[A study of the clinical features and the effect of therapy on acute respiratory distress syndrome patients as a result of severe triphosgene poisoning].

OBJECTIVE: To investigate the clinical features and treatment strategy for acute respiratory distress syndrome (ARDS) caused by phosgene. METHODS: Individualized therapy was carried out in 17 cases of severe phosgene poison patients. Blood routine, electrolytes, blood gas analysis, hepatic and renal function tests and cardiac enzymes were examined before and after treatment. RESULTS: Vital signs, fluid, electrolytes and acid-base disturbances were improved after treatment. As compared to that of pre-treatment period, white blood cells [WBC, ×10(9)/L: 12.18 ± 4.76 vs. 21.93 ± 6.21], neutrophil percentage (0.87 ± 0.05 vs. 0.92 ± 0.03), hemoglobin (Hb, g/L: 128.12 ± 25.65 vs. 173.71 ± 23.53), blood platelet count [PLT,×10(9)/L:165.12 ± 31.70 vs. 254.47 ± 70.80], alanine transaminase (ALT, U/L: 70.71 ± 46.70 vs. 212.71 ± 141.34), aspartate aminotransferase (AST, U/L: 52.47 ± 34.68 vs. 82.41 ± 34.60), blood urea nitrogen (BUN, mmol/L: 5.83 ± 4.09 vs. 7.89 ± 5.96), serum creatinine (SCr, µmol/L: 48.13 ± 14.97 vs. 67.25 ± 24.29), lactate dehydrogenase (LDH, U/L: 280.10 ± 81.77 vs. 586.35 ± 186.71), creatine kinase (CK, U/L: 199.12 ± 106.75 vs. 683.00 ± 323.21), MB isoenzyme of creatine kinase (CK-MB, U/L: 26.94 ± 9.13 vs. 45.59 ± 11.21), serum chlorine anion [Cl(-), mmol/L: 95.88 ± 6.06 vs. 102.29 ± 7.28], respiratory rate (RR, beats/min: 20.88 ± 4.30 vs. 30.06 ± 5.78), heart rate (HR, beats/min: 82.76 ± 17.16 vs. 113.35 ± 16.90), blood pH value (7.34 ± 0.44 vs. 7.39 ± 0.03) were all decreased (P < 0.05 or P < 0.01). Serum sodium ion [Na(+),mmol/L:140.61 ± 6.69 vs. 134.06 ± 4.80], arterial partial pressure of oxygen [PO(2), mm Hg, 1 mm Hg = 0.133 kPa: 84.41 ± 30.58 vs. 59.88 ± 15.19] and pulse oxygen saturation [SpO(2): 0.91 ± 0.08 vs. 0.78 ± 0.15] were increased (P < 0.05 or P < 0.01). Sixteen patients totally recovered, 1 patient died, and the cure rate was 94.12%. CONCLUSIONS: Respiratory system could be mainly injured as the result of exposure to phosgene and leading to ARDS. Early initial combination therapies with corticosteroids and respiratory support should be addressed.

Genotoxicity surveillance programme in workers dismantling World War I chemical ammunition.

PURPOSE: To evaluate the effectiveness of personal protective measures in a dismantling plant for chemical weapons from World War I of the Belgian Defence. METHODS: Seventeen NIOSH level B-equipped plant workers exposed to arsenic trichloride (AsCl(3)) in combination with phosgene or hydrogen cyanide (HCN) were compared to 24 NIOSH level C-protected field workers occasionally exposed to genotoxic chemicals (including AsCl(3)-phosgene/HCN) when collecting chemical ammunition, and 19 matched referents. Chromosomal aberrations (CA), micronuclei (MNCB and MNMC), sister chromatid exchanges (SCE) and high frequency cells (HFC) were analysed in peripheral blood lymphocytes. Urinary arsenic levels and genetic polymorphisms in major DNA repair enzymes (hOGG1(326), XRCC1(399), XRCC3(241)) were also assessed. RESULTS: SCE and HFC levels were significantly higher in plant-exposed versus referent subjects, but MNCB and MNMC were not different. MNCB, SCE and HFC levels were significantly higher and MNMC levels significantly lower in field-exposed workers versus referents. AsCl(3) exposure was not correlated with genotoxicity biomarkers. CONCLUSIONS: Protective measures for plant-exposed workers appear adequate, but protection for field-exposed individuals could be improved.

[Phosgene poisoning: analysis of cases]. / Zatrucie fosgenem--analiza przypadków.

On April 9, 1998, there was a break-down in the Chemical Plant ZACHEM S.A. in Bydgoszcz, which resulted in two cases of lethal phosgene poisoning. Over ten years have passed since that accident. During that period there were new cases of exposure to phosgene, however, all of the victims recovered completely. The aim of this paper was to present stages and symptoms of phosgene poisoning and discuss the undertaken procedures, which led to the recovery of people exposed to toxic effect of phosgene.

