Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets

Abstract

Inhaled nitric oxide (iNO) is routinely used for hypoxic respiratory failure and persistent pulmonary hypertension of the newborn, and investigation of its new indications requiring various levels of iNO is underway. Cumulated exposure of high level of iNO may exert adverse effects on lung function and morphology, which may be confounded with ventilator-associated lung injury. Sixteen healthy piglets (5.5–11 kg) were anaesthetised, intubated and mechanically ventilated at low FiO 2 on continuous positive airway pressure and pressure support mode. The animals were randomly allocated to receive 40 ppm iNO (NO group, n=8) or no iNO (Control group, n=8). In both groups at 24 and 48 h, mild to moderate lung injury was observed, with mean values of PaO 2/FiO 2<300 mmHg. Compared to the Control, iNO at 40 ppm for 24–48 h did not adversely affect dynamic compliance or resistance of respiratory system, oxygenation, pulmonary and systemic hemodynamics. Neither did it affect composition and surface activity of surfactant phospholipids and white cell counts in bronchoalveolar lavage fluid. Inhaled NO resulted in elevated total serum nitrite/nitrate to 352±90 μmol/l and methemoglobin (MetHb) to 5.0±3.4%, in contrast to 88±38 μmol/l and 0.88±0.52% in the Control; 50% of the iNO animals having MetHb>3%. The lung injury scores as well as alveolar expansion were similar between the two groups at 24 h. At 48 h, low wet/dry lung weight ratio and lung injury score were found in the NO group. We conclude that no significant adverse effects on lung physiology and structure were found in the piglets receiving 40 ppm iNO for 24 or 48 h, on the contrary lung injury was moderately alleviated. The significantly impaired gas exchange over time associated with discrete morphological changes suggests adverse effects of prolonged positive pressure breathing and not necessarily exposure to oxides of nitrogen.