title: Pathophysiological responses following phosgene exposure in the anaesthetized pig.
abstract: 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).
authors.affiliation: Biomedical Sciences Department, Defence Science and Technology Laboratory, Chemical and Biological Sciences, Porton Down, Salisbury SP4 0JQ, UK.
authors.forename: R F R
authors.initials: RF
authors.lastname: Brown
authors.forename: B J A
authors.initials: BJ
authors.lastname: Jugg
authors.forename: F M J
authors.initials: FM
authors.lastname: Harban
authors.forename: Z
authors.initials: Z
authors.lastname: Ashley
authors.forename: C E
authors.initials: CE
authors.lastname: Kenward
authors.forename: J
authors.initials: J
authors.lastname: Platt
authors.forename: A
authors.initials: A
authors.lastname: Hill
authors.forename: P
authors.initials: P
authors.lastname: Rice
authors.forename: P E
authors.initials: PE
authors.lastname: Watkins
mesh_terms: D000280:Administration, Inhalation; D000769:Anesthesia, Inhalation; D018686:Anesthetics, Intravenous; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010705:Phosgene / Q000008:administration & dosage / Q000633:toxicity*; D015203:Reproducibility of Results; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D012137:Respiratory System / Q000187:drug effects* / Q000503:physiopathology; D013552:Swine
chemical_list: D018686:Anesthetics, Intravenous; D010705:Phosgene