Inhaled Nitric Oxide to Prevent Bronchopulmonary Dysplasia in Preterm Infants—Less than a Silver Bullet
2014; Elsevier BV; Volume: 165; Issue: 6 Linguagem: Inglês
10.1016/j.jpeds.2014.08.040
ISSN1097-6833
AutoresErik A. Jensen, Haresh Kirpalani,
Tópico(s)Respiratory Support and Mechanisms
ResumoSee related article, p 1104First described over 200 years ago, nitric oxide (NO) was initially known more for its toxic than therapeutic properties.1Priestley J. Experiments and observations on different kinds of air.2nd ed. J. Johnson, London1775Google Scholar, 2Davy H. The collected works of Sir Humphry Davy. Continuum International Publishing, London1839Google Scholar From the 1970s, however, NO has been recognized as a potent vasodilator.3Arnold W.P. Mittal C.K. Katsuki S. Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations.Proc Natl Acad Sci U S A. 1977; 74: 3203-3207Crossref PubMed Scopus (1184) Google Scholar Following a pivotal randomized controlled trial (RCT) led by Ehrenkranz and Finer, inhaled NO (iNO) was approved in the US for the treatment of pulmonary hypertension in term and late preterm infants with hypoxic respiratory failure.4The Neonatal Inhaled Nitric Oxide Study Group Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure.N Engl J Med. 1997; 336: 597-604Crossref PubMed Scopus (788) Google Scholar Further study in animal models revealed that iNO improved surfactant function, stimulated angiogenesis, and enhanced alveolar formation.5Lin 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 (152) Google Scholar, 6McCurnin D.C. Pierce R.A. Chang L.Y. Gibson L.L. Osborne-Lawrence S. Yoder B. 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 (173) Google Scholar, 7Ballard P.L. Gonzales L.W. Godinez R.I. Godinez M.H. Savani R.C. McCurnin D.C. et al.Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide.Pediatr Res. 2006; 59: 157-162Crossref PubMed Scopus (52) Google Scholar, 8Bland 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: 899-906Crossref PubMed Scopus (114) Google Scholar, 9Tang J.R. Markham N.E. Lin Y.J. McMurty I.F. Maxey A. Kinsella J.P. et al.Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L344-L351Crossref PubMed Scopus (172) Google Scholar Hope arose that iNO-mediated improvements in oxygenation and lung development would reduce the need for prolonged respiratory support in preterm infants and prevent bronchopulmonary dysplasia (BPD).Between 1997 and 2011, 14 RCTs and 3 meta-analyses, including an individual patient data meta-analysis, evaluated whether iNO reduced mortality or BPD in preterms (see meta-analyses for citations of the individual trials).10Askie 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 (114) Google Scholar, 11Barrington K.J. Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010; : CD000509PubMed Google Scholar, 12Donohue P.K. Gilmore M.M. Cristofalo E. Wilson R.F. Weinter J.Z. Lau B.D. et al.Inhaled nitric oxide in preterm infants: a systematic review.Pediatrics. 2011; 127: e414-e422Crossref PubMed Scopus (95) Google Scholar Despite the considerable methodological differences between the trials and their sometimes contradictory results, each meta-analysis concluded that the use of iNO for the treatment of respiratory failure in intubated and ventilated preterm infants is not recommended.10Askie 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 (114) Google Scholar, 11Barrington K.J. Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010; : CD000509PubMed Google Scholar, 12Donohue P.K. Gilmore M.M. Cristofalo E. Wilson R.F. Weinter J.Z. Lau B.D. et al.Inhaled nitric oxide in preterm infants: a systematic review.Pediatrics. 2011; 127: e414-e422Crossref PubMed Scopus (95) Google Scholar In 2010, a National Institutes of Health consensus conference determined that “the available evidence does not support the use of iNO in early routine, early rescue or later rescue regimens in the care of premature infants 1500 g and 1500 g and <34 weeks gestation with severe respiratory failure.J Perinatol. 2007; 27: 347-352Crossref PubMed Scopus (28) Google Scholar Schreiber et al, who reported the largest reduction in death or BPD of any iNO trial (relative risk 0.76, 95% CI 0.60-0.97) enrolled the largest proportion of African Americans (71.4%).17Schreiber M.D. Gin-Mestan K. Marks J.D. Huo D. Lee G. Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome.N Engl J Med. 2003; 349: 2099-2107Crossref PubMed Scopus (348) Google Scholar However, the authors did not report a subgroup analysis in this population.17Schreiber M.D. Gin-Mestan K. Marks J.D. Huo D. Lee G. Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome.N Engl J Med. 2003; 349: 2099-2107Crossref PubMed Scopus (348) Google Scholar In the individual patient data meta-analysis, iNO did not significantly reduce death or BPD in whites or non-whites.10Askie 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 (114) Google Scholar A subgroup analysis specific to African Americans was not reported.10Askie 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 (114) Google ScholarThere has been much speculation about this subgroup.25Schreiber MD. Response to Kumar on behalf of the AAP Committee on Fetus and Newborn. http://pediatrics.aappublications.org/content/133/1/164/reply. Accessed July 30, 2014.Google Scholar We suggest that presently there is insufficient evidence to support the use of iNO in preterm African Americans as a standard therapy. Observational data suggests that African American term and near-term infants are at increased risk for persistent pulmonary hypertension.26Van Marter L.J. Leviton A. Allred E.N. Pagano M. Sullivan K.F. Cohen A. et al.Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal anti-inflammatory drug consumption during pregnancy.Pediatrics. 1996; 97: 658-663PubMed Google Scholar, 27Hernández-Díaz S. Van Marter L.J. Werler M.M. Louik C. Mitchell A.A. Risk factors for persistent pulmonary hypertension of the newborn.Pediatrics. 2007; 120: e272-e282Crossref PubMed Scopus (144) Google Scholar This reported association is far from confirmation that iNO will translate into benefit in preterm African Americans. A parallel scenario in African American adults with heart failure is instructive. An initial series of physiological observations suggested that African Americans, compared with Caucasians, have on average, lower bioavailability of NO.28Stein C.M. Lang C.C. Nelson R. Brown M. Wood A.J. Vasodilation in black Americans: attenuated nitric oxide-mediated responses.Clin Pharmacol Ther. 1997; 62: 436-443Crossref PubMed Scopus (132) Google Scholar This triggered retrospective analyses of heart-failure trials finding that African Americans might have a clinically significant response to isosorbide dinitrate (a NO donor) when combined with hydralazine.29Carson P. Ziesche S. Johnson G. Cohn J.N. Racial differences in response to therapy for heart failure: analysis of the vasodilator heart failure trials.J Card Fail. 1999; 5: 178-187Abstract Full Text PDF PubMed Scopus (414) Google Scholar, 30Exner D.V. Dries D.L. Domanski M.J. Cohn J.N. Lesser response to angiotensin-converting–enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.N Engl J Med. 2001; 344: 1351-1357Crossref PubMed Scopus (472) Google Scholar In turn, a prospective RCT confirmed a survival benefit of this regimen in African Americans.31Taylor A.L. Ziesche S. Yancy C. Carson P. D'Agostino Jr., R. Ferdinand K. et al.Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.N Engl J Med. 2004; 351: 2049-2057Crossref PubMed Scopus (1368) Google Scholar Similarly, a prospective study to evaluate potential benefit of iNO in preterm African Americans is needed.In conclusion, iNO may reduce BPD in some specific groups of preterm infants. To identify those that may benefit, subgroup analyses are essential. However, we must continue to retain critical approaches to subgroup analyses. Credible subgroup analyses are prespecified, biologically plausible, and evaluated by robust interaction testing between the subgroup and the treatment.15Martin C.M. Guyatt G. Montori V.M. The sirens are singing: the perils of trusting trials stopped early and subgroup analyses.Crit Care Med. 2005; 33: 1870-1871Crossref PubMed Scopus (9) Google Scholar Even more important is prospective evaluation of subgroup hypotheses. Mercier et al previously, and now Kinsella et al provide important reminders of this.16Kinsella J.P. Cutter G.R. Steinhorn R.H. Nelin L.D. Walsh W.F. Finer N.N. et al.Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns.J Pediatr. 2014; 165: 1104-1108Scopus (26) Google Scholar, 19Mercier J.C. Hummler H. Durrmeyer X. Sanchez-Luna M. Carnielli V. Field D. et al.Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial.Lancet. 2010; 376: 346-354Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar The approach followed by these investigators should now be applied to other promising subgroups in iNO therapy, before they pass into “standard of care.” See related article, p 1104First described over 200 years ago, nitric oxide (NO) was initially known more for its toxic than therapeutic properties.1Priestley J. Experiments and observations on different kinds of air.2nd ed. J. Johnson, London1775Google Scholar, 2Davy H. The collected works of Sir Humphry Davy. Continuum International Publishing, London1839Google Scholar From the 1970s, however, NO has been recognized as a potent vasodilator.3Arnold W.P. Mittal C.K. Katsuki S. Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations.Proc Natl Acad Sci U S A. 1977; 74: 3203-3207Crossref PubMed Scopus (1184) Google Scholar Following a pivotal randomized controlled trial (RCT) led by Ehrenkranz and Finer, inhaled NO (iNO) was approved in the US for the treatment of pulmonary hypertension in term and late preterm infants with hypoxic respiratory failure.4The Neonatal Inhaled Nitric Oxide Study Group Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure.N Engl J Med. 1997; 336: 597-604Crossref PubMed Scopus (788) Google Scholar Further study in animal models revealed that iNO improved surfactant function, stimulated angiogenesis, and enhanced alveolar formation.5Lin 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 (152) Google Scholar, 6McCurnin D.C. Pierce R.A. Chang L.Y. Gibson L.L. Osborne-Lawrence S. Yoder B. 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 (173) Google Scholar, 7Ballard P.L. Gonzales L.W. Godinez R.I. Godinez M.H. Savani R.C. McCurnin D.C. et al.Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide.Pediatr Res. 2006; 59: 157-162Crossref PubMed Scopus (52) Google Scholar, 8Bland 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: 899-906Crossref PubMed Scopus (114) Google Scholar, 9Tang J.R. Markham N.E. Lin Y.J. McMurty I.F. Maxey A. Kinsella J.P. et al.Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L344-L351Crossref PubMed Scopus (172) Google Scholar Hope arose that iNO-mediated improvements in oxygenation and lung development would reduce the need for prolonged respiratory support in preterm infants and prevent bronchopulmonary dysplasia (BPD). See related article, p 1104 See related article, p 1104 Between 1997 and 2011, 14 RCTs and 3 meta-analyses, including an individual patient data meta-analysis, evaluated whether iNO reduced mortality or BPD in preterms (see meta-analyses for citations of the individual trials).10Askie 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 (114) Google Scholar, 11Barrington K.J. Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010; : CD000509PubMed Google Scholar, 12Donohue P.K. Gilmore M.M. Cristofalo E. Wilson R.F. Weinter J.Z. Lau B.D. et al.Inhaled nitric oxide in preterm infants: a systematic review.Pediatrics. 2011; 127: e414-e422Crossref PubMed Scopus (95) Google Scholar Despite the considerable methodological differences between the trials and their sometimes contradictory results, each meta-analysis concluded that the use of iNO for the treatment of respiratory failure in intubated and ventilated preterm infants is not recommended.10Askie 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 (114) Google Scholar, 11Barrington K.J. Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010; : CD000509PubMed Google Scholar, 12Donohue P.K. Gilmore M.M. Cristofalo E. Wilson R.F. Weinter J.Z. Lau B.D. et al.Inhaled nitric oxide in preterm infants: a systematic review.Pediatrics. 2011; 127: e414-e422Crossref PubMed Scopus (95) Google Scholar In 2010, a National Institutes of Health consensus conference determined that “the available evidence does not support the use of iNO in early routine, early rescue or later rescue regimens in the care of premature infants <34 weeks' gestation who require respiratory support.”13Cole 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 (137) Google Scholar The conference noted, however, that “predefined subgroup and post-hoc analyses of previous trials showing potential benefit of iNO have generated hypotheses for future research for clinical trials.”13Cole 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 (137) Google Scholar This statement shows appropriate caution: although subgroup analyses are fertile grounds for formulating new hypotheses, pitfalls abound when subgroup findings are uncritically accepted as guides for therapy.14Oxman A.D. Guyatt G.H. A consumer's guide to subgroup analyses.Ann Intern Med. 1992; 116: 78-84Crossref PubMed Scopus (671) Google Scholar, 15Martin C.M. Guyatt G. Montori V.M. The sirens are singing: the perils of trusting trials stopped early and subgroup analyses.Crit Care Med. 2005; 33: 1870-1871Crossref PubMed Scopus (9) Google Scholar Post-hoc analyses of iNO trials have identified 3 subgroups of preterm infants who may require further investigation: (1) infants with less severe respiratory disease; (2) infants treated with a higher iNO dose; and (3) African American infants. In this issue of The Journal, Kinsella et al report a trial that directly addresses the first subgroup with prospective evaluation of a post-hoc analysis.16Kinsella J.P. Cutter G.R. Ste
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