitis or those of younger age.[14]
Chlorine gas is one of the most common single irritant inhalation exposures, both occupationally and environmentally. In 1983, an estimated 191,000 US workers were at risk of exposure to chlorine in various forms.[15] In a recent study of 323 cases of inhalation exposures reported to poison control centers, the largest single source of exposure (21%) was caused by mixing bleach with other products.[16] The greatest number of victims were injured in manufacturing and the entertainment and recreation services sectors.
International
Internationally, chlorine gas accounts for the largest single cause of major toxic release incidents.[17] Use of chlorine internationally is parallel to use by the US in chemical, paper, and textile industries and in sewage treatment.
Chlorine gas has been used as a mechanism of injury in intentional exposures due to its availability and potential for mass casualty injury. First used in World War I, it has been used more recently in attacks in Iraq[18] and is considered a potential cause of serious mass casualty terrorist activity at home and abroad.[19]
Mortality/Morbidity
Five-year cumulative data (1988-1992) from the American Association of Poison Controls Centers' National Data Collection System revealed 27,788 exposures to chlorine. Of these exposures, the outcome was categorized in 21,437 cases; 40 resulted in a major effect, 2091 resulted in a moderate effect, 17,024 resulted in a minor effect, and 2099 had no effect. Three fatalities occurred.[20, 21, 22, 23, 24] Another case series associated worse outcomes with advanced age, initial low peak expiratory flow rate (PEFR), exposure in an enclosed space, and prolonged short- and long-term exposure.
Minor effects include signs or symptoms that are minimally bothersome and quickly resolved.
Moderate effects include signs or symptoms that are more pronounced or more prolonged than minor effects. These may have a systemic nature and usually require some form of treatment.
Major effects include signs or symptoms that are life-threatening or result in significant residual disability or disfigurement.
Chlorine gas is one of the most common single irritant inhalation exposures, both occupationally and environmentally. Possible sources of exposure are as follows:
Industrial bleaching operations
Sewage treatment
Household accidents involving the inappropriate mixing of hypochlorite cleaning solutions with acidic agents
Transportation releases
Swimming pool chlorination tablet accidents[26]
Storage tank failure
Chemical warfare
Adverse effects of inappropriate mixtures of household cleaners usually are caused by prolonged exposure to an irritant gas in a poorly ventilated area. The most common mixtures of cleaning agents are sodium hypochlorite (bleach) with acids or ammonia. Potential irritants released from such mixtures are chlorine gas, chloramines, and ammonia gas.
Abnormalities include hypoxia[10] and metabolic acidosis.
The metabolic acidosis may be hyperchloremic (nonanion gap). This may be caused by the absorption of hydrochloric acid following the reaction of chlorine gas with water.[27, 28]
Prehospital care providers should take necessary precautions to prevent contamination. The use of a chemical cartridge respirator or self-contained breathing apparatus with full face mask should protect against the effects of chlorine gas on the upper and lower airways.. This, corresponds to an OSHA level A or level B PPE with positive pressure self-contained breathing apparatuses with full face plates as well as protective over garments.[19] ,[30] Chemical-protective clothing should be worn because chlorine gas can condense on the skin and cause irritation and burns.[3] Staging areas should be situated upwind of the chlorine gas site.
Remove the individual from the toxic environment.
Bring container, if applicable, so medical personnel can identify toxic agent.
Commence primary decontamination of the eye and skin, if necessary.
Real-time measurement of chlorine gas, both quantitative and qualitative, is possible through the use of mobile equipment.
Chlorine gas is denser than air and accumulates close to the ground. Therefore, during chlorine-related accidents, people should be instructed to seek higher altitudes to avoid excessive exposure.
For related information, see Medscape's Disaster Preparedness and Aftermath Resource Center.
Eye and skin exposures require copious irrigation with saline. Duration of skin irrigation, although not well studied, should probably be from 3-5 minutes.[3]
In cases of suspected ocular injury, determine initial pH using a reagent strip. Continue irrigation with 0.9% saline until the pH returns to 7.4.
ED healthcare worker protection
Chlorine gas exposure, as opposed to liquid chlorine exposure, is unlikely to result in off-gassing.