NLRP3 gene silencing ameliorates phosgene-induced acute lung injury in rats by inhibiting NLRP3 inflammasome and proinflammatory factors, but not anti-inflammatory factors.

NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P < 0.05), but not ASC (P > 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1ß, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P < 0.05), but not of anti-inflammatory IL-4 and IL-10 (all P > 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phosgene use in World War 1 and early evaluations of pathophysiology.

World War 1 ended 100 years ago. The aftermath included the consolidation of significant advances in medical care of casualties. Some of these advances were made in the care of chemical casualties, in particular the mechanisms of toxicity and treatment of phosgene exposure. Phosgene, or carbonyl chloride, is an extremely poisonous vapour that was used to devastating effect during World War 1. Observations made of acutely poisoned casualties formed the basis of much research in the early post-World War 1 era. Some extremely elegant experiments, some at the nascent Porton Down research facility, further evaluated the toxin and defences against it. Researchers drew on knowledge that was later forgotten and has since been relearnt later in the 20th century and made many correct assumptions. Their work is the bedrock of our understanding of phosgene toxicity that survives to this day. The horrors of chemical warfare prompted the Geneva Protocol of 1925, prohibiting the use of chemical agents in warfare, and chemical warfare on this scale has not been repeated. The ease with which phosgene can be synthesised requires healthcare providers to be familiar with its effects.

Continuous positive airway pressure: An early intervention to prevent phosgene-induced acute lung injury.

Exposure to toxic industrial chemicals such as phosgene may occur through accidental or deliberate release. Inhalation may result in an acute lung injury which manifests as hypoxaemia with insufficient oxygen being delivered to the tissues resulting in hypoxia, respiratory failure and death. No effective pharmacological therapy currently exists and treatment remains supportive, often requiring intensive care facilities. In a mass casualty scenario the logistical burden of managing exposed individuals would rapidly overwhelm healthcare systems. This highlights the need to develop post exposure therapeutic strategies to minimise injury severity and increase survival in individuals exposed to toxic chemicals. Our research objective was to investigate a commercial off the shelf (COTS) therapy; ambient air continuous positive airway pressure (CPAP) support, initiated 1h post exposure to explore the concept that early intervention with positive airway pressure would reduce or ameliorate lung injury following exposure to phosgene. This study has demonstrated that CPAP, initiated before overt signs of exposure become manifest, significantly improved survival as well as improving some clinically relevant physiological measures of phosgene-induced acute lung injury over 24h.

Gas: the greatest terror of the Great War.

The Great War began just over a century ago and this monumental event changed the world forever. 1915 saw the emergence of gas warfare-the first weapon of mass terror. It is relevant to anaesthetists to reflect on these gases for a number of reasons. Firstly and most importantly we should acknowledge and be aware of the suffering and sacrifice of those soldiers who were injured or killed so that we could enjoy the freedoms we have today. Secondly, it is interesting to consider the overlap between poison gases and anaesthetic gases and vapors, for example that phosgene can be formed by the interaction of chloroform and sunlight. Thirdly the shadow of gas warfare is very long and covers us still. The very agents used in the Great War are still causing death and injury through deployment in conflict areas such as Iraq and Syria. Industrial accidents, train derailments and dumped or buried gas shells are other sources of poison gas hazards. In this age of terrorism, anaesthetists, as front-line resuscitation specialists, may be directly involved in the management of gas casualties or become victims ourselves.

[Observation on the protective effect of hyperoxia solution on the acute lung injury caused by phosgene poisoning.].

