Effects of a Nebulized NONOate, DPTA/NO, on Group B Streptococcus–Induced Pulmonary Hypertension in Newborn Piglets

Abstract

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4 -10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 ϫ 10 8 CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p Ͻ 0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p Ͻ 0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates. Group B Streptococcus (GBS) sepsis is characterized by pulmonary hypertension, arterial hypoxemia, metabolic acidosis, decreased cardiac output (CO), and systemic hypotension progressing sometimes to irreversible shock (1). Despite modern intensive care, this condition continues to carry high morbidity and mortality. Many modalities have been proposed for the management of pulmonary hypertension, including cytokine inhibitors and vasodilators (2-7). However, clinical application of these modalities is limited because of significant side effects and lack of selectivity to the pulmonary vasculature.Inhaled nitric oxide (iNO) has emerged in recent years as an effective and selective treatment modality for pulmonary hypertension. Its effectiveness in treating persistent pulmonary hypertension of the newborn was documented in a number of animal models and also clinical trials (8,9). In animal models of pulmonary hypertension induced by GBS sepsis, iNO was

Effects of Intermittent Nebulization of NONOate, DPTA/NO, on Group B <i>Streptococcus</i>-Induced Pulmonary Hypertension in Newborn Piglets

“…A 5-Fr Swan-Ganz thermodilution catheter introduced into the right external jugular vein and advanced under fluoroscopy into the left pulmonary artery was used for cardiac output (CO), pulmonary artery (Ppa), and wedge pressure (Pwp) measurements. A 3.5-Fr catheter was introduced into the right atrium and used for right atrial pressure (Pra) measurements [18] . Vascular pressures were measured with pressure transducers (Model P23; Gould Instruments, Cleveland, Ohio, USA) and recorded on a multichannel recorder (Model 2800; Gould Instruments).…”

“…CO was measured by the thermodilution method using a cardiac output computer (Model 9510-A; Edwards Laboratories, Santa Ana, Calif., USA). Pulmonary vascular resistance (PVR) and SVR were calculated [18] .…”

“…Group B ␤ -hemolytic streptococci type I a/c isolated from an infected neonate were cultured in ToddHewitt broth for 18 h at 37 ° C and then prepared as previously described [18] .…”

“…Using the criterion of attenuation of PH by at least 30% (from 15 min measurements) with minimal side effects, the dose of 50 mg was selected. Timing of the second dose was based on our previous study when a single dose of DPTA/NO was administered to newborn piglets with GBS-induced PH [18] . In that study, we observed significant attenuation of PVR after administration of a single dose of DPTA/NO that lasted up to 120 min, but with the maximum sustained effect for the first 75 min after GBS-induced PH.…”

“…We have previously shown that a single dose of nebulized DPTA/NO can effectively attenuate acute GBS-induced PH in newborn piglets [18] , but this was accompanied by a decrease in systemic vascular resistance (SVR) to values close to those before GBS infusion. This raises the question of the effect of a repeated dose of nebulized NONOate on the systemic vasculature in GBS-induced PH.…”