Supplemental humidified oxygen
Maintain a PaO2 of 60 mm Hg or greater.[31]
Long-term (>24 h) elevated fraction of inspired oxygen (FIO2) greater than 50% may result in oxygen toxicity.
Fluid restriction
Fluid restriction is indicated in patients with ARDS.
Treatment of bronchospasm
Bronchodilators (inhaled albuterol or other beta-agonists) have been used frequently for the management of respiratory symptoms. Animal models have demonstrated improvements in blood gas parameters, airway pressure, and lung compliance with the administration of aerosolized terbutaline.
The role of inhaled ipratropium is not well defined.
Lidocaine (1% solution) added to nebulized albuterol results in both analgesia and cough-suppression.
Intubation for laryngospasm
Fiberoptic aid may be required if significant edema is present.
Consider using the largest size endotracheal tube possible to optimize pulmonary toilet.
Hypoxemic respiratory failure
Treat with positive-pressure ventilation.
High positive end-expiratory pressure (PEEP) (8-10 mm Hg) and inverse ratio ventilation may be beneficial in ARDS.
In an animal model, prone positioning immediately following exposure to chlorine gas improved pulmonary function, whereas treatment in the supine position was associated with further compromise of pulmonary gas exchange.[32]
Sodium bicarbonate
Use of nebulized solution of sodium bicarbonate, although recommended by some authors,[33, 34, 35] lacks sufficient evidence that demonstrates clinically relevant outcomes.
The mechanism of action is thought to be due to neutralization of hydrochloric acid formed when chlorine gas comes into contact with water. Lack of clinical trials and the theoretical possibility that an exothermic reaction may be produced when bicarbonate mixes with hydrochloric acid have led some authors to question its use.[10, 36, 37] Nonetheless, several pediatric and adult case reports describe clinical improvement in patients with chlorine gas induced pulmonary injury treated with inhaled sodium bicarbonate.
In a randomized, controlled trial 44 patients received either nebulized sodium bicarbonate (4 mL of 4.20% NaHCO3 solution) or saline treatment following chlorine gas exposure.[38] Treatment of all patients included corticosteroids and nebulized, short-acting β2-agonists. Compared to the placebo group, the NaHCO3 group had significantly higher FEV1 values at 120 and 240 min but no significant difference in quality of life questionnaire scores.
Steroids
Parenteral steroids, while advocated by some authors to prevent short-term reactions and long-term sequelae,[39, 40] are not recommended by others[10] because of insufficient clinical trials.
Animal studies suggest improvements in pulmonary function and lung compliance with treatment of inhaled steroids, alone and in conjunction with aerosolized beta-agonists. Earlier administration of inhaled steroids in animal studies was associated with more beneficial effects. Inhaled corticosteroid use, although reported,[35] has not been subjected to rigorous human study.
Ocular exposures
Topical anesthetics help limit pain and improve patient cooperation during initial evaluation and management.
Following irrigation, perform slit lamp examination, including fluorescein staining.
Beta-agonists, although not well studied in humans, have been widely used for the management of respiratory symptoms in chlorine gas exposure, and they have demonstrated efficacy in animal models. They should be considered a first-line agent in the setting of chlorine gas exposure and respiratory symptoms or signs.
Clinical Context:
Beta-agonist for bronchospasm. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.
Anti-inflammatory inhaled corticosteroids have been shown in animal models to improve respiratory function following experimental chlorine gas exposure. Exact mechanism of function in chlorine gas exposure unclear.
Clinical Context:
Theoretical reason for use is to reduce tissue injury caused by the acidic agent in airway. Potential decreased benefit if not administered immediately postexposure. Route of administration is inhalation via nebulizer.
Consider hospitalization to observe and treat the patient with chlorine gas exposure in a highly monitored setting in any of the following cases:
Symptoms persist after 6 hours.
Patient was severely exposed (eg, prolonged exposure, exposure in an enclosed space, high concentration of chlorine gas).
Child was exposed.
Patient has a history of underlying respiratory or cardiovascular disease.
