Thromboxane-Associated Pulmonary Hypertension during Three Types of Gram-Positive Bacteremia in Piglets

Abstract

ABSTRACT. Thromboxane-associated pulmonary hypertension occurs in animals during intravenous infusion of group B streptococcus (GBS), a gram-positive neonatal pathogen. We postulated that other gram-positive neonatal pathogens, such as Streptococcus fecalis (ENT) and Staphylococcus epidermidis (S. epi) would also induce increased thromboxane synthesis and pulmonary hypertension when infused into piglets. We observed similar hemodynamic and gas exchange abnormalities during stepwise increases in the dose of GBS, Ent, and S. epi (n = 3,4, and 4 piglets receiving each bacteria, respectively). Pulmonary vascular resistance increased significantly in the absence of acidosis or reduced arterial or mixed venous pOz at a dose of 2.5 x 10' cfu/kg/h for Ent and S. epi. In 14 additional piglets, pulmonary vascular resistance increased markedly after 60 min of intravenous infusion of 4 f 1 x 10' cfu/kg/h for each organism (p < 0.05, GBS: 11.7 f 1.8 to 75.6 f 18.4 mm Hg/liter/min, Ent: 12.7 f 1.7 to 64.9 f 10.6 mm Hg/ liter/min, S. epi: 10.5 f 0.8 to 56.9 f 6.0 mm Hg/liter/ min), and blood thromboxane B2 levels increased (p < 0.05, GBS: 30 f 10 to 1830 f 330 pglml, Ent: 20 f 7 to 1110 f 300 pglml, S. epi: 31 f 9 to 1260 f 350 pg/ml).This dose of each bacteria caused a similar degree of mild arterial hypoxemia (57-66 mm Hg). The thromboxane synthetase inhibitor, dazmegrel, completely reversed pulmonary hypertension, reduced TxB2 levels to near baseline values, and partially reversed arterial hypoxemia despite ongoing bacterial infusion. We conclude that thromboxaneassociated pulmonary hypertension occurs in piglets during infusion of different gram-positive neonatal pathogens. (Pediatr Res 23: 553-556, 1988) Abbreviations cfu, colony forming units C.O., cardiac output DAZ, dazmegrel Ent, Streptococcus fecalis (enterococcus) P,,, proximal airway pressure P,,, systemic arterial pressure GBS, a common gram-positive neonatal pathogen, causes acute pulmonary hypertension, arterial hypoxemia, and decreased cardiac output when infused into both adult and neonatal animals (1-3). In animals with GBS bacteremia and in some human newborns with GBS sepsis, pulmonary hypertension is associated with elevated blood levels of TxB2, the stable metabolite of the potent vasoconstrictor thromboxane A2 (2, 4, 5). Inhibitors of thromboxane synthesis, such as DAZ (UK 38,485),can prevent or reverse pulmonary hypertension in animals with GBS bacteremia (4, 6).The fact that both gram-positive bacteria, e.g. GBS, and some gram-negative bacteria, e.g. E scherichia coli and Aeromonas hydrophilia (7,8), can cause thromboxane-associated pulmonary hypertension suggests a lack of bacterial specificity for this pulmonary vascular response. Gram-positive neonatal pathogens other than GBS, such as Ent and S. epi, can contribute to respiratory failure and morbidity in human newborns (9, 10).However, there are no reports on the pulmonary hemodynamic effects of these other gram-positive bacteria.We postulated that the intravenous infusion of gram-positive neona...

Group B Streptococcus Promotes Oxygen Radical-Dependent Thromboxane Accumulation in Young Piglets

“…Multiple lines of evidence point to products of arachidonic acid metabolism, both thromboxane A2 and sulfidopeptide leukotrienes, as important participants in the adverse cardiopulmonary response (1)(2)(3)(4). Studies in our laboratory indicate that DMTU, a scavenger of hydroxyl radical and, at higher doses, hypochlorous acid (5, 6), suppresses GBS-induced pulmonary hypertension and arterial hypoxemia in young piglets (7), thereby suggesting that toxic oxygen radicals also participate in this model of sepsis-related pulmonary dysfunction.…”

Effects of Respiratory Alkalosis on Thromboxane-Induced Pulmonary Hypertension in Piglets

“…Intravenous epinephrine, indomethacin, dazmegrel, and the leukotriene receptor antagonist FPL5723 1 have been administered, and all reduce the degree of elevated PVR by both reducing Ppa and improving CO. The cyclooxygenase inhibitor, indomethacin, and the thromboxane synthetase inhibitor, dazmegrel, completely reversed the elevation in Ppa (17,(21)(22)(23). Epinephrine and FPL5723 1 reduced Ppa by only 20 and 35%, respectively (21,22).…”

“…In seven previous reports, intravenous group B streptococci produced a common hemodynamic response which included an increase in Ppa of 260-350% of baseline values, a reduction in CO by 30-60%, and an increase in PVR of 420-775% (17)(18)(19)(20)(21)(22)(23). Each of these reports has investigated a pharmacologic intervention that might improve hemodynamic function in septic infant animals.…”

Impact of Prostaglandin and Thromboxane Synthesis Blockade on Disposition of Group B Streptococcus in Lung and Liver of Intact Piglet

“…Blockade of prostaglandin H synthase (cyclooxygenase) with indomethacin or blockade of thromboxane synthase with dazmegrel forestalls increases in Ppa and pulmonary vascular resistance provoked by GBS in young piglets (1,2). Thromboxane also accumulates in systemic blood after challenge with GBS or other gram-positive organisms (3). Administration of a thromboxane mimetic elevates Ppa in a manner similar to the response to GBS (4).…”