GROUP-B STREPTOCOCCAL SEPSIS IN PIGLETS - EFFECT OF COMBINED PENTOXIFYLLINE AND INDOMETHACIN PRETREATMENT

Group B streptococcus (GBS), a common neonatal gram-positive pathogen, causes similar pathophysiology in human newborns and neonatal animal models of sepsis. Animal models of GBS sepsis demonstrate a two-phase response: 1) an acute phase (< 1 h) of increased pulmonary artery pressure (P(pa)) and reduced arterial oxygen pressure (PaO2) that is associated with increased serum thromboxane B2 (TxB2) and 2) a late phase (2-4 h) of persistently increased P(pa) and reduced PaO2, reduced systemic arterial pressure, and progressive fall in cardiac output that is associated with increased serum TxB2, 6-keto-prostaglandin F1-alpha (6-keto-PGF1-alpha), and tumor necrosis factor-alpha (TNF-alpha). We hypothesized that pretreatment of piglets with both pentoxifylline (PTF), an inhibitor of TNF-alpha production and activity, and indomethacin (INDO) would 1) inhibit GBS-induced TxB2, 6-keto-PGF1-alpha, and TNF-alpha and 2) prevent both the acute- and late-phase physiologic responses of GBS sepsis. Combined PTF and INDO pretreatment of anesthetized, mechanically ventilated piglets infused with GBS (1.25 x 10(9) colony forming units/kg/h) for 4 h prevented GBS-induced increases in P(pa) at 1 h (GBS + PTF + INDO: 1.8 +/- 0.07 kPa versus GBS alone: 4.7 +/- 0.1 kPa) and markedly attenuated increases in P(pa) at 4 h (GBS + PTF + INDO: 2.1 +/- 0.1 kPa versus GBS alone: 4.4 +/- 0.1 kPa). PTF + INDO treatment prevented GBS-induced reductions in both mixed venous oxygen pressure and PaO2 at 1, 2, and 4 h (GBS + PTF + INDO: 11.5 +/- 0.4 kPa versus GBS alone: 7.1 +/- 0.4 kPa), and attenuated GBS-induced declines in cardiac output. PTF + INDO treatment significantly attenuated GBS-induced serum TNF-alpha polypeptide levels (ELISA, pg/mL) at 4 h (GBS + PTF + INDO: 143 +/- 45 versus GBS alone: 502 +/- 147) and blocked GBS-induced increases in serum TxB2 and 6-keto-PGF1-alpha (all levels < 10 pg/0.1 mL by RIA). INDO pretreatment alone prevented GBS-induced increases in serum TxB2 and 6-keto-PGF-1-alpha levels but did not significantly inhibit GBS-induced TNF-alpha production. INDO pretreatment alone did not attenuate GBS-induced increases in Ppa at 4 h, nor prevent late-phase reductions in both PaO2 and mixed venous oxygen pressure. PTF + INDO treatment of GBS sepsis in piglets is superior to treatment with INDO or PTF alone. Inhibition of both blood eicosanoid and TNF-alpha production may provide adjunctive therapy for human newborns with sepsis and pulmonary hypertension.