Inhaled Nitric Oxide for Preterm Infants: A Marksman's Approach
2012; Elsevier BV; Volume: 161; Issue: 3 Linguagem: Inglês
10.1016/j.jpeds.2012.05.004
ISSN1097-6833
AutoresMolly K. Ball, Robin H. Steinhorn,
Tópico(s)Congenital Diaphragmatic Hernia Studies
ResumoSee related article, p 397Inhaled nitric oxide (iNO) is a well-established front-line therapy for term infants with persistent pulmonary hypertension of the newborn (PPHN). PPHN typically occurs in full-term neonates after a failure of normal cardiopulmonary transition in extrauterine life. This transitional failure is not unique to term infants. Preterm birth and respiratory failure impairs endothelial nitric oxide synthase activity and its downstream mechanisms of signaling, and these deficiencies contribute to the vascular and lung injury associated with respiratory failure in preterm infants.1Afshar S. Gibson L.L. Yuhanna I.S. Sherman T.S. Kerecman J.D. Grubb P.H. 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-L758Crossref PubMed Scopus (49) Google Scholar If nitric oxide production is deficient in the preterm lung, a logical step is extension of its use to premature infants. Preliminary work in preterm animal models showed a promising potential of iNO to induce rapid vasodilation and favorably modulate pulmonary development.2McCurnin D.C. Pierce R.A. Chang L.Y. Gibson L.L. Osborne-Lawrence S. Yoder B.A. 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-L459Crossref PubMed Scopus (177) Google Scholar, 3Lin Y.J. Markham N.E. Balasubramaniam V. Tang J.R. Maxey A. Kinsella J.P. et al.Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats.Pediatr Res. 2005; 58: 22-29Crossref PubMed Scopus (159) Google Scholar However, large clinical trials attempting to duplicate these findings in preterm infants revealed only a modest benefit when iNO was used to prevent bronchopulmonary dysplasia (BPD).4Donohue P.K. Gilmore M.M. Cristofalo E. Wilson R.F. Weiner J.Z. Lau B.D. et al.Inhaled nitric oxide in preterm infants: a systematic review.Pediatrics. 2011; 127: e414-e422Crossref PubMed Scopus (100) Google Scholar, 5Steinhorn R.H. Shaul P.W. deRegnier R.A. Kennedy K.A. Inhaled nitric oxide and bronchopulmonary dysplasia [letter].Pediatrics. 2011; 128 (author reply e6-7): e255-e256Crossref PubMed Scopus (6) Google Scholar, 6Askie L.M. Ballard R.A. Cutter G.R. Dani C. Elbourne D. Field D. et al.Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials.Pediatrics. 2011; 128: 729-739Crossref PubMed Scopus (118) Google Scholar These studies highlight the complex, multifactorial nature of BPD and underscore the need for a better understanding of the role of endogenous and iNO in preterm lung development and lung injury. See related article, p 397 Even though the clinical trials were well designed and appropriately powered, one of the problems encountered when interpreting their findings is the diverse nature of respiratory failure in preterm infants. It is particularly difficult to use the available data to understand whether specific populations of infants might benefit from iNO. This question is timely given the increasing realization that specific patterns of early or persistent respiratory failure increase the risk of poor pulmonary outcomes.7Laughon M. Allred E.N. Bose C. O'Shea T.M. Van Marter L.J. Ehrenkranz R.A. et al.Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants.Pediatrics. 2009; 123: 1124-1131Crossref PubMed Scopus (147) Google Scholar Unfortunately, as noted in the National Institutes of Health Consensus Development Conference Statement,8Cole F.S. Alleyne C. Barks J.D. Boyle R.J. Carroll J.L. Dokken D. et al.NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants.Pediatrics. 2011; 127: 363-369Crossref PubMed Scopus (144) Google Scholar few previous trials prospectively identified subpopulations of respiratory failure, and none was designed or sufficiently powered to detect subgroup differences. The Consensus Committee also commented on the very small numbers of patients with pulmonary hypoplasia or pulmonary hypertension enrolled in the clinical trials. However, to date, no prospective randomized trial has been launched to define the potential benefit of iNO in this population. In this issue of The Journal, Aikio et al9Aikio O. Metsola J. Vuolteenaho R. Perhomaa M. Hallman M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure.J Pediatr. 2012; 161: 397-403Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar report on a cohort of very preterm infants (≤32 weeks gestational age) with hypoxic respiratory failure and persistent pulmonary hypertension who were identified by prospectively defined oxygenation and echocardiographic criteria and treated with iNO. Excellent comparison groups of infants born after preterm premature rupture of membranes (PPROM), spontaneous labor, and preeclampsia were selected to help elucidate what is unique about PPHN in preterm infants. In their entire population of very preterm infants, 15% of those with PPROM for more than 7 days developed PPHN. In addition, all of the infants with PPHN were born after PPROM, and in the majority, PPROM began before 24 weeks gestation and persisted for more than 7 days. These findings suggest that in preterm infants with PPROM, oligohydramnios and pulmonary hypoplasia contribute to the development of PPHN. Ten of the infants with PPROM had at least one positive blood culture while hospitalized, but the rates of infection in this cohort was not significantly greater than that in the other cohorts and was not associated with response to iNO. The incidence of BPD was not strikingly different between the infants with PPHN and the comparison groups. The findings reported by Aikio et al also add to previous reports on the use of iNO in