Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia

ABSTRACT

We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO₂ response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO₂ of 39 ± 50 mm Hg versus a mean decrease of 11 ± 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

KEYWORDS

Nitric oxide - pulmonary hypoplasia - oligohydramnios - PPROM - bronchopulmonary dysplasia

REFERENCES

• 1 Mercer B M, Goldenberg R L, Meis P J et al.. The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.  Am J Obstet Gynecol. 2000;  183 738-745
• 2 Winn H N, Chen M, Amon E, Leet T L, Shumway J B, Mostello D. Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes: a critical analysis.  Am J Obstet Gynecol. 2000;  182 1638-1644
• 3 Kilbride H W, Yeast J, Thibeault D W. Defining limits of survival: lethal pulmonary hypoplasia after midtrimester premature rupture of membranes.  Am J Obstet Gynecol. 1996;  175 675-681
• 4 Kumar V H, Hutchison A A, Lakshminrusimha S, Morin III F C, Wynn R J, Ryan R M. Characteristics of pulmonary hypertension in preterm neonates.  J Perinatol. 2007;  27 214-219
• 5 Geary C, Whitsett J. Inhaled nitric oxide for oligohydramnios-induced pulmonary hypoplasia: a report of two cases and review of the literature.  J Perinatol. 2002;  22 82-85
• 6 Peliowski A, Finer N N, Etches P C, Tierney A J, Ryan C A. Inhaled nitric oxide for premature infants after prolonged rupture of the membranes.  J Pediatr. 1995;  126 450-453
• 7 Van Meurs K P, Wright L L, Ehrenkranz R A et al.. Inhaled nitric oxide for premature infants with severe respiratory failure.  N Engl J Med. 2005;  353 13-22
• 8 Van Meurs K P, Hintz S R, Ehrenkranz R A et al.. Inhaled nitric oxide in infants > 1500 g and < 34 weeks gestation with severe respiratory failure.  J Perinatol. 2007;  27 347-352
• 9 Kabra N S, Kluckow M R, Powell J. Nitric oxide in preterm infant with pulmonary hypoplasia.  Indian J Pediatr. 2004;  71 427-429
• 10 Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios.  Pediatr Int. 2004;  46 10-14
• 11 Clark R H, Kueser T J, Walker M W et al.. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group.  N Engl J Med. 2000;  342 469-474
• 12 Hoffman G M, Nelin L D. Mean airway pressure and response to inhaled nitric oxide in neonatal and pediatric patients.  Lung. 2005;  183 441-453
• 13 Rossaint R, Falke K J, Lopez F, Slama K, Pison U, Zapol W M. Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med. 1993;  328 399-405
• 14 Bland R D, Albertine K H, Carlton D P, MacRitchie A J. Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs.  Am J Respir Crit Care Med. 2005;  172 899-906
• 15 Roberts Jr J D, Chiche J D, Weimann J, Steudel W, Zapol W M, Bloch K D. Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups.  Circ Res. 2000;  87 140-145
• 16 Kinsella J P, Parker T A, Galan H, Sheridan B C, Halbower A C, Abman S H. Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease.  Pediatr Res. 1997;  41 457-463
• 17 Verma S, Wang C H, Li S H et al.. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis.  Circulation. 2002;  106 913-919
• 18 Ziesche R, Petkov V, Williams J et al.. Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue.  Proc Natl Acad Sci U S A. 1996;  93 12478-12483
• 19 Kinsella J P, Cutter G R, Walsh W F et al.. Early inhaled nitric oxide therapy in premature newborns with respiratory failure.  N Engl J Med. 2006;  355 354-364
• 20 American Academy of Pediatrics Committee on Fetus and Newborn . Use of inhaled nitric oxide.  Pediatrics. 2000;  106 344-345
• 21 Barrington K J, Finer N N. Inhaled nitric oxide for preterm infants: a systematic review.  Pediatrics. 2007;  120 1088-1099