Some authors suggest observation for a minimum of 24 hours because pulmonary edema may occur for 24 hours after exposure. Patients who are asymptomatic 24 hours after exposure may be discharged from hospital.[41]
Deterrence may decrease the number of accidental exposures to chlorine gas. Proper descriptions on swimming pool chlorinator solutions with detailed warnings to avoid mixing solutions would prevent a great number of accidents.
As accidental occupational exposures to chlorine gas comprise a significant percentage of severe exposures, proper methods of training and supervision are beneficial. Enforcement of existing work safety regulations may lead to fewer exposures.
Long-term exposure to small amounts of chlorine gas may contribute to pulmonary disease.
The current US legal limit for occupational exposure to chlorine gas enforceable by the Occupational Safety and Health Administration (OSHA) is 0.5 ppm averaged over a 10-hour day or a 40-hour work week and a short-term exposure limit of 1 ppm.[42, 43]
Short-term effects of acute exposures of chlorine gas
Smokers and those with asthma are most likely to demonstrate persistence of obstructive pulmonary defects.[4]
In serious exposures, sloughing of the pulmonary mucosa occurs in 3-5 days, and oozing areas become covered with mucopurulent exudate. This chemical pneumonitis is often complicated by secondary bacterial invasion.
Residual effects following acute exposures of chlorine gas
Long-term follow-up studies of acute human exposures to chlorine gas provide conflicting data on the potential for long-term adverse effects from short-term chlorine exposure.
In one study, after 2 years of follow-up, research subjects displayed decreased vital capacity, diffusing capacity, and total lung capacity with a trend towards higher airway resistance.[44] This suggests that persistent dose-related lung function deficits may occur following acute chlorine gas exposure.
Other studies demonstrated no consistent pattern of pulmonary function deficits following acute exposure.[45, 29, 46, 47]
Jones et al found that long-term sequelae after acute chlorine gas exposure were more affected by cigarette smoking than by the chlorine gas exposure.[4]
Although no definite conclusion can be drawn concerning the long-term effects of an acute chlorine gas exposure, findings point to a persistent increased nonspecific airway responsiveness. Following an acute exposure, some patients displayed eventual repair of injured pulmonary epithelium with fibrosis.[48] Bronchiolitis obliterans and emphysema have also been described in patients following acute exposures.
Irritant-induced asthma (formerly known as reactive airway dysfunction syndrome [RADS]), is a variant of occupational asthma that occurs in individuals who are acutely exposed to high concentrations of an irritant product and develop respiratory symptoms in the minutes or hours that follow.[49] They develop persistent bronchial hyperresponsiveness after the inhalational incident.[50] A similar pathology may occur with repeated exposures.[51]
Persistent anxiety following acute exposure to chlorine gas has been observed. In one large scale accident, 37% of respondents were classified as having a positive posttraumatic stress (PTTS) screen 8-10 months post disaster, about half of which (44%) were considered severe. Twenty-seven percent of all individuals were found to have a positive indication for tendency to panic. Severe PTTS score was independently associated with FEV1, acute injury, and the HPSI Psychiatric Subscale, and the latter two were also associated with a moderate PTS score. Tendency to panic was significantly associated with acute injury and female sex.[52]
Hypoxia on room air and PO2/FiO2 ratio predicted severity of outcome as assessed by the duration of hospitalization and the need for intensive care support.[18]
Resolution of pulmonary abnormalities in most individuals occurs over the course of one week to one month following exposure.
Eli Segal, MD, CM, FRCP, Assistant Professor, Department of Family Medicine, McGill University; Attending Physician, Department of Emergency Medicine, Jewish General Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Eddy S Lang, MDCM, CCFP(EM), CSPQ, Associate Professor, Senior Researcher, Division of Emergency Medicine, Department of Family Medicine, University of Calgary Faculty of Medicine; Assistant Professor, Department of Family Medicine, McGill University Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
Specialty Editors
Peter MC DeBlieux, MD, Professor of Clinical Medicine and Pediatrics, Section of Pulmonary and Critical Care Medicine, Program Director, Department of Emergency Medicine, Louisiana State University School of Medicine in New Orleans
Disclosure: Nothing to disclose.
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center
Disclosure: Nothing to disclose.
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
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.
References
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