OBJECTIVE: To study the protective effect of hyperoxia solution on acute lung injury caused by phosgene poisoning by observing the changes of PaO2 and malondialdehyde (MDA) contents, superoxide dismutase (SOD) activity in serum and Glutathione (GSH/GSSG) contents in lung tissues. METHODS: The rabbits were divided into normal control group, hyperoxia solution (H0) and balance salt (BS) groups. Group HO and Group BS inhaled phosgene and the former was given intravenously hyperoxia solution (which was replaced by balance salt solution in Group BS). The content of MDA and the activity of SOD in serum were observed at different time points, the amount of GSH and GSSG in lung tissue were also measured. RESULTS: (1) The serum MDA contents increased and PaO2, SOD activity decreased significantly in Group HO and Group BS along with time increasing as compared with control group. The contents of GSH in lung tissue decreased in two groups compared with that in control group, however the contents of GSSG ascended instead. (2) At 3 and 8 h of the experiment, PaO2 of Group HO [(9.91 +/- 0.49), (9.15 +/- 0.46) mm Hg respectively] were significantly higher than those of Group BS [(9.03 +/- 0.76), (8.11 +/- 0.57) mm Hg respectively] (P < 0.01). The contents of MDA of Group HO (3.66 +/- 0.35), (5.31 +/- 0.15) micromol/L respectively] were lower than those of Group BS [(4.32 +/- 0.26), (7.4 +/- 0.33) micromol/L respectively] (P < 0.01). SOD activity in Group HO [(237.37 +/- 29.96), (208.10 +/- 18.80) NU/ml respectively] were higher than those of Group BS [(195.02 +/- 21.44), (144.87 +/- 21.26) NU/ml respectively] (P < 0.05 or P < 0.01). The content of GSSG lung tissue in Group HO (423.67 +/- 38.21) micromol/L were lower than those of Group BS (523.85 +/- 43.14) mol/L (P < 0.01). There were no significant differences in the content of GSH in lung tissues between Group HO and group BS. CONCLUSION: Hyperoxia solution can reduce acute lung injury of rabbits following phosgene poisoning.

Pulmonary reactions caused by welding-induced decomposed trichloroethylene.

This is the report of a welder who performed argon-shielded electric arc welding in an atmosphere containing trichloroethylene. He developed immediate respiratory symptoms, pulmonary edema 12 hours after exposure, and recurring dyspnea ten days after exposure. These pulmonary reactions might be explained by inhalation of decomposition products of trichloroethylene such as dichloroacetyl chloride and phosgene.

Pulmonary toxicity following exposure to methylene chloride and its combustion product, phosgene.

Chemical paint removers containing methylene chloride are widely used in domestic and industrial settings where exposure to a heat source with conversion to phosgene is possible. We describe a case of noncardiogenic pulmonary edema and subsequent hyperreactive airways following such an exposure. In addition, the various problems that have been associated with exposure to methylene chloride and phosgene are reviewed.

Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators.

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotension II and KCl.

Phosgene exposure: mechanisms of injury and treatment strategies.

Phosgene (carbonyl chloride, CAS 75-44-5) is a highly reactive gas of historical interest and current industrial importance. Phosgene has also proved to be a useful model for the study of those biochemical mechanisms that lead to permeability-type pulmonary edema (adult respiratory distress syndrome). In turn, the study of phosgene-induced adult respiratory distress syndrome has provided insights leading to revised treatment strategies for exposure victims. We summarized recent findings on the mechanisms of phosgene-induced pulmonary edema and their implications for victim management. In light of that research, we also provide a comprehensive approach to the management and treatment of phosgene exposure victims.

[Clinical and radiological studies on 15 cases of acute phosgene poisoning].

A clinical and radiological observation on 15 cases of acute phosgene poisoning were reported. The pulmonary edema after acute phosgene poisoning can be classified into two types: interstitial and alveolar. The X-ray findings were described in detail in correlation with the clinical symptoms. Taking X-ray early can benefit on preventing and treating acute pulmonary edema. Meanwhile, the patients with chronic respiratory or digestive diseases can develop pulmonary encephalopathy or upper gastrointestinal bleeding after acute phosgene poisoning.

[Effect of acute phosgene inhalation on antioxidant enzymes, nitric oxide and nitric-oxide synthase in rats].

OBJECTIVE: To study the effect of acute phosgene inhalation on the antioxidant enzymes, nitric oxide (NO) and nitric oxide synthase (NOS) in rats. METHODS: Phosgene was produced by decomposing bis (trichdomethyl) carbonate in the presence of N,N-dimethyl formamide. SD rats were randomly divided into two groups: control and phosgene exposure groups. In a special experimental device with equipment modulating the gas flow, phosgene exposed rats inhaled phosgene quantitatively for five minutes. Two hours later, all the rats were sacrificed and the ratio of wet weight to dried weight of lung (WW/DW) was calculated. Peripheral blood, serum and liver were collected to examine the activities of antioxidant enzymes including glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), NOS, and NO level. The total content of proteins were also determined. RESULTS: The WW/DW ratio of lung in phosgene exposure group was much higher than that in control group (P < 0.01). The activities of GST in serum and liver of phosgene exposure group increased significantly (P < 0.05). The activities of SOD, CAT, GSHPx and NOS in serum or blood and liver of phosgene exposure group were also increased significantly (P < 0.05). But the content of NO was significantly decreased (P < 0.01). CONCLUSION: Acute phosgene inhalation may cause a dramatically changes of several antioxidant enzyme activities, and acute injury of liver to some extent in rats. The latter is related to reactive oxygen species. But the elevation of antioxidant enzyme activities suggests that antioxidative treatment for acute phosgene poisoning should not be considered first.