Phosgene Poisoning Research Articles

Basic research and clinical innovative treatment in patients with sudden mass phosgene poisoning

Phosgene is not only a dangerous asphyxiating chemical warfare agent, but also an important chemical raw material, which is widely used in chemical production. According to statistics, there are more than 1 000 phosgene production enterprises in China, with an annual production volume of more than 3 million tons and hundreds of thousands of employees. Therefore, once the leakage accident occurs during production, storage and transportation, it often causes a large number of casualties. In the past 20 years, phosgene poisoning accidents in China have occurred from time to time, and due to the weak irritation, high density, and high concentration of phosgene at the scene of the accident, it often results in acute high-concentration inhalation of the exposed, triggering acute lung injury (ALI), and is very likely to progress to acute respiratory distress syndrome (ARDS), with a mortality rate up to 40%-50%. In view of the characteristics of sudden, mass, concealed, rapid and highly fatal phosgene, and the mechanism of its toxicity and pathogenicity is still not clear, there is no effective treatment and standardized guidance for the sudden group phosgene poisoning. In order to improve the efficiency of clinical treatment and reduce the mortality, this paper has summarized the pathophysiological mechanism of phosgene poisoning, clinical manifestations, on-site treatment, research progress, and innovative clinical therapies by combining the extensive basic research on phosgene over the years with the abundant experience in the on-site treatment of sudden mass phosgene poisoning. This consensus aims to provide guidance for the clinical rescue and treatment of patients with sudden mass phosgene poisoning, and to improve the level of treatment.

Alpha-1 antitrypsin protects against phosgene-induced acute lung injury by activating the ID1-dependent anti-inflammatory response

Phosgene is widely used as an industrial chemical, and phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, an antidote for phosgene poisoning is not known. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor used to treat patients with emphysema who are deficient in α1-AT. Recent studies have revealed that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. Herein, we aimed to investigate the role of α1-AT in phosgene-induced ALI. We observed a time-dependent increase in α1-AT expression and secretion in the lungs of rats exposed to phosgene. Notably, α1-AT was derived from neutrophils but not from macrophages or alveolar type II cells. Moreover, α1-AT knockdown aggravated phosgene- and lipopolysaccharide (LPS)-induced inflammation and cell death in human bronchial epithelial cells (BEAS-2B). Conversely, α1-AT administration suppressed the inflammatory response and prevented death in LPS- and phosgene-exposed BEAS-2B cells. Furthermore, α1-AT treatment increased the inhibitor of DNA binding 1 (ID1) gene expression, which suppressed NF-κB pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived α1-AT acts as a self-protective mechanism, which protects against phosgene-induced ALI by activating the ID1-dependent anti-inflammatory response. This study may provide novel strategies for the treatment of patients with phosgene-induced ALI.

Effects of acute phosgene exposure on kidney in rats

Objective: To investigate the changes in kidney and its mechanism during the development of acute phosgene exposure in rats. Methods: Rats were randomized into 2 groups: control and phosgene group (including 1, 3, 6, 12 and 24 h after exposed to phosgene) , 6 rats in each group. Rats in control group were exposed to air for 5 min, while rats in phosgene group were exposed to 8.33 mg/L phosgene for 5 min. The blood samples were collected at 1, 3, 6, 12 and 24 h after phosgene exposure. The blood creatinine (Cr) , urea nitrogen (BUN) and blood gas analysis were detected. HE staining and immunohistochemical staining were performed to observe the expression levels of 8-hydroxy deoxyguanosine and myeloperoxidase. Results: The arterial partial pressure of oxygen and oxygenation index of rats in the phosgene group were significantly lower than those in the control group at 3, 6 and 12 h after exposure (P<0.01) . The lowest points were reached at 6 h, which were (58.67±7.89) mmHg and (202.30±27.20) mmHg, respectively. The Cr and BUN of rats in the phosgene group were significantly higher than those in the control group at 3, 6, 12, and 24 h, and the renal organ coefficients were significantly higher than those in the control group at 3, 6 and 12 h (P<0.01) . HE staining showed that there were more erythrocytes in the glomeruli of rats in the phosgene group, the volume of renal tubular epithelial cells increased, and the cytoplasm was loose and lightly stained. The damage was most obvious at 6 h. The results of immunohistochemical staining showed that the positive expressions of 8-hydroxy deoxyguanosine and myeloperoxidase in the kidney tissue of the phosgene group increased. Conclusion: Hypoxemia and oxidative stress caused by phosgene poisoning may be the cause of renal damage in rats.

