Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hypertension. The hemodynamic effects of ET-1 are ...due to activation of its receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ET(B) receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ET(B) receptor activity and gene expression are decreased. To determine whether prolonged ET(B) receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ET(B) receptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ET(B) receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ET(B) receptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries (P < 0. 05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 (P < 0.05). We conclude that prolonged selective ET(B) receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.
Objective: To describe the outcome of a group of term newborn infants treated with inhaled nitric oxide for severe persistent pulmonary hypertension.
Study design: We performed a prospective ...longitudinal medical and neurodevelopmental follow-up of 51 infants treated as neonates for persistent pulmonary hypertension of the newborn with inhaled nitric oxide. The original number of treated infants was 87, of whom 25 died in the neonatal period; of 62 infants who survived, 51 were seen at 1 year of age and 33 completed a 2-year evaluation. Statistical analysis used population medians, means, and standard deviations for parameters assessed. Paired
t tests and chi-square analysis were used to compare outcomes measured at 1 year with assessments at 2 years for the 32 infants seen at both 1- and 2-year visits.
Results: At 1-year follow-up median growth percentiles were 20%, 72.5%, and 50% for weight, length, and occipitofrontal circumference, respectively. Thirteen of 51 infants (25.5%) were <5th percentile in weight. Nine of 51 infants (17.6%) had feeding problems (need for gastrostomy feeding or gastroesophageal reflux), and 14 (27.5%) had a clinical diagnosis of reactive airways disease. Infant development as measured by the Bayley Scales of Infant Development was 104 ± 16 for the mental development index and 97 ± 20 for the psychomotor index. Six of 51 infants (11.8%) were found to have severe neurologic handicaps, defined as a Bayley score on either the mental development or psychomotor index of <68, abnormal findings on neurologic examination, or both. Fewer children (6.1% vs 15.7%) required supplemental oxygen at 2 years compared with 1 year, and performance on the psychomotor index of the Bayley Scales improved significantly.
Conclusions: One- and 2-year follow-up of a cohort of infants with persistent pulmonary hypertension of the newborn who were treated with inhaled nitric oxide had an 11.8% (1 year) and 12.1% (2-year) rate of severe neurodevelopmental disability. There are ongoing medical problems in these infants including reactive airways disease and slow growth that merit continued close longitudinal follow-up. (J Pediatr 1997;131:70-5)
Monitoring lung volume is important in the treatment of acute hypoxemic respiratory failure. However, there are no tools available for lung volume measurement to guide ventilator management during ...high-frequency oscillatory ventilation (HFOV) and during dynamic changes in conventional ventilation (CV). We studied the performance of a new respiratory inductive plethysmograph (RIP) with modified software. We measured Delta changes in lung volume above end-expiratory volume (V(RIP)) during HFOV and studied whether changes in V(RIP) parallel changes in mean airway pressure. Calibration of the plethysmograph was made by serial injections of a known gas volume in six term (140 d gestation) and eight preterm (125 d gestation) lambs. Linear regression analysis of the relationship between injected gas volume and V(RIP) showed strong correlation (r(2) = 0.93-1.00 term animals, r(2) = 0.86-1.00 preterm animals). The pressure volume curves from the calibration with the injected gas volumes also correlated well with the pressure volume curves extrapolated from changes in V(RIP). Lung hysteresis was clearly demonstrated with RIP after changes in mean airway pressure during HFOV and after changes in positive end-expiratory pressure during CV. We conclude that measurements of lung volume in term and preterm lambs by use of modified RIP correlate well with changes in mean airway pressure during HFOV, with static pressure volume curves and with changes in positive end-expiratory pressure during CV. We speculate that this technique may provide clinically useful information about changes in lung volume during HFOV and CV. However, evaluation of the precision and chronic stability of RIP measurements over prolonged periods will require further studies.
Persistent pulmonary hypertension of the newborn (PPHN) is a clinical disorder characterized by abnormal vascular structure, growth, and reactivity. Disruption of vascular growth during early ...postnatal lung development impairs alveolarization, and newborns with lung hypoplasia often have severe pulmonary hypertension. To determine whether pulmonary hypertension can directly impair vascular growth and alveolarization in the fetus, we studied the effects of chronic intrauterine pulmonary hypertension on lung growth in fetal lambs. We performed surgery, which included partial constriction of the ductus arteriosus (DA) to induce pulmonary hypertension (PH, n = 14) or sham surgery (controls, n = 13) in fetal lambs at 112-125 days (term = 147 days). Tissues were harvested near term for measurement of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), mean linear intercepts (MLI), wall thickness, and vessel density of small pulmonary arteries. Chronic DA constriction caused RVH (P < 0.0001), increased wall thickness of small pulmonary arteries (P < 0.002), and reduced small pulmonary artery density (P < 0.005). PH also reduced alveolarization, causing a 27% reduction in RAC and 20% increase in MLI. Furthermore, prolonged DA constriction (21 days) not only decreased RAC and increased MLI by 30% but also caused a 25% reduction of lung-body weight ratio. We conclude that chronic PH reduces pulmonary arterial growth, decreases alveolar complexity, and impairs lung growth. We speculate that chronic hypertension impairs vascular growth, which disrupts critical signaling pathways regulating lung vascular and alveolar development, thereby interfering with alveolarization and ultimately resulting in lung hypoplasia.
