Stellenwert der Inhalation von Stickstoffmonoxid (NO) bei Frühgeborenen<34 Gestationswochen

Zusammenfassung

In Europa wurde inhalatives NO (iNO) Ende 2001 als Medikament zur Behandlung der pulmonalen Hypertension beim reifen Neugeborenen und älteren Frühgeborenen >34 Gestationswochen zugelassen. INO scheint auch bei einem Teil der Frühgeborenen <34 Gestationswochen eine Hypoxämie verbessern zu können. In insgesamt 21 randomisiert-kontrollierten Studien wurden 3 336 Frühgeborene <34 Gestationswochen eingeschlossen. Die Behandlung mit iNO reduziert jedoch weder die Sterblichkeit noch die Rate der bronchopulmonalen Dysplasie (BPD). Auch das kombinierte Risiko aus Tod und BPD wird durch die iNO-Behandlung in dieser Altersgruppe für Frühgeborene mit einem manifesten Lungenversagen oder einem erhöhten BPD-Risiko nicht verändert. Möglicherweise kann eine frühe prophylaktische iNO-Gabe bei Atemstörung die Rate der Frühgeborenen erhöhen, welche ohne BPD, intraventrikuläre Blutungen ≥ III. Grades oder periventrikuläre Leukomalazie überleben. Aufgrund der derzeitigen Datenlage kann die Behandlung Frühgeborener <34 Gestationswochen mit iNO außerhalb randomisiert-kontrollierter Studien nicht empfohlen werden.

Abstract

In 2001, NO was approved as a therapeutic agent in Europe for the treatment of persistent pulmonary hypertension in late preterm infants >34 weeks of gestational age and term newborns. Recent observational studies suggest, that preterm infants <34 weeks of gestation with acute hypoxic lung failure could benefit from inhaled NO (iNO) by improved oxygenation. To date, 21 randomised-controlled trials have enrolled 3 336 preterm infants <34 weeks of gestation for iNO treatment. Overall, iNO treatment does not reduce the rate of bronchopulmonary dysplasia (BPD) or death compared to controls. In addition, iNO treatment of preterm infants with hypoxic respiratory failure or increased risk of BPD does not affect the combined incidence of death and BPD. However, early prophylactic use of iNO in preterm infants with respiratory distress seems to improve survival without BPD or severe cerebral damage. Current data of long term neurological outcome of iNO-treated preterm infants do not seem to justify iNO administration. Outside of well designed clinical trials iNO-treatment of preterm infants can currently not be recommended.

Schlüsselwürter

Frühgeborene - inhalatives Stickstoffmonoxid - Atemnotsyndrom - bronchopulmonale Dysplasie

Key words

preterm infant - nitric oxide - respiratory distress syndrome - bronchopulmonary dysplasia