Mechanism of Phosgene-Induced Acute Lung Injury and Treatment Strategy.

Phosgene (COCl2) was once used as a classic suffocation poison and currently plays an essential role in industrial production. Due to its high toxicity, the problem of poisoning caused by leakage during production, storage, and use cannot be ignored. Phosgene mainly acts on the lungs, causing long-lasting respiratory depression, refractory pulmonary edema, and other related lung injuries, which may cause acute respiratory distress syndrome or even death in severe cases. Due to the high mortality, poor prognosis, and frequent sequelae, targeted therapies for phosgene exposure are needed. However, there is currently no specific antidote for phosgene poisoning. This paper reviews the literature on the mechanism and treatment strategies to explore new ideas for the treatment of phosgene poisoning.

Clinical diagnosis and treatment of acute phosgene poisoning and its research progress

Clinical diagnosis and treatment of acute phosgene poisoning and its research progress

Probabilistic predictive mathematical model of chronic respiratory conditions to reduce the risk of disability in case of poisoning with substances with a pulmonotoxic effect.

In the experimental model of poisoning of rats with phosgene of severe degree (single administration in Tox dose 1 of Lt50 - 3.92 mgґmin/l), the parameters of the respiratory system and histopathological changes of the lung parenchyma were investigated. It was established that 45 days after exposure to phosgene, half of the surviving animals formed a complex of persistent physiological, functional, and structural changes in the syndrome of the syndrome and the chronic respiratory state (J68.4 ICD-10). The main independent predictors from the number of laboratory and functional parameters in the acute period of pulmonary toxicant poisoning (6 hours) were established by the method of mathematical analysis, on the basis of which a model was developed to predict the likelihood of chronic respiratory states in poisoned animals as consequences of severe phosgene poisoning. It is shown that an increase in the concentration of lipid peroxidation products in the blood plasma by 25% determines the likelihood of late effects of more than 0.95. The obtained mathematical model will allow predicting the characteristics of the flow of affected, in need of emergency medical prevention of chronic respiratory conditions in the provision of medical care in the acute period of pulmonary toxicity poisoning.

Extracorporeal membrane oxygenation for acute respiratory distress syndrome caused by acute phosgene poisoning: a report of 4 cases

