Chronic lung disease of early infancy, or bronchopulmonary dysplasia, is a frequent complication of prolonged mechanical ventilation after premature birth. Pulmonary hypertension and edema are common features of this condition, which is often attributed to long-term, repetitive overinflation of incompletely developed lungs. The overall objective of this work was to examine the effects on the pulmonary circulation and lung fluid balance of different ventilation strategies using large versus small inflation volumes in an animal model of bronchopulmonary dysplasia. We studied 16 newborn lambs that were delivered prematurely (124+/-3 d gestation, term = 147 d) by cesarean section and mechanically ventilated for 3 to 4 wk. Ten lambs were ventilated at 20 breaths/min, yielding a tidal volume of 15+/-5 mL/kg, and six lambs were ventilated at 60 breaths/min, yielding a tidal volume of 6+/-2 mL/kg. All lambs received surfactant at birth and had subsequent surgery for closure of the ductus arteriosus and catheter placement to allow serial measurements of pulmonary vascular resistance and lung lymph flow. Chronic lung injury, documented by serial chest radiographs and postmortem pathologic examination, developed in all lambs irrespective of the pattern of assisted ventilation. Pulmonary vascular resistance, which normally decreases during the month after birth at term, did not change significantly from the first to the last week of study. Lung lymph flow, an index of net transvascular fluid filtration, increased with time in lambs that were ventilated at 20 breaths/min, but not in lambs ventilated at 60 breaths/min. Lymph protein concentration decreased with time, indicative of increased fluid filtration pressure, without evidence of a change in lung vascular protein permeability. Postmortem studies showed interstitial lung edema, increased pulmonary arteriolar smooth muscle and elastin, decreased numbers of small pulmonary arteries and veins, and decreased capillary surface density in distal lung of chronically ventilated lambs compared with control lambs that were killed either 1 d (same postconceptional age) or 3 wk (same postnatal age) after birth at term. Thus, chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance and leads to lung edema from increased fluid filtration pressure. These abnormalities of the pulmonary circulation may contribute to the abnormal respiratory gas exchange that often exists in infants with bronchopulmonary dysplasia.
Nitric oxide (NO), produced in lung vascular endothelium and airway epithelium, has an important role in regulating smooth muscle cell growth and tone. Chronic lung disease, a frequent complication of premature birth, is characterized by excess abundance, tone, and reactivity of smooth muscle in the pulmonary circulation and conducting airways, leading to increased lung vascular and airway resistance. Whether these structural and functional changes are associated with diminished pulmonary expression of endothelial nitric oxide synthase (eNOS) protein is unknown. Both quantitative immunoblot analysis and semiquantitative immunohistochemistry showed that there was less eNOS protein in the endothelium of small intrapulmonary arteries and epithelium of small airways of preterm lambs that were mechanically ventilated for 3 wk compared with control lambs born at term. No significant differences were detected for other proteins (inducible NOS, alpha-smooth muscle actin, and pancytokeratin). Lung vascular and respiratory tract resistances were greater in the chronically ventilated preterm lambs compared with control term lambs. These results support the notion that decreased eNOS in the pulmonary circulation and respiratory tract of preterm lambs may contribute to the pathophysiology of chronic lung disease.
Rationale: Bronchopulmonary dysplasia (BPD) is a frequent cause of morbidity in preterm infants that is characterized by prolonged need for ventilatory support in an intensive care environment. BPD is characterized histopathologically by persistently thick, cellular distal airspace walls. In normally developing lungs, by comparison, remodeling of the immature parenchymal architecture is characterized by thinning of the future alveolar walls, a process predicated on cell loss through apoptosis. Objectives: We hypothesized that minimizing lung injury, using highfrequency nasal ventilation to provide positive distending pressure with minimal assisted tidal volume displacement, would increase apoptosis and decrease proliferation among mesenchymal cells in the distal airspace walls compared with a conventional mode of support (intermittent mandatory ventilation). Methods: Accordingly, we compared two groups of preterm lambs: one group managed by high-frequency nasal ventilation and a second group managed by intermittent mandatory ventilation. Each group was maintained for 3 days. Measurements and Main Results: Oxygenation and ventilation targets were sustained with lower airway pressures and less supplemental oxygen in the high-frequency nasal ventilation group, in which alveolarization progressed. Thinning of the distal airspace walls was accompanied by more apoptosis, and less proliferation, among mesenchymal cells of the high-frequency nasal ventilation group, based on morphometric, protein abundance, and mRNA expression indices of apoptosis and proliferation. Conclusions: Our study shows that high-frequency nasal ventilation preserves the balance between mesenchymal cell apoptosis and proliferation in the distal airspace walls, such that alveolarization progresses.
Ibuprofen-induced patent ductus arteriosus closure improved pulmonary mechanics, decreased total lung water, increased epithelial sodium channel expression, and decreased the detrimental effects of preterm birth on alveolarization.
BackgroundShort-term high-frequency nasal ventilation (HFNV) of preterm neonates provides acceptable gas exchange compared to endotracheal intubation and intermittent mandatory ventilation (IMV). Whether long-term HFNV will provide acceptable gas exchange is unknown. We hypothesized that HFNV for up to 21d would lead to acceptable gas exchange at lower inspired oxygen (O2) levels and airway pressures compared to intubation and IMV.MethodsPreterm lambs were exposed to antenatal steroids, and treated with perinatal surfactant and postnatal caffeine. Lambs were intubated and resuscitated by IMV. At ~3h of age, half of the lambs were switched to non-invasive HFNV. Support was for 3d or 21d. By design, PaO2 and PaCO2 were not different between groups.ResultsAt 3d (n=5) and 21d (n=4) of HFNV, fractional inspired O2 (FiO2), peak inspiratory pressure, mean airway, intra-tracheal, and positive end-expiratory pressures, oxygenation index, and Alveolar-arterial gradient were significantly lower than matched periods of intubation and IMV. PaO2/FiO2 ratio was significantly higher at 3d and 21d of HFNV compared to matched intubation and IMV. HFNV led to better alveolarization at 3d and 21d.ConclusionLong-term HFNV provides acceptable gas exchange at lower inspired O2 levels and respiratory pressures compared to intubation and IMV.
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