The injured lung: clinical issues and experimental models.

Exposure of military and civilian populations to inhaled toxic chemicals can take place as a result of deliberate release (warfare, terrorism) or following accidental releases from industrial concerns or transported chemicals. Exposure to inhaled toxic chemicals can result in an acute lung injury, and in severe cases acute respiratory distress syndrome, for which there is currently no specific medical therapy, treatment remaining largely supportive. This treatment often requires intensive care facilities that may become overwhelmed in mass casualty events and may be of limited benefit in severe cases. There remains, therefore, a need for evidence-based treatment to inform both military and civilian medical response teams on the most appropriate treatment for chemically induced lung injury. This article reviews data used to derive potential clinical management strategies for chemically induced lung injury.

Exposure-response effects of inhaled sulfur mustard in a large porcine model: a 6-h study.

CONTEXT: Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. A reproducible, characterized in vivo model is required to investigate novel therapies targeting HD-induced lung injury. MATERIALS AND METHODS: Anesthetized, spontaneously breathing large white pigs (~50 kg) were exposed directly to the lung to HD vapor at 60, 100, or 150 µg/kg, or to air, for ~10 min, and monitored for 6 h. Cardiovascular and respiratory parameters were recorded. Blood and bronchoalveolar lavage fluid (BALF) were collected to allow blood gas analysis, hematology, and to assay for lung inflammatory cells and mediators. Urine was collected and analyzed for HD metabolites. Histopathology samples were taken postmortem (PM). RESULTS: Air-exposed animals maintained normal lung physiology whilst lying supine and spontaneously breathing. There was a statistically significant increase in shunt fraction across all three HD-exposed groups when compared with air controls at 3-6 h post-exposure. Animals were increasingly hypoxemic with respiratory acidosis. The monosulfoxide ß-lyase metabolite of HD (1-methylsulfinyl-2-[2(methylthio)ethylsulfonyl)ethane], MSMTESE), was detected in urine from 2 h post-exposure. Pathological examination revealed necrosis and erosion of the tracheal epithelium in medium and high HD-exposed groups. CONCLUSION: These findings are consistent with those seen in the early stages of acute lung injury (ALI).

Preliminary studies of sulphur mustard-induced lung injury in the terminally anesthetized pig: exposure system and methodology.

ABSTRACT Although normally regarded as a vesicant, inhalation of sulphur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. Novel therapies for HD-induced lung injury are best investigated in an in vivo model that allows monitoring of a range of physiological variables. HD vapor was generated using two customized thermostatically controlled glass flasks in parallel. The vapor was passed into a carrier flow of air (81 L. min(-1)) and down a length of glass exposure tube (1.75 m). A pig was connected to the midpoint of the exposure tube via a polytetrafluoroethylene-lined endotracheal tube, Fleisch pneumotachograph, and sample port. HD vapor concentrations (40-122.8 mg. m(-3)) up-and downstream of the point of exposure were obtained by sampling onto Porapak absorption tubes with subsequent analysis by gas chromatography-flame photometric detection. Real-time estimates of vapor concentration were determined using a photo-ionization detector. Lung function indices (respiratory volumes, lung compliance, and airway resistance) were measured online throughout. Trial runs with methylsalicylate (MS) and animal exposures with HD demonstrated that the exposure system rapidly reached the desired concentration within 1 min and maintained stable output throughout exposure, and that the MS/HD concentration decayed rapidly to zero when switched off. A system is described that allows reproducible exposure of HD vapor to the lung of anesthetized white pigs. The system has proved to be robust and reliable and will be a valuable tool in assessing potential future therapies against HD-induced lung injury in the pig. Crown Copyright (c) 2007 Dstl.

Pathophysiological responses following phosgene exposure in the anaesthetized pig.

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).