Citation

Veress LA, Anderson DR, Hendry-Hofer TB, Houin PR, Rioux JS, Garlick RB, Loader JE, Paradiso DC, Smith RW, Rancourt RC, Holmes WW, White CW. Toxicol. Sci. 2014; 143(1): 178-184.

Affiliation

Department of Pediatrics, University of Colorado Denver, Aurora, Colorado; Medical Toxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.

Copyright

(Copyright © 2014, Oxford University Press)

DOI

10.1093/toxsci/kfu225

PMID

25331496

Abstract

Rationale: Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, that can lead to respiratory failure and death. Mortality in those requiring intubation is >80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress et al., 2013). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome.

METHODS: Adult rats were exposed to SM, and when oxygen saturation reached <85% (median: 6.5h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4h for 48h. Oxygen saturation, clinical distress and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts.

RESULTS: Intratracheal tPA treatment eliminated mortality (0% at 48 h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction.

CONCLUSIONS: tPA given via airway >6h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life-saving rescue therapy after a significant SM inhalation exposure incident.

Language: en