To evaluate the protective effect and curative effect of early treatment with extracorporeal membrane oxygenation (ECMO) in severe patients with acute respiratory distress syndrome (ARDS) caused by acute phosgene poisoning. The course of treatment of 4 cases of ARDS caused by acute phosgene poisoning admitted to intensive care unit (ICU) of Jiangxi Provincial People's Hospital in April 2018 was retrospectively analyzed. The treatment parameters in patients before and after the ECMO treatment at 1, 3, 7 days were collected, including pH of the arterial blood, arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), blood lactic acid (Lac) and systemic vascular resistance index (SVRI), cardiac index (CI), extravascular lung water index (ELWI), plateau pressure (Pplat), positive end-expiratory pressure (PEEP), driving pressure (ΔP), and acute physiology and chronic health evaluation II (APACHE II), the length of ICU stay, the treatment duration of ECMO and the duration of mechanical ventilation. After admitted in hospital, the 4 patients were all put on tracheal intubation and ventilator, but the ventilator support conditions were high, the oxygenation and internal environment were unstable. Therefore, ECMO therapy was performed on the next day after admission. Oxygenation was improved obviously after treatment, ventilator support conditions could be obviously reduced, including 3-6 mL/kg of the small tidal volume, 8-10 cmH2O (1 cmH2O = 0.098 kPa) of the PEEP, 0.30 of the inhaled oxygen concentration (FiO2), and other lung protection rest strategies. The parameters were improved obviously after the ECMO treatment compared with before, from the 1st day after the ECMO treatment, PaO2, SVRI rose obviously, Lac, ELWI, Pplat, PEEP, ΔP, APACHE II were significantly decreased [PaO2 (mmHg, 1 mmHg = 0.133 kPa): 85.5±10.7 vs. 54.2±4.5, SVRI (kPa×s×L-1×m-2): 153.6±9.4 vs. 118.0±12.6, Lac (mmol/L): 2.15±0.19 vs. 4.93±0.96, ELWI (mL/kg): 17.73±2.99 vs. 20.45±4.13, Pplat (cmH2O): 19.25±2.21 vs. 35.75±2.22, PEEP (cmH2O): 9.0±1.2 vs. 13.5±1.7, ΔP (cmH2O): 10.25±1.26 vs. 22.25±3.86, APACHE II: 17.25±2.22 vs. 26.50±2.08, all P < 0.05]; pH and CI were significantly increased after 3 days treatment, and PaCO2 was significantly decreased [pH: 7.43±0.05 vs. 7.21±0.13, CI (mL×s-1×m-2): 64.35±3.17 vs. 59.51±3.17, PaCO2 (mmHg): 42.0±2.2 vs. 55.0±8.5, all P < 0.05]. All the 4 patients were treated successfully and discharged after improvement. The length of ICU stay was 8-27 days, with an average (13.5±9.0) days; the treatment duration of ECMO was 6-12 days, with an average (8.0±2.7) days; the duration of mechanical ventilation was 6-20 days, with an average (10.75±6.19) days. Early treatment with ECMO can significantly improve the oxygenation of severe ARDS caused by acute phosgene poisoning, eliminate excessive CO2 in the body, reduce ventilator-associated lung injury, and improve the prognosis.

Three patients with acute phosgene poisoning

我院于2005年8月5日收治3例急性光气中毒病例,现报告如下. 1.一般资料:2005年8月4日上午10时许,天津某有机化工厂氯代脂车问因管道突然破裂,使含有光气和辛醇等气体、液体喷出,造成3人中毒.中毒患者均为男性,年龄46、53、54岁。

Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation.

Phosgene inhalation causes a severe noncardiogenic pulmonary edema characterized by an influx of neutrophils into the lung. To study the role of neutrophils in lung injury and mortality after phosgene, we investigated the effects of leukocyte depletion with cyclophosphamide, inhibiting the generation of the chemotaxin leukotriene B4 with the 5-lipoxygenase inhibitor AA861 and impairing neutrophil migration with the microtubular poison colchicine. Cyclophosphamide, AA861, and colchicine injected before exposure significantly reduced percent neutrophils, protein, and thiobarbituric acid-reactive products in bronchoalveolar lavage fluid of rats exposed to phosgene (0.5 ppm X 60 min). Cyclophosphamide, AA861, and colchicine also significantly decreased mortality from phosgene (2.0 ppm X 90 min) in mice. Colchicine significantly reduced neutrophil influx, lung injury, and mortality even when given 30 min after phosgene exposure. We conclude that lung injury and mortality after phosgene exposure are associated with an influx of neutrophils into the lung. Prevention of neutrophil migration with colchicine may hold therapeutic potential in phosgene poisoning.

Health Effects and Toxicity of Phosgene : Scientific Review

The chemistry and toxicology of phosgene are reviewed at length. Manufacture, physical and chemical properties and industrial application of this important chemical intermediate are presented. Both acute and chronic exposure studies on animals and some human exposure data are also discussed. Pathology of phosgene poisoning and reliable therapeutic measures are critically examined.