To determine maturation-related changes in nitric oxide (NO) activity in the developing pulmonary circulation, we studied the hemodynamic effects of endogenous NO inhibition under basal conditions in ...the premature ovine fetus and the response to birth-related stimuli and exogenous NO in 30 fetal sheep at three different gestational ages. At 0.95 term, pulmonary vasodilation during inhaled NO (20 parts per million) was equivalent to the dilator response to 100% O2, but at 0.86 term vasodilation during inhaled NO was greater than the dilator response to 100% O2 (P < 0.05). At 0.78 term, left pulmonary arterial flow (QLPA) did not increase with exposure to either NO or 100% O2. Intrapulmonary infusion of nitro-L-arginine (L-NA) increased basal pulmonary vascular resistance 38% in the premature fetus at 0.78 term. L-NA treatment decreased the ventilation-induced rise in QLPA by 60% compared with controls (P < 0.05). Inhaled NO but not 100% O2 increased QLPA after L-NA treatment to levels achieved with ventilation alone in the controls. We conclude that in the premature pulmonary circulation (0.78 term) 1) basal pulmonary vascular resistance is modulated by endogenous NO, 2) pulmonary vasodilation at birth is partly mediated by endogenous NO activity, and 3) inhaled NO causes potent vasodilation.
Growth and development of the lung normally occur in the low oxygen environment of the fetus. The role of this low oxygen environment on fetal lung endothelial cell growth and function is unknown. We ...hypothesized that low oxygen tension during fetal life enhances pulmonary artery endothelial cell (PAEC) growth and function and that nitric oxide (NO) production modulates fetal PAEC responses to low oxygen tension. To test this hypothesis, we compared the effects of fetal (3%) and room air (RA) oxygen tension on fetal PAEC growth, proliferation, tube formation, and migration in the presence and absence of the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine (LNA), and an NO donor, S-nitroso-N-acetylpenicillamine (SNAP). Compared with fetal PAEC grown in RA, 3% O(2) increased tube formation by over twofold (P < 0.01). LNA treatment reduced tube formation in 3% O(2) but had no affect on tube formation in RA. Treatment with SNAP increased tube formation during RA exposure to levels observed in 3% O(2). Exposure to 3% O(2) for 48 h attenuated cell number (by 56%), and treatment with LNA reduced PAEC growth by 44% in both RA and 3% O(2). We conclude that low oxygen tension enhances fetal PAEC tube formation and that NO is essential for normal PAEC growth, migration, and tube formation. Furthermore, we conclude that in fetal cells exposed to the relative hyperoxia of RA, 21% O(2), NO overcomes the inhibitory effects of the increased oxygen, allowing normal PAEC angiogenesis and branching. We speculate that NO production maintains intrauterine lung vascular growth and development during exposure to low O(2) in the normal fetus. We further speculate that NO is essential for pulmonary angiogenesis in fetal animal exposed to increased oxygen tension of RA and that impaired endothelial NO production may contribute to the abnormalities of angiogenesis see in infants with bronchopulmonary dysplasia.
We performed serial measurements of plasma endothelin-1 and cytokine levels (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) in 23 children with severe acute respiratory distress ...syndrome during their first 7 days of disease. We report plasma endothelin-1 and interleukin-6 levels are increased in patients with acute respiratory distress syndrome, and that plasma endothelin-1 levels are significantly greater early in the clinical course of nonsurvivors than survivors. We conclude that plasma endothelin-1 levels are markedly increased in children with severe acute respiratory distress syndrome and speculate that high levels may serve as an early marker of poor outcome. (J Pediatr 1999;135:246-9)
To determine the effects of inhaled nitric oxide (NO) on pulmonary hemodynamics and gas exchange in experimental hyaline membrane disease (HMD), we studied 16 premature lambs (0.78 term) in two ...separate protocols. All animals were treated with exogenous surfactant before mechanical ventilation. In protocol 1, we measured the acute response to brief treatment with inhaled NO (20 ppm, 20 min) after 2 h of mechanical ventilation with fraction of inspired oxygen of 1.00 (n = 5). After 2 h, brief NO treatment lowered pulmonary vascular resistance from 0.26 +/- 0.05 to 0.16 +/- 0.03 mm Hg.(mL/min)-1 (p < 0.01) and improved gas exchange (arterial PO2, 44 +/- 9 mm Hg baseline to 168 +/- 45 mm Hg NO, p < 0.01; arterial PCO2 45 +/- 5 mm Hg baseline to 35 +/- 4 mm Hg NO, p < 0.05). In protocol 2, to determine whether early and continuous treatment with inhaled NO could sustain improvement in gas exchange and pulmonary hemodynamics in severe HMD, we compared the physiologic effects of ventilation with high inspired oxygen concentrations for 3 h with NO (20 ppm, n = 6) and without NO (controls, n = 5). After 3 h, the NO treatment group had sustained reduction in pulmonary vascular resistance (0.10 +/- 0.01 mm Hg.(mL/min)-1 NO versus 0.25 +/- 0.04 mm Hg.(mL/min)-1 control, p < 0.05), increased left pulmonary artery blood flow (204 +/- 24 mL/min NO versus 109 +/- 15 mL/min control, p < 0.05), and increased arterial PO2 (114 +/- 27 mm Hg NO versus 36 +/- 11 mm Hg control, p < 0.05).
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