Literatur

• 1 Afshar S. et al . Pulmonary NO synthase expression is attenuated in a fetal baboon model of chronic lung disease.  Am J Physiol Lung Cell Mol Physiol. 2003;  284 L749-L758
• 2 Ahluwalia J. et al . A dose response study of inhaled nitric oxide in hypoxic respiratory failure in preterm infants.  Early Hum Dev. 2006;  82 477-483
• 3 Andrews WW. et al . Early preterm birth: association between in utero exposure to acute inflammation and severe neurodevelopmental disability at 6 years of age.  Am J Obstet Gynecol. 2008;  198 466.e1-466.e11
• 4 Arul N, Konduri GG. Inhaled nitric oxide for preterm neonates.  Clin Perinatol. 2009;  36 43-61
• 5 Ballard RA. et al . Inhaled nitric oxide in preterm infants undergoing mechanical ventilation.  NEJM. 2006;  355 343-353
• 6 Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants (Review).  Cochrane Database Syst Rev. 2007;  18 CD000509
• 7 Bennett AJ. et al . Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide.  Acta Paediatr. 2001;  90 573-576
• 8 Chock VY. et al . Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnions, and pulmonary hypoplasia.  Am J Perinatol. 2009;  26 317-322
• 9 DŽAlquen D. et al . Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.  Pediatr Res. 2005;  57 263-269
• 10 Dani C. et al . Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome.  Acta Paediatr. 2006;  95 1116-1123
• 11 Day RW. et al . Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension.  Pediatrics. 1996;  98 698-705
• 12 Di Fiore JM. et al . The effect of inhaled nitric oxide on pulmonary function in preterm infants.  J Perinatol. 2007;  27 766-771
• 13 Field D. et al . Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infantswith severe respiratory failure: the INNOVO multicentre randomised controlled trial.  Pediatrics. 2005;  115 926-936
• 14 Gutierrez HH. et al . Nitric oxide regulation of superoxide-dependent lung injury: oxidant protective actions of endogenously produced and exogenously administered nitric oxide.  Free Radic Biol Med. 1996;  21 43-52
• 15 Hascoet JM. et al . The safety and efficacy of nitric oxide therapy in premature infants.  J Pediatr.. 2005;  146 318-323
• 16 Hibbs AM. et al . One-year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial.  J Pediatr. 2008;  153 525-529
• 17 Huddy CL. et al . for the INNOVO Trial collaborating group.  Arch Dis Child Fetal Neonatal Ed. 2008;  83 F430-F435
• 18 Issa A. et al . Inhaled nitric oxide decreases hyperoxia-induced surfactant abnormality in preterm rabbits.  Pediatr Res. 1999;  45 247-254
• 19 Kinsella JP. et al . Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial.  Lancet. 1999;  354 1061-1065
• 20 Kinsella JP. et al . Early inhaled nitric oxide therapy in premature newborns with respiratory failure.  NEJM. 2006;  355 354-364
• 21 Kramer BW. et al . Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth.  Pediatr Res. 2005;  58 607-612
• 22 Lavallee M. et al . Crosstalk between endothelin and nitric oxide in the control of vascular tone.  Heart Fail Rev. 2001;  6 265-276
• 23 Lindner U. et al . Drug utilisation in very preterm infants: any changes during the past decade?.  Klin Padiatr. 2008;  220 238-242
• 24 Lindwall R. et al . A pilot study of inhaled nitric oxide in preterm infants treated with nasal continous positive airwaypressure for respiratory distress syndrome.  Intensive Care Med. 2005;  31 959-964
• 25 McCurnin DC. et al . Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease.  Am J Physiol Lung Cell Mol Physiol. 2005;  288 L450-L459
• 26 Mercier JC. et al . for the Franco-Belgium collaborative NO trial group. Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial.  Lancet. 1999;  354 1066-1071
• 27 Mercier JC. et al . Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates.  Semin Fetal Neonatal Med. 2009;  14 28-34
• 28 Mestan KK. et al . Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide.  N Engl J Med. 2005;  353 23-32
• 29 Pearson DL. et al . Neonatal pulmonary hypertension.  New Engl J Med. 2001;  344 1832-1838
• 30 Phatak RS. et al . Heliox with inhaled nitric oxide: a novel strategy for severe localized interstitial pulmonary emphysema in preterm neonatal ventilation.  Respir Care. 2008;  53 1731-1738
• 31 Schmidt B. et al . Chorioamnionitis and inflammation of the fetal lung.  Am J Obstet Gynecol. 2001;  185 173-177
• 32 Schreiber MD. et al . Inhaled nitric oxide in premature infants with the respiratory distress syndrome.  New Engl J Med. 2003;  349 2099-2107
• 33 Shaul PW. Nitric oxide in the developing lung.  Adv Pediatr. 1995;  42 367-414
• 34 Skimming JW. et al . Nitric oxide inhalation in infants with respiratory distress syndrome.  J Pediatr. 1997;  130 225-230
• 35 Skinner JR. et al . Pulmonary and systemic arterial pressure in hyaline membrane disease.  Arch Dis Child. 1992;  67 366-373
• 36 Soll RF. Current trials in the treatment of respiratory failure in preterm infants.  Neonatology. 2009;  95 368-372
• 37 Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia.  Neonatology. 2009;  95 353-361
• 38 Speer CP. Surfactantsubstitutionstherapie. Ein entscheidender Durchbruch in der Behandlung des Atemnotsyndroms Frühgeborener.  Monatsschr Kinderheilkd. 2002;  150 659-668
• 39 Srisuparp P. et al . Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome.  J Med Assoc Thai. 2002;  85 S469-S478
• 40 Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure.  J Perinatol. 2008;  28 112-116
• 41 Subhedar NV. et al . Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants.  Arch Dis Child Fetal Neonatal Ed. 1997;  77 F185-F190
• 42 Thomas W. et al . Airway concentrations of angiopoietin-1 and endostatin in ventilated extremely premature infants are decreased after funisitis and unbalanced with bronchopulmonary dysplasia/death.  Pediatr Res. 2009;  65 468-473
• 43 Truffert P. et al . for the Franco-Belgian iNO Study Group. Early inhaled nitric oxide in moderately hypoxemic preterm and term newborns with RDS: the RDS subgroup analysis of the Franco-Belgian iNO Randomized Trial.  Eur J Pediatr. 2003;  162 646-647
• 44 Van Meurs KP. et al . Inhaled nitric oxide for premature infants with severe respiratory failure.  NEJM. 2005;  353 13-22
• 45 Van Meurs KP. et al . Inhaled nitric oxide in infants >1 500 g and <34 weeks gestation with severe respiratory failure.  J Perinatol. 2007;  27 347-352
• 46 Wink DA. et al . Mechanisms of the antioxidant effects of nitric oxide.  Antioxid Redox Signal. 2001;  2 203-213
• 47 Wirbelauer J, Speer CP. Die Inhalation von Stickstoffmonoxid in der Neonatologie: Stellenwert dieser Therapie im Jahre 2004.  Z Geburtsh Neonatol. 2004;  208 79-90
• 48 Wirbelauer J, Speer CP. The role of surfactant treatment in preterm infants and term newborns with acute respiratory distress syndrome (ARDS).  J Perinatol. 2009;  29 ((S 2)) 18-22
• 49 Zupancic JA. et al . Economic evaluation of inhaled nitric oxide in preterm infants undergoing mechanical ventilation.  Pediatrics. 2009;  epub ahead off print

Korrespondenzadresse