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 (Ppa) 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 Ppa and reduced Pao2, reduced systemic arterial pressure, and progressive fall in cardiac output that is associated with increased serum TxB2, 6-keto-prostaglandin Fl$$ (6-keto-PGFi$$), and tumor necrosis factor-α (TNF$$). We hypothesized that pretreatment of piglets with both pentoxifylline (PTF), an inhibitor of TNF$$ production and activity, and indomethacin (INDO) would 1) inhibit GBS-induced TxB2, 6-keto-PGF1%, and TNF“ 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 109 colony forming units/ kg/h) for 4 h prevented GBS-induced increases in Ppa at 1 h (GBS+PTF+INDO: 1.8 $$ 0.07 kPa versus GBS alone: 4.7 ± 0.1 kPa) and markedly attenuated increases in Ppa at 4 h (GBS+PTF+INDO: 2.1 ± 0.1 kPa versus GBS alone: 4.4 ± 0.1 kPa). PTF+INDO treatment prevented GBS-induced reductions in both mixed venous oxygen pressure and Pao2 at 1, 2, and 4 h (GBS+PTF+INDO: 11.5 ± 0.4 kPa versus GBS alone: 7.1 ± 0.4 kPa), and attenuated GBS-induced declines in cardiac output. PTF+INDO treatment significantly attenuated GBS-induced serum TNF$$ 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% (all levels < 10 pg/0.1 mL by RIA). INDO pretreatment alone prevented GBS-induced increases in serum TxB2 and 6-keto-PGF1$$* levels but did not significantly inhibit GBS-induced TNF$$ 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$$ production may provide adjunctive therapy for human newborns with sepsis and pulmonary hypertension.