Human chlorine gas exposition and its management – an umbrella review on human data

Figures & data

Figure 1. PRISMA flow diagram.

Table 1. Characteristics of excluded studies.

Study	Reason for exclusion
(Hoyle and Svendsen 2016)	No treatment nor case report
(Pino et al. 1993)	Full article not available
(Russell et al. 2006)	Critical review of the literature
(Traub et al. 2002)	Full article not available

Table 2. Characteristics of included studies with a comparator.

Study ID		Population					Exposure		Management				Outcome
Author (year)	Study design	Geographic location	Number of cases	Female, %	Children, %	Age (years)	Circumstances	Duration	Pre-hospital care	Testing (besides vital signs and chest auscultation)	Treatment	Follow-up (time between exposure and outcome assessment)	Recovery/Discharge with treatment or sequelae / Death
(Aslan et al. 2006)	RC	Turkey	44	91	Unknown	17–56 (mean: 33 ± 10)	Exposure to sodium hypochlorite (NaOCl) or to a mixture of NaOCl with hydrochloric acid (HCl) during cleaning of bathroom-kitchen, toilet room or other	<1h for 28 patients 1–3h for 12 patients >3h for 4 patients	Unknown	Chest x-ray Electrocardiogram Arterial blood gas Blood cell count Pulmonary function tests	Standard therapy with intravenous corticosteroid (prednisolone, 1 mg/kg/day) Short-acting β2-agonist (salbutamol inhaler, 5 mg) Nebulized sodium bicarbonate (4 cm^3 of 4.20% sodium bicarbonate solution) or nebulized placebo	240 minutes	Discharged after clinical improvement
(Chester et al. 1977)	CR	USA	2	100	0	28–30	Exposed in the same room of their home during an industrial accident	Unknown	Unknown	Chest x-ray Spirometric studies Arterial blood gas Flow expiratory rates test Pulmonary functions test Measurement of the Residual volume (RV), airway resistance (Raw) and specific airway resistance (SRaw)	Patient 1: Therapy with oxygen only Patient 2: Therapy with oxygen + corticosteroid Intramuscular injection of 100 mg of hydrocortisone + oral dose of 60 mg of prednisone Oral therapy with continuous daily prednisone for 2 days, then daily reduced to 45 mg daily	55 months for patient 1 24 months for patient 2	Discharged without further examination

CR: case report, RC: randomized controlled study.

Table 3. Characteristics of included studies without comparator.

