Development of chlorine-induced lung injury in the anesthetized, spontaneously breathing pig.

Chlorine is a toxic industrial chemical produced in vast quantities globally, being used in a range of applications such as water purification, sanitation and industrial processes. Its use and transport cannot be restricted; exposure may occur following accidental or deliberate releases. The OPCW recently verified the use of chlorine gas against civilians in both Syria and Iraq. Chlorine inhalation produces damage to the lungs, which may result in the development of an acute lung injury, respiratory failure and death. Treatment remains an intractable problem. Our objective was to develop a clinically relevant pre-clinical model of a moderate to severe lung injury in the pig. This would enable future assessment of therapeutic drugs or interventions to be implemented in the pre-hospital phase after exposure. Due to the irritant nature of chlorine, a number of strategies for exposing terminally anesthetized pigs needed to be investigated. A number of challenges (inconsistent acute changes in respiratory parameters; early deaths), resulted in a moderate to severe lung injury not being achieved. However, most pigs developed a mild lung injury by 12 h. Further investigation is required to optimize the model and enable the assessment of therapeutic candidates. In this paper we describe the exposure strategies used and discuss the challenges encountered in establishing a model of chlorine-induced lung injury. A key aim is to assist researchers navigating the challenges of producing a clinically relevant model of higher dose chlorine exposure where animal welfare is protected by use of terminal anesthesia.

An in-silico porcine model of phosgene-induced lung injury predicts clinically relevant benefits from application of continuous positive airway pressure up to 8 h post exposure.

We present the first computational model of the pathophysiological consequences of phosgene-induced lung injury in porcine subjects. Data from experiments previously performed in several cohorts of large healthy juvenile female pigs (111 data points from 37 subjects), including individual arterial blood gas readings, respiratory rate and heart rate, were used to develop the computational model. Close matches are observed between model outputs (PaO2 and PaCO2) and the experimental data, for both terminally anaesthetised and conscious subjects. The model was applied to investigate the effectiveness of continuous positive airway pressure (CPAP) as a pre-hospital treatment method when treatment is initiated at different time points post exposure. The model predicts that clinically relevant benefits are obtained when 10 cmH2O CPAP is initiated within approximately 8 h after exposure. Supplying low-flow oxygen (40%) rather than medical air produced larger clinical benefits than applying higher CPAP pressure levels. This new model can be used as a tool for conducting investigations into ventilation strategies and pharmaceutical treatments for chemical lung injury of diverse aetiology, and for helping to refine and reduce the use of animals in future experimental studies.

Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.

The toxic industrial chemical (TIC1) 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.

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.