Prophylactic and antidotal effects of hexamethylenetetramine against phosgene poisoning in rabbits.

New Zealand white rabbits were exposed to phosgene doses, expressed as Ct factors, of 125-3120 ppm X min. Hexamethylenetetramine (HMT), 0.3 gm/kg as a 40% aqueous solution, was injected via an ear vein into separate groups of animals at 5-10 min pre-exposure or at 15 min post-exposure to the gas. Non-exposed and exposed, non-HMT-treated animals served as controls. As assessed by survival times, gross morphology of the lungs, percent lung water measurements, serum LDH values, and respiratory gas parameters, pre-exposure administration of HMT at Ct factors as high as 3120 ppm X min provided significant prophylaxis against the effects of phosgene. Post-exposure administration of HMT, however, provided no antidotal effect even when administered as soon as 15 min after exposure to 125 ppm X min phosgene.

Late sequelae after phosgene poisoning: a literature review.

The vast majority of phosgene intoxications (including cases with pulmonary edema) have a good prognosis. However, nearly all patients complain of exertional dyspnea and reduced physical fitness for several months to years after the accident; normalization of lung function values, too, may require several years. Occasional impairment of pulmonary function appears to be dependent more on smoking habits than on the severity of the original intoxication. Pre-existing chronic bronchitis may undergo severe and progressive deterioration after toxic pulmonary edema due to phosgene. Occupational health check-ups (including pulmonary function tests) are recommended for all persons handling irritant gases. Every patient having undergone the inhalation of phosgene or other irritants will ask the question of possible late sequelae. Due to new forms of treatment (glucocorticoids, positive pressure ventilation) the prognosis of severe cases has considerably improved during the last decades. The paper tries to summarize the present state of our knowledge.

Therapeutic strategy in phosgene poisoning.

For the treatment of phosgene poisoning, glucocorticoids and positive pressure ventilation can be recommended as well as supporting measures such as physical rest, antitussives, buffers, sedatives, antibiotics, antispasmodics and possibly diuretics. Roentgenological evaluation of the lungs is advisable. A therapeutic strategy is presented which is based on the phosgene exposure intensity.

Pathogenesis of Phosgene Poisoning

Phosgene inhalation in concentrations greater than 1 ppm may produce a transient bioprotective vagus reflex with rapid shallow breathing in some individuals. Phosgene concentrations greater than 3 ppm are moderately irritating to eyes and upper airways. Toxic phosgene doses (greater than or equal to 30 ppm X min) inhaled into the terminal respiratory passages render the blood-air-barrier more permeable to blood plasma, which gradually collects in the lung. Some time passes, however, until the collection of fluid provokes signs and symptoms. This period in which the patient experiences relative well-being is known as the clinical latent phase. The clinical symptoms which follow and the pathological changes underlying them are discussed in detail; dose-effect relationships are demonstrated. The regression phase after poisoning has been overcome is briefly sketched.

A literature review: therapy for phosgene poisoning.

A literature search designed to collect information on therapy for phosgene poisoning has been conducted for the period 1920-1982. To achieve this goal, literature services were consulted, cross references were carefully followed and, whenever possible, unpublished reports (e.g., from Edgewood Arsenal and Porton Research Station) were evaluated. The various therapeutic agents and measures described in the literature are presented in alphabetical order. When available, detailed data are given for the phosgene dose, interval of time between exposure and institution of therapy, therapeutic effect and parameters used to assess efficacy. A final summary presents general recommendations for therapy and for further research.

The Methenamine Misunderstanding in the Therapy of Phosgene Poisoning

The Methenamine Misunderstanding in the Therapy of Phosgene Poisoning

Treatment of phosgene poisoning with antiserum. Anaphylactic shock by phosgene.

