Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.

This report is based on the proceedings from the Inhalational Lung Injury Workshop jointly sponsored by the American Thoracic Society (ATS) and the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program on May 21, 2013, in Philadelphia, Pennsylvania. The CounterACT program facilitates research leading to the development of new and improved medical countermeasures for chemical threat agents. The workshop was initiated by the Terrorism and Inhalational Disasters Section of the Environmental, Occupational, and Population Health Assembly of the ATS. Participants included both domestic and international experts in the field, as well as representatives from U.S. governmental funding agencies. The meeting objectives were to (1) provide a forum to review the evidence supporting current standard medical therapies, (2) present updates on our understanding of the epidemiology and underlying pathophysiology of inhalational lung injuries, (3) discuss innovative investigative approaches to further delineating mechanisms of lung injury and identifying new specific therapeutic targets, (4) present promising novel medical countermeasures, (5) facilitate collaborative research efforts, and (6) identify challenges and future directions in the ongoing development, manufacture, and distribution of effective and specific medical countermeasures. Specific inhalational toxins discussed included irritants/pulmonary toxicants (chlorine gas, bromine, and phosgene), vesicants (sulfur mustard), chemical asphyxiants (cyanide), particulates (World Trade Center dust), and respirable nerve agents.

This study aimed to develop a reproducible model of phosgene-induced lung injury in the pig to facilitate the future development of therapeutic strategies. Ten female young adult large white pigs were used. Following induction of anaesthesia using a halothane/oxygen/nitrous oxide mixture, arterial and venous catheters were inserted together with a pulmonary artery thermodilution catheter, and a suprapubic urinary catheter by laparotomy. Anaesthesia was maintained throughout the experiment by intravenous infusion of ketamine, midazolam and alfentanil. On completion of surgery the animals were allowed to equilibrate for 1 h and then were divided into two groups. Group 1 (n = 5) was exposed to phosgene for 10 min (mean Ct = 2443 +/- 35 mg min m(-3)) while spontaneously breathing, whereas control animals (Group 2 n = 5) were exposed to air. At 30 min post-exposure, anaesthesia was deepened in order to allow the initiation of intermittent positive pressure ventilation and the animals were monitored for up to 24 h. Cardiovascular and respiratory parameters were monitored every 30 min and blood samples were taken for arterial and mixed venous blood gas analysis and clinical chemistry. A detailed post-mortem and histopathology was carried out on all animals following death or euthanasia at the end of the 24-h monitoring period. Control animals (Group 2) all survived until the end of the 24-h monitoring period with normal pathophysiological parameters. Histopathology showed only minimal passive congestion of the lung. Following exposure to phosgene (Group 1) there was one survivor to 24 h, with the remainder dying between 16.5 and 23 h (mean = 20 h). Histopathology from these animals showed areas of widespread pulmonary oedema, petechial haemorrhage and bronchial epithelial necrosis. There was also a significant increase in lung wet weight/body weight ratio (P < 0.001). During and immediately following exposure, a transient decrease in oxygen saturation and stroke volume index was observed. From 6 h there were significant decreases in arterial pH (P < 0.01), P(a)O(2) (P < 0.01) and lung compliance (P < 0.01), whereas oxygen delivery and consumption was reduced from 15 h onwards in phosgene-exposed animals. Mean pulmonary artery pressure of phosgene-exposed animals was increased from 15 h post-exposure, with periods of increased pulmonary vascular resistance index being recorded from 9 h onwards. We have developed a reproducible model of phosgene-induced lung injury in the anaesthetized pig. We have followed changes in cardiovascular and pulmonary dynamics for up to 24 h after exposure in order to demonstrate evidence of primary acute lung injury from 16 h post-exposure. Histopathology showed evidence of widespread damage to the lung and there was also a significant increase in lung wet weight/body weight ratio (P < 0.001).

These findings are consistent with those seen in the early stages of acute lung injury (ALI).

The toxic industrial chemical (TIC) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury.

Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces a life-threatening pulmonary edema within hours of exposure, to which no specific antidote exists. This study aims to examine the pathophysiological changes seen with low tidal volume ventilation (protective ventilation (PV)) strategies compared to conventional ventilation (CV), in a model of phosgene-induced acute lung injury. Anesthetized pigs were instrumented and exposed to phosgene (concentration x time (Ct), 2,350 mg x min x m(-3)) and then ventilated with intermittent positive pressure ventilation (tidal volume (TV) = 10 ml x kg(-1); positive end expiratory pressure, 3 cm H2O; frequency, 20 breaths x min(-1); fractional concentration of inspired oxygen, 0.24), monitored for 6 hours after exposure, and then randomized into treatment groups: CV, PV (A) or (B) (TV, 8 or 6 ml x kg(-1); positive end expiratory pressure, 8 cm H2O; frequency, 20 or 25 breaths x min(-1); fractional concentration of inspired oxygen, 0.4). Pathophysiological parameters were measured for up to 24 hours. The results show that PV resulted in improved oxygenation, decreased shunt fraction, and mortality, with all animals surviving to 24 hours compared to only three of the CV animals. Microscopy confirmed reduced hemorrhage, neutrophilic infiltration, and intra-alveolar edema.

Toxic industrial chemicals e.g., phosgene, are widely used as reactive intermediates in industrial processes. Inhalation exposure to these chemicals can result in life-threatening acute lung injury (ALI), to which no specific antidote exists. This study aimed to assess the potential benefit of steroids in treating phosgene induced ALI. Anesthetized pigs were instrumented, exposed to phosgene Ct 2000 mg.min.m(-3) (Ct is the product of concentration [mg.m(-3)] x time [min]), and ventilated with intermittent positive pressure ventilation before being randomized to study part 1: treatment with intravenous glucose saline (20 mL) or methylprednisolone (12.5 mg.kg(-1) in 20 mL) 6 h postexposure or study part 2: treatment with inhaled glucose saline (2 mL) or budesonide (2 mL of 0.5 mg.mL(-1) solution) at 1, 6, 12, and 18 h postexposure. Biochemical parameters and animal physiology were monitored to 24 h postexposure. The results show no change in mortality, lung edema, or shunt fraction; however, some beneficial effects on cardiac parameters e.g., stroke volume, left ventricular stroke work, were noted. Steroids were neither beneficial nor detrimental in the treatment of phosgene induced ALI. This study does not support the use of steroids alone as a treatment, but their use in a combined therapy strategy should be investigated.

Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces life-threatening pulmonary edema within hours of exposure; no antidote exists. This study examines pathophysiological changes seen following treatment with elevated inspired oxygen concentrations (Fi(O2)), in a model of phosgene-induced acute lung injury. Anesthetized pigs were exposed to phosgene (Ct 2500 mg min m(-3)) and ventilated (intermittent positive pressure ventilation, tidal volume 10 ml kg(-1), positive end-expiratory pressure 3 cm H(2)O, frequency 20 breaths min(-1)). The Fi(O2) was varied: group 1, Fi(O2) 0.30 (228 mm Hg) throughout; group 2, Fi(O2) 0.80 (608 mm Hg) immediately post exposure, to end; group 3, Fi(O2) 0.30 from 30 min post exposure, increased to 0.80 at 6 h post exposure; group 4, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 (304 mm Hg) at 6 h post exposure. Group 5, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 at 12 h post exposure. The current results demonstrate that oxygen is beneficial, with improved survival, arterial oxygen saturation, shunt fraction, and reduced lung wet weight to body weight ratio in all treatment groups, and improved arterial oxygen partial pressure in groups 2 and 3, compared to phosgene controls (group 1) animals. The authors recommend that treatment of phosgene-induced acute lung injury with inspired oxygen is delayed until signs or symptoms of hypoxia are present or arterial blood oxygenation falls. The lowest concentration of oxygen that maintains normal arterial oxygen saturation and absence of clinical signs of hypoxia is recommended.