INHALED NITRIC OXIDE SURFACTANT AND NASAL CPAP

Respiratory distress syndrome (RDS) still represents one of the main problems in the treatment of premature infants. Despite the use of surfactant replacement therapy RDS adds to the need for endotracheal intubation and mechanical ventilation (MV). Enhancing the efficacy of CPAP treatment could reduce the use of MV thereby possibly minimising complications such as bronchopulmonary dysplasia (BPD) The overall aim was to find methods to reduce the severity of lung damage in newborns by augmenting the efficacy of early treatment by combining nasal CPAP and exogenous surfactant with inhaled nitric oxide (iNO). We devised an iNO delivery system by modifying a commercially available nCPAP system and measured the NO2 formation at different stock gas concentrations. We used this system to record the acute effects on oxygenation, respiratory rate and CO2 levels in 15 RDS infants during a short term exposure to 10 ppm iNO under nCPAP treatment in a cross-over study. The modified system had a low rate of NO2 formation. Stock gas cylinder concentration of 50 ppm NO had several advantages allowing simplification of administration and monitoring in comparison with 1000 ppm. Applying the system to premature newborns with moderate RDS, results in significantly improved oxygenation especially in the more premature patients. Respiratory rate and CO2 levels remain unaffected in spontaneously breathing patients during a 30-min exposure. A secondary aim was to investigate different possible adverse effects of iNO to patients and staff. We measured the occupational exposure levels encountered working close to a baby on iNOCPAP and described the expected addition of NO and NO2 to the air in an ICU room. We also investigated the levels produced in case of a sudden release from an NO gas cylinder in an ICU room. The system contributes only to a small extent to ICU room levels of NOx. As a point source, brief peaks of more concentrated but still low NO levels were seen. The total release of a 20 litre cylinder 1000 ppm NO resulted in room levels of 30 ppm NO and 0.8 ppm NO2. Our proposal to use early NO in illnesses characterized by surfactant dysfunction clearly calls for studies of larger groups of patients. It was therefore important to investigate to what extent NO or concurrently produced NO2 might damage surfactant and at what dose such effects would occur. Sedated spontaneously breathing piglets were given a high NO dose of 100 ppm for 4h or 10 ppm NO2. The effect of only sedation on surfactant function was studied separately. The exposure to 100 ppm NO in air for 4 hours resulted in slightly impaired surfactant function with higher surface tension of lung lavage fluid compared to control. This was not due to concomitantly formed NO2 since piglets exposed to only 10 ppm NO2 had normal surfactant function. We also exposed sedated piglets under assisted spontaneous breathing to 40 ppm iNO for 24 and 48 h which resulted in no surfactant abnormalities and preserved features in lung tissue histology. Just as clinical use of exogenous surfactant has moved in the direction of prophylaxis from rescue, after extensive studies, clinical use of iNO may face a similar development with an increased emphasis on lung development and anti-inflammatory action rather than acute improvements in oxygenation and pulmonary vascular tone. LIST OF PUBLICATIONS Papers will be referred to in the text by roman numerals I. Lindwall R, Frostell CG, Lonnqvist PA. Delivery characteristics of a combined nitric oxide nasal continuous positive airway pressure system. Paediatr Anaesth. 2002 Jul;12(6):530-6. II. Lindwall R, Blennow M, Svensson M, Jonsson B, BerggrenBoström E, Flanby M, Lönnqvist PA, Frostell CG, Norman M. A pilot study of inhaled nitric oxide in preterm infants treated with nasal CPAP for RDS. Intensive care medicine, Accepted for Publication 2005 02 17. III. Lindwall R, Svensson M, Frostell CG, Eksborg S, Gustafsson LE. Occupational exposure to NO and NO2 during combined treatment of infants with nasal CPAP and nitric oxide. Manuscript. IV. Lindwall R, Högman M, Linderholm B, Robertson B, Eksborg S, Frostell CG. High dose nitric oxide alters surfactant function in spontaneously breathing piglets. Under review. V. Zhang H, Lindwall R, Zhu L, Frostell CG, Sun B. Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets. Pulm Pharmacol Ther. 2003;16(3):163-9.