Clinical and Economic Effects of iNO in Premature Newborns With Respiratory Failure at 1 Year

BACKGROUND: The long-term consequences of inhaled nitric oxide (iNO) use in premature newborns with respiratory failure are unknown. We therefore studied the clinical and economic outcomes to 1 year of corrected age after a randomized controlled trial of prophylactic iNO. METHODS: Premature newborns (gestational age ≤34 w, birth weight 500–1250 g) with respiratory failure randomly received 5 ppm iNO or placebo within 48 h of birth until 21 d or extubation. We assessed clinical outcomes via in-person neurodevelopmental evaluation at 1 y corrected age and telephone interviews every 3 m. We estimated costs from detailed hospital bills and interviews, converting all costs to 2008 US$. Of 793 trial subjects, 631 (79.6%) contributed economic data, and 455 (77.1% of survivors) underwent neurodevelopmental evaluation. RESULTS: At 1 y corrected age, survival was not different by treatment arm (79.2% iNO vs. 74.5% placebo, P = .12), nor were other post-discharge outcomes. For subjects weighing 750–999 g, those receiving iNO had greater survival free from neurodevelopmental impairment (67.9% vs. 55.6%, P = .04). However, in subjects weighing 500–749 g, iNO led to greater oxygen dependency (11.7% vs. 4.0%, P = .04). Median total costs were similar ($235 800 iNO vs. $198 300 placebo, P = .19). Quality-adjusted survival was marginally better with iNO (by 0.011 quality-adjusted life-years/subject). The incremental cost-effectiveness ratio was $2.25 million/quality-adjusted life-year. CONCLUSIONS: Subjects in both arms commonly experienced neurodevelopmental and pulmonary morbidity, consuming substantial health care resources. Prophylactic iNO beginning in the first days of life did not lower costs and had a poor cost-effectiveness profile.

[1]  M. Gold.  Cost-effectiveness in health and medicine , 2016 .

[2]  Stephen W Lagakos,et al.  Statistics in medicine--reporting of subgroup analyses in clinical trials. , 2007, The New England journal of medicine.

[3]  Xianqun Luan,et al.  Surfactant Function and Composition in Premature Infants Treated With Inhaled Nitric Oxide , 2007, Pediatrics.

[4]  B. Morris,et al.  Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. , 2007, The Journal of pediatrics.

[5]  G. Cutter,et al.  Early inhaled nitric oxide therapy in premature newborns with respiratory failure. , 2006, The New England journal of medicine.

[6]  Bo Sun,et al.  Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs , 2006, Respiratory research.

[7]  D. Carlton,et al.  Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs. , 2005, American journal of respiratory and critical care medicine.

[8]  W. Poole,et al.  Inhaled nitric oxide for premature infants with severe respiratory failure. , 2005, The New England journal of medicine.

[9]  J. Marks,et al.  Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. , 2005, The New England journal of medicine.

[10]  S. Abman,et al.  Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats , 2005, Pediatric Research.

[11]  J. Crapo,et al.  Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[12]  M. Walsh,et al.  Impact of a Physiologic Definition on Bronchopulmonary Dysplasia Rates , 2004, Pediatrics.

[13]  K. Barnhart,et al.  Cost-effectiveness of inhaled nitric oxide for the management of persistent pulmonary hypertension of the newborn. , 2004, Pediatrics.

[14]  G. Clermont,et al.  Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States. , 2003, Pediatrics.

[15]  J. Marks,et al.  Inhaled nitric oxide in premature infants with the respiratory distress syndrome. , 2003, The New England journal of medicine.

[16]  Walter Allan,et al.  Change in cognitive function over time in very low‐birth‐weight infants. , 2003, JAMA.

[17]  Mark S. Roberts,et al.  Understanding costs and cost-effectiveness in critical care: report from the second American Thoracic Society workshop on outcomes research. , 2002, American journal of respiratory and critical care medicine.

[18]  M. Boyle,et al.  Multiattribute and Single‐Attribute Utility Functions for the Health Utilities Index Mark 3 System , 2002, Medical care.

[19]  K. Moons,et al.  Sequelae after Bacterial Meningitis in Childhood , 2002, Scandinavian journal of infectious diseases.

