Prophylactic and delayed treatment with indomethacin in a porcine model of early adult respiratory distress syndrome induced by endotoxaemia.

Abstract

The effects of prophylactic and delayed treatment with indomethacin were evaluated in a porcine model of early adult respiratory distress syndrome (ARDS) induced by endotoxaemia. Spontaneously breathing pigs under ketamine anaesthesia were infused i.v. with E. coli endotoxin (10 micrograms . h-1 . kg-1) over 6 h. Twenty animals received endotoxin without treatment. Eight animals were pretreated with indomethacin i.v., 5 mg . kg-1 in 30 min, followed by further infusion at a rate of 2 mg . h-1 . kg-1. Ten animals received the same dosage of indomethacin beginning 2 h after the start of endotoxin infusion. Pretreatment with indomethacin inhibited the endotoxin-induced impairment in pulmonary gas exchange, but did not prevent pulmonary oedema. The pulmonary hypertension was counteracted. Oxygen delivery did not improve, because of a marked reduction in cardiac output (Qt). Systemic vascular resistance (SVR) increased markedly, and mean arterial pressure (MAP) was higher. Survival was improved. Delayed indomethacin treatment prevented a further deterioration in pulmonary gas exchange and restored it towards the baseline level. The pulmonary oedema was not counteracted, while the pulmonary hypertension was reduced. O2 delivery was not restored, owing to the greater decrease in Qt compared with the untreated endotoxin group. SVR increased considerably, and MAP was better maintained. Survival was not improved. These results indicate that cyclo-oxygenase inhibitors might benefit pulmonary gas exchange in human ARDS. Drugs which interfere with arachidonate metabolism will probably be of great importance in the prophylaxis, in particular, and also in the treatment of ARDS.