Study ID		Population					Exposure		Management				Outcome
Author (year)	Study design	Geographic location	Number of cases	Female, %	Children, %	Age (years)	Circumstances	Duration	Pre-hospital care	Testing (besides vital signs and chest auscultation)	Treatment	Follow-up (time between exposure and outcome assessment)	Recovery/Discharge with treatment or sequelae / Death
(Akdur et al. 2006)	CR	Turkey	1	100	0	26	Inhalation of gas produced by a mixture of household cleaning products (5% sodium hypochlorite with the same amount of 18% hydrochloric acid)	Unknown	Unknown	Arterial blood gas Lung x-ray Computed tomography scan of the neck and thorax Lung roentgenograms	50% humidified oxygen via a non-rebreathing facemask Mixed ipratropium bromide and salbutamol nebulization Intravenous methylprednisolone and aminophylline infusions for the bronchospasm	6 days	Complete recovery
(Babu et al. 2008)	CR	USA	1	100	0	23	Exposure to a cloud of chlorine while relaxing at her hotel pool	Unknown	Supplemental oxygen + nebulized albuterol	Chest x-ray Arterial blood gas Blood cell count Beta-human chorionic gonadotropin (BHCG) Electrocardiogram Computed tomography scan of the thorax Fiberoptic bronchoscopy Transthoracic echocardiography Tracheostomy	Endotracheal intubation and ventilatory support Oxygen 250 mg of methylprednisolone received intravenously Bronchodilator therapy Inhaled triamcinolone 4 puffs 3 times a day (total of 1200 μg/d) 2 mg/kg of methylprednisolone bolus followed by 2 mg/kg in 2 divided doses per day Ventilator bundle Transfer to intensive care unit	28 days	Discharged with a 10 mg dose of prednisone and outpatient follow-up
(Bellenger and Frizzi 2014)	CR	Afghanistan	1	0	0	45	Workplace exposure to liquid chlorine without protection	Unknown	Unknown	Electrocardiogram Chest x-ray Arterial blood gas	Intubation Mechanical ventilator Oxygen + albuterol, 2.5 mg, with ipratropium by nebulizer Inhalation of albuterol via a metered dose every 30–45 min A regimen of 10 L/min of oxygen by mask	2 weeks	Discharged with advice on the use of albuterol inhaler
(Bosse 1994)	CS	USA	86	47	Unknown	5–71 (mean: 33.5)	Misuse of products (chlorine producing acid/hypochlorite mixtures) (63 patients) Industrial settings (6 patients) Swimming pool settings (12 patients) Bleach, chlorine powder or chlorine blocks for septic tank (4 patients)	Unknown	Unknown	Chest x-ray	Nebulized sodium bicarbonate (all the 86 patients, protocol) Inhaled bronchodilator (7 patients) Steroids (1 patient) Inhaled steroids (1 patient) Intravenous theophylline (1 patient)	1–3 days (mean: 1.4)	All discharged 2 patients with prescriptions for inhaled bronchodilators 1 patient on a course of outpatient steroids
(Carpenter et al. 2016)	CR	Sierra Leone	1	0	0	26	During routine maintenance procedures at the military-run Kerry Town Ebola Treatment Unit	Unknown	Remove personal protective equipment	Pulse oximetry Peak expiratory flow rate test Chest x-ray	15 L/min of oxygen Inhaled salbutamol 100 mg of intravenous hydrocortisone	<1 week	Discharged with retrosternal chest pain
(Cevik et al. 2009)	CR	Turkey	25	0	Unknown	22.04 ± 2.98 (mean)	Exposure from mixing sodium hypochlorite with hydrochloric acid during cleaning activities	∼ 4 h	Unknown	Chest x-ray Electrocardiogram (for 5 patients only) Pulse oximetry Pulmonary function test Haematological and biochemical parameters	Humidified oxygen combined with nebulized salbutamol Nebulized salbutamol Inhaled budesonide and nebulized sodium bicarbonate (4 mL 3.75% solution) Ampicillin-sulbactam Intravenous methylprednisolone	4 days (hospital mean stay)	All were discharged in good health 11 patients with inhaled budesonide and nebulized sodium bicarbonate
(Fleta et al. 1986)	CR	Spain	76	72	100	0–14	Accidental exposure during the routine procedure of chlorination of drinking water in 1981	Unknown	Unknown	Chest x-rays Anamnesis Auscultation Gasometry	Oxygen gas Corticosteroids (1 mg of Urbason/kg body weight)	12 hours	Discharged
(Gapany-Gapanavicius et al. 1982)	CR	Israel	2	0	0	24–27	Inhalation of gas liberated from a mixture of household cleaners (5% sodium hypochlorite with 10% hydrochloric acid)	About 1 min About 3 min	Unknown	Chest x-rays White blood cell count Blood gas analysis	Oxygen humidified 40% + terbutaline sulfate inhalations Intravenous aminophylline and hydrocortisone infusions (patient 1 only)	7 days 10 days	Discharged
(Güloğlu et al. 2002)	CS	Turkey	106	45	56.6	0.25–75	Accidental chlorine gas exposure in the city center of Diyarbakir	Unknown	Unknown	Chest x-ray Complete blood count Electrocardiogram Arterial blood gas	Oxygen inhalation (46 patients) Oxygen inhalation  + methylprednisolone (32 patients) Oxygen inhalation  + methylprednisolone  + salbutamol + digoxin (2 patients) Oxygen  + methylprednisolone  + salbutamol  + lidocoine  + antibiotherapy + sodium bicarbonate (1 patient)	24 hours	Discharged (69 patients) Hospitalized at 24 h (37 patients)
(Heidemann and Goetting 1991)	CR	USA	1	0	100	12	Accidental exposure at swimming pool	Unknown	Unknown	Chest x-ray Arterial blood gas White blood cell count Cardiovascular examination	Oxygen Intubation and mechanical ventilation with 100% oxygen Positive end-expiratory pressure Pancuronium bromide + sedation with morphine + infusion of midazolam Administration of theophylline Intravenous fluid Crystalloid infusion of 20 ml/kg	1 month	Discharged
