Indomethacin, dazoxiben and extravascular lung water after Escherichia coli infusion

The effects of selectively inhibiting synthesis of thromboxane A2 (TXA2) with dazoxiben and of all cyclooxygenase products with indomethacin were studied in goats after infusion of 5 X 10(8) live Escherichia coli bacteria/kg. Pulmonary and systemic pressures, cardiac output, and double indicator dilution extravascular lung water (EVLW) were measured at 15-min intervals. EVLW was determined gravimetrically at 6 hr to confirm the final double indicator dilution values. Plasma levels of TXA2 and prostacyclin (PGI2) were measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Dazoxiben blocked the increase in plasma TXB2, prevented pulmonary hypertension, and attenuated the increase in EVLW after E. coli. Mean gravimetric EVLW was 8.7 ml/kg in the dazoxiben-treated group compared to 11.3 ml/kg in the untreated control group. Indomethacin blocked the increased plasma TXB2 and 6-keto-PGF1 alpha, attenuated pulmonary hypertension, and prevented almost all increases in EVLW. Mean gravimetric EVLW was 8.2 ml/kg after indomethacin. We conclude that in acute bacteremia, the early pulmonary hypertension is mediated largely by TXA2 (however, a second phase of hypertension results from non-cyclooxygenase products), either production of cyclooxygenase products (perhaps PGI2) inhibits part of the action of pulmonary vasoconstrictors, or indomethacin stimulates the production of other vasoconstrictors (such as lipoxygenase products), and indomethacin prevents the accumulation of EVLW by blocking formation of cyclooxygenase products or by other nonspecific actions.