infants with respiratory failure due to pulmonary hypoplasia. Small case series and a retrospective comparative study have reported significantly improved oxygenation in response to iNO, as well as decreased ventilatory support and trends toward improved survival, in preterm infants with oligohydramnios and PPROM.10Peliowski 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: 450-453Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 11Uga 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: 10-14Crossref PubMed Scopus (34) Google Scholar More recently, a subpopulation of 12 infants with suspected pulmonary hypoplasia after prolonged premature rupture of membranes and oligohydramnios was identified retrospectively in a large randomized, placebo-controlled trial of preterm infants with severe respiratory failure.12Chock V.Y. Van Meurs K.P. Hintz S.R. Ehrenkranz R.A. Lemons J.A. Kendrick D.E. et al.Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia.Am J Perinatol. 2009; 26: 317-322Crossref PubMed Scopus (69) Google Scholar Half of the infants were treated with iNO, and these infants demonstrated improved oxygenation as well as a trend toward lower mortality and BPD relative to placebo-treated infants. The results reported by Aikio et al may add mechanistic insights to the patterns of response to iNO in preterm infants. In infants with PPHN, nitric oxide byproducts (nitrite and nitrate) were undetectable before iNO administration. In contrast, the comparison PPROM group without pulmonary hypertension had normal baseline nitrite/nitrate levels, implying that PPROM/oligohydramnios alone does not directly impair nitric oxide production. After initiation of iNO, nitric oxide byproduct levels increased, and levels remained stable even after discontinuation of iNO. This suggests that an acute deficiency in endogenous nitric oxide production could trigger persistent pulmonary hypertension in preterm neonates exposed to prolonged PPROM. On the other hand, the cohort of preterm infants born after preeclampsia also had low nitrite/nitrate levels, indicating that diminished nitric oxide activity is not sufficient to induce acute respiratory failure. The role of nitric oxide production and signaling in the preterm lung is clearly complex and merits further investigation. Although Aikio et al comment that a randomized study is needed to confirm their observations, their findings actually underscore why an appropriately powered study would be virtually impossible in this population. Very low birth weight infants represent only 1.5% of births annually. In the cohort of Aikio et al, 144 of 765 neonates (18.8%) born at <32 weeks gestational age required mechanical ventilation, but only 17 (2.2%) developed hypoxic respiratory failure with pulmonary hypertension. These findings match the frequency of pulmonary hypertension in other very low birth weight cohorts,9Aikio O. Metsola J. Vuolteenaho R. Perhomaa M. Hallman M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure.J Pediatr. 2012; 161: 397-403Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and any trial would be further complicated by high mortality rates.13Kumar V.H. Hutchison A.A. Lakshminrusimha S. Morin 3rd, F.C. Wynn R.J. Ryan R.M. Characteristics of pulmonary hypertension in preterm neonates.J Perinatol. 2007; 27: 214-219Crossref PubMed Scopus (108) Google Scholar As a result, fewer than 0.03% of births would qualify for a randomized study, posing substantial barriers to feasibility and funding. Finally, the findings of Aikio et al have important implications for how we view hypoxic respiratory failure in preterm infants. Although we now understand that routine nitric oxide use in the preterm population at large has not translated to global pulmonary benefits,8Cole F.S. Alleyne C. Barks J.D. Boyle R.J. Carroll J.L. Dokken D. et al.NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants.Pediatrics. 2011; 127: 363-369Crossref PubMed Scopus (144) Google Scholar we would be remiss to dismiss its use entirely. Instead of an "all-or-nothing" approach, the key may lie in the identification of specific preterm subpopulations for selective use of iNO therapy. Given the substantial barriers to large trials, it is important to consider the merits of smaller case-control and cohort studies. In the case of preterm infants with severe respiratory failure after PPROM, multiple small studies over the past 10-15 years9Aikio O. Metsola J. Vuolteenaho R. Perhomaa M. Hallman M. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure.J Pediatr. 2012; 161: 397-403Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 10Peliowski 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: 450-453Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 11Uga 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: 10-14Crossref PubMed Scopus (34) Google Scholar, 12Chock V.Y. Van Meurs K.P. Hintz S.R. Ehrenkranz R.A. Lemons J.A. Kendrick D.E. et al.Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia.Am J Perinatol. 2009; 26: 317-322Crossref PubMed Scopus (69) Google Scholar all point toward a benefit of iNO in the treatment arsenal. Targeting iNO use to subpopulations in which nitric oxide therapy does successfully treat underlying respiratory pathology may further improve our ability to minimize disease and mortality in the preterm population. Transient Defect in Nitric Oxide Generation after Rupture of Fetal Membranes and Responsiveness to Inhaled Nitric Oxide in Very Preterm Infants with Hypoxic Respiratory FailureThe Journal of PediatricsVol. 161Issue 3PreviewTo study antenatal risk factors and inflammatory responses during hypoxic respiratory failure (HRF) in infants of very low gestational age (VLGA, ≤32.0 weeks). Full-Text PDF
Referência(s)