(Ho et al. 2010)	CR	China	1	100	100	15	At a community swimming pool	6 min	Unknown	Arterial blood gas Chest x-ray Pulse oximetry Laboratory data including blood cell count Electrocardiogram	100% oxygen Intravenous fluid Corticosteroid Inhalation of β2 agonist every 6 hours Supplementary oxygen Oral prednisolone 10 mg Inhaled budesonide 2 puff every 8 hour for 4 days	5 days	Discharged with a follow-up x-ray
			6	Unknown	Unknown	Unknown		Probably <6 min		Unknown	Supplementary oxygen Intravenous fluid Inhaled β2 agonist therapy	1 day	Discharged
(Howard et al. 2007)	CR	USA	1	100	0	38	Misuse of cleaning products in the bathroom	Unknown	Unknown	Arterial blood gas Chest x-ray	Humidified oxygen At home treatment: Nebulized albuterol sulfate Nebulized sodium bicarbonate Eye irrigation with normal saline solution	3 hours	Discharged
(Kim et al. 2014)	CR	South Korea	2	0	0	35–38	Accidental release of chlorine gas in a factory in Gumi-si	Unknown	Unknown	Arterial blood gas Chest x-ray Pulmonary function test Blood cell count Chest computed tomography scan Bronchoscopy Peak expiratory flow rate test Pulse oximetry Hepatic function test Serum electrolyte test Urinalysis	100% oxygen (rate of 10 L/min) Empirical broad-spectrum antibiotics Inhaled corticosteroid Administration of a bronchodilator Inhalation therapy of salbuterol, budesonide, and ipratropium 4 times a day Treatment of metabolic acidosis, sodium bicarbonate Treatment of ascorbic acid, methylprednisolone, and third-generation cephalosporin antibiotics One patient moved to the intensive care unit	7 and 35 days	Discharged Patient 1 with inhaled corticosteroid and administration of bronchodilator for 6 months
			209	27	Unknown	<29 to >50				Chest x-ray Blood cell count Serum chemistry test Serum electrolyte test	Unknown	Within 1 hour to >6 hours	Discharged
(Li et al. 2011)	CR	China	2	50	100	13–15	Chlorine gas exposure at swimming-pool	About 2 min for one case	Unknown	Chest x-ray Arterial blood gas Electrocardiogram Pulse oximetry Blood cell count Chest computed tomography scan	Endotracheal intubation Ventilator-assisted breathing A skin incision 1 cm under the sternal notch Use of a continuous drainage tube One patient admitted to the intensive care unit	5 and 15 days	Discharged Patient 1 with oxygen therapy, respiratory support, glucocorticoid, anti-infection, and nutrition support treatment
(Mackie et al. 2014)	CR	USA	1069	Unknown	Unknown	Unknown	Train derailment carrying three tanker cars of liquid chlorine under pressure	Unknown	Unknown	Pulse oxygenation readings Arterial blood gas Portable x-rays	Oxygen Inhaled beta-agonists and ipratropium bromide Inhaled corticosteroids Oral corticosteroids Nebulized sodium bicarbonate Intubation Some patients admitted to an intensive care unit	4 days (median hospital stay)	Discharged (1060 patients) 8 patients died at the scene 1 patient died in hospital
(Mangat et al. 2012)	CR	Canada	1	0	100	2.6	Accidental chemical burn with chlorine bleach and Windex ammonia that had fallen on the child clothes	∼ 10 min	immediate removal of clothes Placed in the shower for ∼5 min Administration of high-flow oxygen on route to hospital	Chest x-ray Computed tomography scan of the head Electroencephalography	Irrigation with normal saline until the skin was neutralized to a normal pH Intubation Admission to intensive care unit Examination of the oral mucosa and posterior pharynx Delivery of enteral tube feeds Administration of Lasix Administration of 10 L/min of high-flow oxygen Extracorporeal membrane oxygenation	32 days	Died
(Matos et al. 2017)	CR	Brazil	1	0	0	55	When cleaning the swimming pool at his home	Unknown	Unknown	Arterial blood gas Chest x-ray Computed tomography scan Blood cell count Spirometry	Venous hydration Bronchodilators Oxygen therapy Noninvasive mechanical ventilation with 60% of fraction of inspired oxygen (FiO2) 7 cm H2O support pressure (SP) 10 cm H2O positive end expiratory pressure (PEEP) Admission to intensive care unit Antibiotic therapy with cefepime (2g every 8 hours) Intravenous corticosteroid (methylprednisolone 125 mg every 6 hours) Nebulization with a beta-agonist and an anticholinergic A Dixtal 3010 mechanical ventilator with a full-face mask interface Oxygen macro-nebulization	7 days	Discharged with bronchodilator and oral corticosteroid and with a follow-up x-ray
(Mohan et al. 2010)	CS	India	64	41	Unknow	Mean: 44 ± 6.4	During a leak in the chlorination system of the public bathing pool of a temple	Unknown	Unknown	Hemogram Serum biochemistry Chest x-ray Electrocardiogram Arterial blood gas Pulmonary function test Pulse oximetry Noninvasive blood pressure measurement	Humidified oxygen β-2 agonist nebulization Intravenous hydrocortisone Aminophylline administration Admitted to the intensive care unit (3 patients) Intravenous frusemide administration	5.1 ± 2.1 days (mean hospital stay)	Discharged 3 patients treated with inhaled salbutamol and budesonide at 3 months
