Effects of the Thromboxane Synthetase Inhibitor, Dazmegrel (UK 38,485), on Pulmonary Gas Exchange and Hemodynamics in Neonatal Sepsis

ABSTRACT. Group B streptococcal (GBS) sepsis produces arterial hypoxemia in newborns. In piglets we previously found that hypoxemia develops because of increased ventilation perfusion heterogeneity, and reduced mixed venous pO2occurring in association with decreased pulmonary blood flow. We hypothesize that increased thromboxane A2(TxA2) synthesis mediates the immediate alterations in gas exchange found in GBS sepsis. We studied 18 anesthetized, ventilated piglets before, during, and after a 30-min infusion of 2 × 109colony forming units/kg of GBS. Nine piglets were pretreated with 8 mg/ kg of dazmegrel (DAZ), a TxA2synthetase inhibitor, and nine animals received GBS without DAZ pretreatment. Pulmonary and systemic arterial pressures, pulmonary vascular resistance, pulmonary blood flow, respiratory gas tensions, intrapulmonary shunt, and SD of pulmonary blood flow, an index of ventilation perfusion mismatching, were measured. Systemic and pulmonary arterial levels of thromboxane B2and 6-keto-PGF1αwere also measured. The sham-treated animals showed the expected rise in pulmonary arterial pressure from 12 ± 3 to 29 ± 7 torr, (p<0.02). By comparison, the animals pretreated with DAZ did not demonstrate pulmonary arterial hypertension and had a delay in the fall in pulmonary blood flow until 2 h postinfusion. Arterial PO2did not decline significantly after the GBS infusion in the DAZ-pretreated animals; the untreated animals showed a significant fall in pO2from baseline. There was no significant change in intrapulmonary shunt or SD of pulmonary blood flow compared to baseline in the DAZ-pretreated animals. The elevation in thromboxane B2occurring with GBS sepsis did not occur in the DAZ-pretreated animals. We conclude that TxA2in part mediates the immediate gas exchange and pulmonary hemodynamic abnormalities during GBS sepsis. Inhibition of TxA2synthetase results in preservation of normal pulmonary gas exchange and a delay in the fall in Qp following GBS infusion.