Background Respiratory distress syndrome is an important cause of mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The LAD (MC3 Inc., Ann Arbor, MI) is a pumpless, low-pressure extracorporeal oxygenator. The LAD has reproducibly improved mortality in adult animals. In an earlier study, we demonstrated the feasibility of the LAD in improving gas exchange in juvenile piglets. Objective To test the effect of the LAD on pulmonary histopathology and mechanics in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by mechanical ventilation (IMV). Design/Methods Three- to 4-week-old acutely instrumented and intubated piglets were randomized (n = 4 each) to no further intervention (normal), SLL (30 cc/kg 3 4), SLL + IMV 3 6 hrs or SLL + IMV + LAD 3 6 hrs. The LAD was attached between the carotid artery and jugular vein. Flow through the device, gas exchange, pulmonary arterial pressure, hemodynamic variables, and cardiac output were measured with and without flow through the device. Mechanical ventilation was systemically weaned in both study groups to keep PaCO2 = 35-45 mm and PaO2 = 50-60 mm Hg. Lung histology was scored by an observer masked to treatment group following a standardized system for lung injury scoring. Data were compared by ANOVA to detect differences between the groups. Results There was no difference in hemodynamic variables between the study groups. Mechanical ventilation could be successfully weaned in the SLL + IMV + LAD group. Adequate flow (25-40% of cardiac output) could be achieved through the LAD. There was a significant increase in the total lung injury score in the SLL + IMV group (p = .03) but the SLL + IMV + LAD group was comparable to both control groups. Prolonged mechanical ventilation significantly increased inflammation (p = .02) and airway injury (p < .01), while there were no differences in hemorrhage, septal thickening, and formation of hyaline membranes. Conclusions These results demonstrate the feasibility and potential of a novel pumpless low-pressure gas exchange assist device to decrease ventilator-induced lung injury in a neonatal animal model.

Introduction Respiratory failure and persistent pulmonary hypertension are important causes of mortality in term infants. Extracorporeal membrane oxygenation reduces mortality but is associated with morbidity. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. LAD (MC3 Inc., Ann Arbor, MI) is a pumpless, low pressure extracorporeal oxygenator. It has improved gas exchange in adult animals. Purpose To test the feasibility of the LAD in juvenile piglets with hypoxia-induced pulmonary hypertension. Methods The LAD was attached between the carotid artery and jugular vein of 4-week-old acutely instrumented piglets (n = 3). Pulmonary hypertension was acutely induced by hypoxia (FiO2 = 10%). Gas exchange, pulmonary pressure, hemodynamic variables, and cardiac output were measured with and without flow through the device. Results Successful LAD cannulation was achieved in all 3 animals with no complications. The LAD increased PaO2 from 26 mm Hg (pre-device) to 530 mm Hg (post-device) and decreased PaCO2 from 45 mm Hg (pre-device) to 5 mm Hg (post-device) (n = 2). In the three animals, systemic arterial pressure decreased by 1-9%, cardiac output remained stable, and hematocrit decreased by 1-10%. Acidosis developed in one animal. In one animal, pulmonary arterial pressures decreased by 62% (Figure) and systemic oxygenation improved marginally (PaO2 increased by 12%) with initiation of flow through LAD. Conclusion These preliminary results demonstrate the feasibility and potential of a novel pumpless low-pressure gas exchange assist device that is perfused by the cardiac output to maintain perfusion, improve gas exchange, and decrease pulmonary hypertension.

Introduction Randomized trials indicate vitamin A (VA) supplementation decreases bronchopulmonary dysplasia or death in extremely premature infants. It is important to understand the mechanisms by which VA and its derivative retinoic acid (RA) prevent or reverse lung injury. Aims The hypothesis was that newborn C57BL/6 mice administered VA in combination with RA would reduce hyperoxic lung injury and increase lung retinyl ester (RE) content as compared to animals administered VA, RA, or vehicle alone (canola oil). Methods Newborn C57BL/6 mice were exposed to 95% O2 or room air from birth and sacrificed at 4 days of age. The agent (VA, RA or the combination VARA)/vehicle was given orally daily. Lungs were evaluated for lung injury (epithelial damage and hemorrhage) by a masked observer, and RE were measured by HPLC in the lung and liver. Results Hyperoxia led to lung injury, which was reduced more by VARA than by either VA or RA alone (Figure). Epithelial damage and hemorrhage correlated well with each other (r = .94, p < .001). RE levels increased more with VARA than by VA or RA alone (data not shown). Conclusions Retinoids reduce hyperoxic lung injury in newborn mice. The combination of VA and RA may have synergistic effects on tissue retinoid levels.

Levcromakalim (LKM; a K(ATP) channel opener) reverses hypoxic pulmonary vasoconstriction in isolated pulmonary arteries and perfused lungs. This vasorelaxation is blocked by glibenclamide (GLB; a K(ATP) channel blocker). We evaluated the hemodynamic effect of LKM followed by GLB in a chronically instrumented neonatal porcine model of pulmonary hypertension, created by exposing piglets to hypoxia (n = 7) or heat-killed group B streptococci (GBS) (n = 6). Hypoxia increased pulmonary arterial pressure (PAP), which LKM decreased, and GLB subsequently increased in a dose-dependent manner. Systemic arterial pressure (SAP) did not change with hypoxia but was also decreased by LKM and increased by GLB. GBS also led to increased PAP, but LKM significantly reduced only SAP, which was then increased by GLB. We conclude LKM is capable of reversing hypoxic, but not GBS-induced, pulmonary hypertension but lacks specificity for the neonatal pulmonary vasculature.

RATIONALE Cigarette smoke exposure in the perinatal period increases the risk of various prenatal and postnatal complications, including sudden infant death syndrome (SIDS) and persistent pulmonary hypertension of the newborn (PPHN). We investigated the cellular effects of cigarette smoke extract (CSE) in the developing vasculature. METHODS Vascular smooth muscle cells (VSMC) were isolated from neonatal porcine carotid arteries, splenic arteries, and main and resistance pulmonary arteries. Effects of CSE on VSMC proliferation, viability, apoptosis, and media nitrates and nitrites were evaluated. The effects of known constituents of CSE (nicotine, benzopyrene, acrolein, acetaldehyde), aged CSE, CSE with added hemoglobin, devolatilized CSE, CSE with added dithiothreitol (DTT), and reduced glutathione (GSH) on cell proliferation and viability were assessed. RESULTS CSE caused a dose- and time-dependent decrease in neonatal VSMC numbers isolated from all four sites, mainly as a result of increased cell necrosis and not apoptosis. Nitrates and nitrites were below the threshold of detection. Nicotine and benzopyrene did not affect cell counts, while acrolein and acetaldehyde decreased cell counts in a dose-dependent manner. Addition of hemoglobin, devolatilization, and the addition of DTT or GSH slightly decreased CSE inhibition. CONCLUSIONS CSE causes necrosis of neonatal VSMC, and this toxicity is mediated mainly by volatile components such as acrolein and acetaldehyde, possibly in association with nitric oxide and carbon monoxide.