[20]  D C Angus,et al.  Quality-adjusted survival in the first year after the acute respiratory distress syndrome. , 2001, American journal of respiratory and critical care medicine.

[21]  Michael D. Ernst,et al.  Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia , 2001, Archives of disease in childhood. Fetal and neonatal edition.

[22]  A. Zaritsky,et al.  Early postnatal dexamethasone treatment and increased incidence of cerebral palsy , 2000, Archives of disease in childhood. Fetal and neonatal edition.

[23]  M. Keszler,et al.  Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. , 2000, The New England journal of medicine.

[24]  D. Cornfield,et al.  Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial , 1999, The Lancet.

[25]  D. J. Goldstein,et al.  Randomized Placebo-controlled Trial of a 42-Day Tapering Course of Dexamethasone to Reduce the Duration of Ventilator Dependency in Very Low Birth Weight Infants: Outcome of Study Participants at 1-Year Adjusted Age , 1999, Pediatrics.

[26]  T. Pauly,et al.  A Three-day Course of Dexamethasone Therapy to Prevent Chronic Lung Disease in Ventilated Neonates: A Randomized Trial , 1999, Pediatrics.

[27]  W. Furlong,et al.  Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents. , 1999, JAMA.

[28]  A. Leviton,et al.  Characteristics of cranial ultrasound white‐matter echolucencies that predict disability: a review , 1999, Developmental medicine and child neurology.

[29]  M. Fine,et al.  Relationship of provider characteristics to outcomes, process, and costs of care for community-acquired pneumonia. , 1998, Medical care.

[30]  T. O'Shea,et al.  Prenatal events and the risk of cerebral palsy in very low birth weight infants. , 1998, American journal of epidemiology.

[31]  J..  Economic outcome for intensive care of infants of birthweight 500–999 g born in Victoria in the post surfactant era , 1997, Journal of paediatrics and child health.

[32]  Cook,et al.  Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. , 1997, The New England journal of medicine.

[33]  D. DeMets,et al.  Surrogate End Points in Clinical Trials: Are We Being Misled? , 1996, Annals of Internal Medicine.

[34]  David P Miller,et al.  In-hospital cost of percutaneous coronary revascularization. Critical determinants and implications. , 1995, Circulation.

[35]  P. Kubes,et al.  Nitric oxide is an antiadhesive molecule for leukocytes. , 1995, New horizons.

[36]  D. Ivy,et al.  Inhaled Nitric Oxide Improves Gas Exchange and Lowers Pulmonary Vascular Resistance in Severe Experimental Hyaline Membrane Disease , 1994, Pediatric Research.

[37]  R. Klein,et al.  The Beaver Dam Health Outcomes study , 1993, Medical decision making : an international journal of the Society for Medical Decision Making.

[38]  R. Prentice.  Surrogate endpoints in clinical trials: definition and operational criteria. , 1989, Statistics in medicine.

[39]  R. Savani,et al.  Surfactant Composition and Function in a Primate Model of Infant Chronic Lung Disease: Effects of Inhaled Nitric Oxide , 2006, Pediatric Research.

[40]  A. Halbower,et al.  Effects of Inhaled Nitric Oxide on Pulmonary Edema and Lung Neutrophil Accumulation in Severe Experimental Hyaline Membrane Disease , 1997, Pediatric Research.

[41]  C. Roelofs.  Prevention effectiveness: A guide to decision analysis and economic evaluation , 1997 .

[42]  B. Freeman,et al.  Nitric oxide regulation of superoxide-dependent lung injury: oxidant-protective actions of endogenously produced and exogenously administered nitric oxide. , 1996, Free radical biology & medicine.

[43]  D W Young,et al.  The ratio of costs to charges: how good a basis for estimating costs? , 1995, Inquiry : a journal of medical care organization, provision and financing.

[44]  J. Rogowski,et al.  Treatment Costs for Very Low Birthweight Infants , 1995 .

[45]  High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants: assessment of pulmonary function at 9 months of corrected age. HiFi Study Group. , 1990, Jornal de Pediatria.