Phosgene poisoning can be prevented by injection of antiserum prior to phosgene poisoning. Phosgene poisoning can be treated by injection of antiserum following phosgene poisoning. Immunization against phosgene poisoning is obtained by injection of extract of lung treated with phosgene. The immunity is long lasting (60 days). An anaphylactic shock is observed when antiserum is injected either before or after phosgene poisoning. For the prevention of anaphylactic shock a high dose of serum is recommended.

The Clinical, Roentgenological and Morphological Effects of an Acute Exposure of Phosgene on the Lungs of Dogs

Phosgene still plays an important role as a toxic substance in the chemical industry. Thiess (1968) recently reported observations on numerous cases of phosgene poisoning. A serious difficulty in the clinical handling of phosgene poisoning cases is a relatively long latent period, up to 12 hours, with no obvious signs of severity. At about 12 hours heavy lung edema appears suddenly, however changes can be seen in routine X-rays taken after only a few hours' exposure (Diller et al., 1969). This study was undertaken to correlate these early changes seen by the roengenologist with morphological alterations in the lungs seen in the'light and electron microscopes.Forty-two adult male and female Beagle dogs were selected for these exposure experiments. Treated animals were exposed to 94.5-107-5 ppm phosgene for 10 min. in a 15 m3 chamber. Roentgenograms were made of the thorax of each animal before and after exposure, up to 24 hrs.

Winternitz and Emphysema

To Editor:— In editorial Pulmonary Emphysema: An Experimental Model ( JAMA 190 : 774 [Nov 23] 1964) and Archives of Pathology communication Histopathology of Exposure to ( 78 :544 [Nov] 1964), you note development of changes in lungs of dogs after phosgene exposure. Bronchiolitis, scarring, and bronchiolar obliteration are cited, together with adjacent parenchymal foci of alveolitis and rupture of alveolar walls. Mention of Winternitz (Pathology of Phosgene Poisoning, in Collected Studies on Pathology of War Gas Poisoning , New Haven, Conn: Yale University Press, 1920) reminds me that his work is now almost forgotten. In summarizing effects of phosgene he observes that the epithelium of trachea and larger bronchi is not damaged, while that of smaller bronchi and bronchioles is seriously injured, more distal portion suffering most.... These, in turn, lead to mechanical disturbances in air sacs, resulting in atelectasis or

Phosgene Poisoning as an Example of Neuroparalytic Acute Pulmonary Edema: The Sympathetic Vasomotor Reflex Involved

SUMMARY Conditions of acute pulmonary edema are classified into two great groups, according to certain empirically useful anatomic, physiologic, pharmacologic, clinical and radiologic criteria. The hyperactive-sympathetic group is characterized by diffuse lung hyperemia, pulmonary hypertension, amelioration by sympatholytic agents, systemic hypertension and uniformly dense lung fields; it includes epinephrine toxicity and brainstem irritation. The hypoactive-sympathetic or neuroparalytic group is characterized by patchy lung hyperemia, pulmonary normo- or hypotension, non-amelioration by sympatholytic agents, systemic normo- or hypotension and generalized reticulogranular images in the lung fields; it includes vagal section, so-called high altitude pneumonia, hyaline membrane disease, explosive recompression, probably paroxysmal nocturnal dyspnea, and phosgene poisoning. The basic assumption of this classification, specifically in relation to the neuroparalytic group, is tested by direct assay of total electrical activity of the right cervical sympathetic nerve in the rabbit before and after a lethal dose of phosgene. An immediate abrupt marked drop in systemic sympathetic outflow which precedes the lung changes occurs upon phosgene poisoning in the rabbit. Other data are marshalled to establish that the sympathetic neuroparalysis of phosgene poisoning is reflex in nature and associated with vasoconstriction of the lung vascular bed, such pulmonary shutdown being essentially a post-capillary phenomenon. The autonomic sensorimotor negative feedback reflex thus identified as controlling the vascular dynamics of the lung is presented as coursing afferently with the vagus, synapsing at the bulbar reticular formation, and coursing efferently with the upper thoracic sympathetics.