(Myers 1997)	CR	USA	1	100	100	4	Inhaling fumes from a canister of chlorine tablets used in swimming pools	Immediate	Unknown	Chest x-ray Arterial blood gas Pulse oximetry Blood cell count Urinalysis	15 L/min of oxygen Furosemide (Lasix) 15 mg + dexamethasone (Decadron) 2.5 gm Midazolam (Versed) 5 mg Lidocaine 20 mg Morphine sulfate Intubation Nebulized albuterol 2.5 ml of Sodium bicarbonate + 2.5 ml of sterile saline solution Transferred to Intensive care unit	Unknown	Full recovery was expected
(Ngo et al. 2007)	CR	Singapore	36	50	50	1–62	Accidental mixing of sodium hypochloride with hydrochloric acid in the dosing tanks	Up to 15 min	Decontamination station outside of the emergency department	Chest x-ray Arterial blood gas Electrocardiogram Spirometry	Oxygen Nebulized salbutamol	6 weeks	28 patients discharged with advice 8 hospitalized and discharged
			464	Unknown	Unknown	Unknown			Unknown	Unknown	Unknown	Unknown	Unknown
(Parimon et al. 2004)	CR	USA	1	0	0	23	Accidental exposure at a community swimming pool	About 5 min	Unknown	Chest x-ray Arterial blood gas Computed tomography scan Blood cell count Pulmonary function tests	Supplementary oxygen Inhaled albuterol Oral corticosteroids Inhaled β2 agonist	5 months	Discharged on albuterol (via metered-dose inhaler, every 6 h) and prednisone (1 mg/kg/d, for a 4-week course)
(Sever et al. 2009)	CR	Turkey	39	18	74	2–66	Explosion of chlorine tank used to purify city water sources	Unknown	Unknown	Chest x-ray Blood cell count Electrocardiogram Arterial blood gas Consultations	Supplementary humidified oxygen Parenteral fluids (normal saline, dextrose and Isolyte) Methylprednisolone Ranitidine Ranitidine  + metoclopramide combination Inhaled salbutamol combination Wide spectrum antibiotic Theophylline measure Antibiotic measure combination Some patients admitted to intensive care unit	24 hours	Discharged 6 patients hospitalized
			129	Unknown	Unknown	Unknown		Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
(Shin et al. 2017)	CR	South Korea	1	100	0	74	Fell in her bathroom dropping a pouch of chlorine-containing bleach she was carrying and lost consciousness	∼1 hour	Unknown	Chest x-ray Computed tomography scan Arterial blood gas Blood cell count	Oxygen Broad-spectrum antibiotics Diuretics Intubation Mechanical ventilation	18 days	Transfer to a local clinic for further treatment of chemical burns (improvement of wounds before)
(Vajner and Lung 2013)	CR	USA	1	100	100	3	Exposed at neighborhood swimming pool by sitting near an outflow jet in children’s pool	∼45 sec	Administration of 15–30 min of continuous nebulized albuterol on the route to hospital	Chest x-ray Pulse oximetry	15 L/min of oxygen Nebulized albuterol/ipratropium bromide solution Nebulized mixture of 3 mL of 8.4 % sodium bicarbonate solution + 2 mL of normal saline Intravenous corticosteroids administration 1 h after nebulized sodium bicarbonate Transferred to the intensive unit care	15 hours	Recovery (breathing in room-air)
(Van Sickle et al. 2009)	CR	USA	71	13	0.01	0.3–76 (mean: 40)	Train derailment carrying three tanker cars of liquid chlorine under pressure	Unknown	Unknown	Pulse oximetry Arterial blood gas Chest x-ray Computed tomography scan Bronchoscopy Spirometry Pulmonary function test	Oxygen Intubation Nebulized or inhaled β-agonists Ipratropium bromide Inhaled corticosteroids Intravenous corticosteroids Oral corticosteroids Antibiotics Intravenous NaHCO3 Nebulized NaHCO3 Some patients admitted to intensive care unit	Between 1–29 days (median: 4 days)	1 died 70 discharged with prescription of medication: inhaled β-agonists, ipratropium bromide, inhaled corticosteroids, and oral corticosteroids
			526	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
(Vinsel 1990)	CR	USA	3	0	0	19–20	Exposed due to a leak in the chlorination system of an indoor pool at their workplace	Immediate	Unknown	Arterial blood gas Chest x-ray	Nebulized solution of 3.75% sodium bicarbonate	Unknown	Discharged
(Vohra and Clark 2006)	CR	USA	1	100	100	9	Inhalation of air bubbles mixed with granules of water purification tablets into the pool	Unknown	Unknown	Pulse oximetry Chest x-ray	Supplemental oxygen Nebulized bronchodilators every 2h Nebulized albuterol and ipratropium Inhaled sodium bicarbonate Antibiotics	2 days	Discharged with a 5-day course of montelukast and a metered-dose inhaled bronchodilator as needed for dyspnea
(Warren et al. 2016)	CR	USA	1	0	0	47	Inadvertently inhaled chlorine gas while mixing an industrial grade chlorine solution with a sulfuric acid solution	Immediate	Unknown	Arterial blood gas Chest x-ray	Endotracheal intubation Lung protective ventilation strategy (SIMV+, PEEP 12mm Hg, and Vt 700 mL/kg) Nebulized 20% N-acetylcysteine (3 mL/4h) Aerosolized heparin (10,000 U/mL/4h) Nebulized albuterol sulfate (0,5 mL/4h) Inhalation protocol continued for 7 days Tracheostomy on the postinjury day 8	38 days	Discharged with less than daily requirement for albuterol nebulized therapy
(Wenck et al. 2007)	CR	USA	597	41	Unknown	<1–85 (mean: 36)	Train derailment carrying three tanker cars of liquid chlorine under pressure	Up to 3 days	Wet decontamination	Unknown	Unknown	Unknown	9 deaths

