Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep

Objectives: Inhalation injury contributes to the morbidity and mortality of burn victims. In humans and in an ovine model of combined smoke inhalation and burn injury, bronchospasm and acute airway obstruction contribute to progressive pulmonary insufficiency. This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide, an M1 and M3 muscarinic receptor antagonist, will decrease the airway constrictive response and acute bronchial obstruction to improve pulmonary function compared to injured animals without treatment. Design: Randomized, prospective study involving 32 sheep. Setting: Large-animal intensive care research laboratory. Interventions: The study consisted of six groups: a sham group (n = 4, instrumented noninjured), a control group (n = 6, injured and not treated), and tiotropium bromide-treated groups, including both preinjury and postinjury nebulization protocols. Treatments for these groups included nebulization with 36 μg of tiotropium bromide 1 hr before injury (n = 6) and postinjury nebulization protocols of 18 μg (n = 6), 36 μg (n = 6), and 72 μg (n = 4) administered 1 hr after injury. All treated groups received an additional 14.4 μg every 4 hrs for the 24-hr study period. Main results: Pretreatment with tiotropium bromide significantly attenuated the increases in ventilatory pressures, pulmonary dysfunction, and upper airway obstruction that occur after combined smoke inhalation and burn injury. Postinjury treatments with tiotropium bromide were as effective as pretreatment in preventing pulmonary insufficiency, although a trend toward decreased obstruction was present only in all post-treatment conditions. There was no improvement noted in pulmonary function in animals that received a higher dose of tiotropium bromide. Conclusions: This study describes a contribution of acetylcholine to the airway constrictive and lumenal obstructive response after inhalation injury and identifies low-dose nebulization of tiotropium bromide as a potentially efficacious therapy for burn patients with severe inhalation injury.