Andrew J. Graham, MD,* and Winston K.Y. Chan, M D ~. Summary. We hypothesized that nitric oxide (NO) inhalation in a model of meconium aspiration.
Pediatric Pulmonology 20:27-33 (1995)
Inhaled Nitric Oxide Improves Oxygenation in Piglets With Meconium Aspiration Keith J. Barrington, MB ChB,' Neil N. Finer, MD,3 Abraham Peliowski, ID,^ Philip C. Etches, M B B C ~ Andrew ~ , J. Graham, MD,* and Winston K.Y. Chan, M
D ~
Summary. We hypothesizedthat nitric oxide (NO) inhalation in a model of meconium aspiration in newborn piglets would decrease pulmonary vascular resistance. Seven neonatal piglets were obtained at less than 48 hr of age and instrumented under fentanyl anesthesia. Inhaled NO (40 parts per million) was administered during normoxia and again after hypoxia was induced by reducing FiO, to 0.13. During normoxia NO inhalation caused a fall in pulmonary artery pressure from a mean of 3.15 (SD 0.8) kPa to 2.84 (SD 0.7) kPa (P < 0.01). Hypoxia (mean arterial 0, saturation 35%) increased PA pressures to a mean of 5.4 (SD1.6) kPa and NO administration during hypoxia decreased PA pressures to 3.6 (SD 1.2) kPa (P< 0.001). In order to determine the effects of NO in a model of meconium aspiration, 6 to 7 mUkg of 20% human meconium in normal saline was instilled into the trachea. This procedure induced hypoxemia (mean SaO, 43.4%, SD 19), respiratory acidosis, (mean PaCO, 12.1 kPa, SD 0.5; mean pH 7.04, SD 0.03), and pulmonary arterial hypertension (mean pulmonary artery pressure 6.0 kPa, SD 1.3) despite ventilation with 90% oxygen. Inhaled NO was then administered in concentrations of 5, 10, 20, 30, 40, 60, and 80 parts per million in random order according to a Latin square design. After meconium instillation, NO inhalation led to significant increases in mean arterial saturation of between 18 and 24 percentage points at all doses, and to statistically significant decreases in pulmonary arterial pressure (from 6.0 kPa, SD 1.3 to 5.1 kPa, SD 1.5, P < 0.01) and pulmonary vascular resistance index (from 0.033 kPaimLiminlkg, SD 0.003 to 0.029 kPalmLiminikg, SD 0.003, P < 0.01). Systemic blood pressure, cardiac index and systemic vascular resistance index did not change. The ratio between pulmonary and systemic vascular resistances fell, therefore, from a mean of 0.54 (SD 0.18) to 0.46 (SD 0.14). The effects of NO inhalation after meconium aspiration were qualitatively different to the effects during aveolar hypoxia, in that there was a lesser fall in the PAP and PVRl and a significant increase in SaO,. These results suggest that inhaled NO may be beneficial in meconium aspiration syndrome in human neonates, improving oxygenation by decreasing extrapulmonary shunting and by improving o 1995Wiley-Liss, Inc. ventilationiperfusionratios. Pediatr Pulmonol. 1995; 20:27-33. Key words: Nitric oxide, meconium aspiration, pulmonary hypertension, animal models, piglets, coronary blood flow.
INTRODUCTION It has recently been demonstrated that NO is a modulator of vasular tone,"2 and furthermore that inhaled NO gas will reduce hypoxic pulmonary artery hypertension without producing systemic effects in lamb^,^-^ piglets6,' and in human volunteers.8 However, the preliminary studies of inhaled NO utilized subjects without parenchymal or airway abnormalities. We were concerned that the efficacy, mode of action and dose response of NO may be significantly affected by parenchymal lung disease and/or airway abnormalities as observed in the majority of human infants treated with inhaled NO for pulmonary hypertension, e.g., infants with pneumonia or meconium aspiration pneumonitis. Recent studies of inhaled NO therapy have used models with lung injury relevant to adult lung diseases.',' Although these are important studies, the models are not directly relevant to the human 0 1995 Wiley-Liss, Inc.
infant with meconium aspiration because meconium often causes airway obstruction and a very patchy lung injury. We designed a study in an animal mode with meconium aspiration, severe hypoxemia, respiratory acidosis and pulmonary hypertension, and examined the effects of different concentrations of inhaled NO. We hypothesized that NO inhalation, after meconium instil-
From the 'University of Alberta Perinatal Research Centre and Departments of 'Pediatrics and 2Surgery, and 'The Royal Alexandra Hospital, Department of Newborn Medicine, Edmonton, Alberta, Canada. Received September 19, 1994; (revision) accepted for publication February 28, 1995. Address correspondence and reprint requests to Dr. Keith J . Barrington, 3A3 Walter Mackenzie Centre, 8220 114 Street, Edmonton, Alberta, Canada, T6G 2B7.
28
Barrington et al.
lation into the lungs of newborn piglets, would decrease pulmonary vascular resistance, improve oxygenation, and lessen intrapulmonary shunting. Inhaled NO in concentrations up to 80 ppm appears to have no systemic This is probably due to NO binding with hemoglobin to from nitrosyl-hemoglobin which is no longer vasoactive.” The effects of inhaled NO on the coronary circulation have not specifically been investigated. Since the coronary circulation is the first systemic vascular bed after the lungs, it would be the most likely to be affected. To obtain more information regarding the safety of NO therapy we, therefore, measured coronary artery blood flow in this model. METHODS NO Administration Nitric oxide in nitrogen in concentrations of approximately 800 parts per million (ppm) was obtained (Canadian Liquid Air, Montreal, Quebec). This source was certified to be +- 2% of the analyzed component (NO) and to contain