CR: case report; CS: case series.

Figure 2. Summary of risk of bias assessment. N/A: Not applicable, #studies with comparator.

Table 4. Summary of findings.

Human chlorine gas exposition and its management
Population: any human exposure to chlorine gas
Settings: all countries and settings
Intervention: all the treatment and management
Comparator: oxygen and exposure cessation
Outcome	Intervention category	Assumed risk Number of participants (studies)	Quality of the evidence	Comments
Following chlorine inhalation: Recovery/discharge with treatment or sequelae/death	Exposure cessation	637 cases (6 CR)^a	⊕⊕ High	We upgraded 4 levels due to a large magnitude of effect and dose-response relationship between the duration before the exposure cessation and the outcome
	Oxygen gas administration	1512 cases (24 CR, 1 CS)^b	⊕⊝ Moderate^d	We upgraded 3 levels due to a large magnitude of effect and dose-response relationship between the duration before the exposure cessation and the outcome. Downgraded 1 level due to serious risk of bias and 1 level due to imprecision
	Other treatments (β2, corticosteroids, intubation, …)	3523 cases (27 CR, 2 CS)^c	⊝⊝ Low^e	We upgraded 2 levels due to a large magnitude of effect. Downgraded 1 level due to serious risk of bias and 1 level due to imprecision
		44 cases (1 RCT)^c	⊝⊝ Low	We downgraded 2 levels due to a very serious risk of bias
CR: case report, CS: case series, RCT: randomized controlled trial.
Navigation Guide quality of evidence ratings
High quality: Further research is very unlikely to change our confidence in the quality assessment.
Moderate quality: Further research is likely to have an important impact on our confidence in the quality assessment and may change the assessment.
Low quality: Further research is very likely to have an important impact on our confidence in the quality assessment and is likely to change the assessment.

^aTotal number of cases reported by studies that documented pre-hospital management of patients after chlorine gas exposure.

^bTotal number of cases reported by studies that documented an oxygen gas administration to patients exposed to chlorine gas.

^cTotal number of cases reported by studies that documented other treatments (β2, corticosteroids, …) administration to patients exposed to chlorine gas.

^dStudies contributing data to this intervention were assessed at probably high risk of selection (3 studies), probably high risk of confounding bias (9 studies), probably high risk of reporting bias (5 studies), and high risk of detection bias (1 study).

^eStudies contributing data to this intervention were assessed at probably high risk of selection (3 studies), probably high risk of confounding bias (12 studies), probably high risk of reporting bias (5 studies), and high risk of detection bias (1 study).

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