Original Article
Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation
N Engl J Med 2006; 355:343-353July 27, 2006
- Abstract
Background
Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial.
Methods
We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age.
Results
Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns.
Conclusions
Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548.)
Media in This Article
Table 1
Baseline Characteristics of the Infants.Table 2
Incidence of the Primary Outcome.Article Activity
- Article
Survival among preterm infants has improved markedly in recent decades, in large part because of the ability to enhance fetal-lung maturation with antenatal corticosteroids and manage the respiratory distress syndrome. Chronic lung disease, or bronchopulmonary dysplasia,1,2 is now the most important long-term pulmonary complication in these infants and is associated with prolonged hospitalization and long-term pulmonary and neurodevelopmental problems.3-5 Severe bronchopulmonary dysplasia is associated with inflammation,6 pulmonary hypertension,7 and increased airway resistance,8,9 as well as abnormalities of lung growth, including disturbed angiogenesis and alveolarization.2,6,9,10
Inhaled nitric oxide is an effective treatment for pulmonary hypertension in term infants11-13; however, its efficacy in preterm infants is controversial. Kinsella et al.14 initially found neither a benefit nor adverse effects of inhaled nitric oxide in preterm infants but demonstrated a trend toward decreased bronchopulmonary dysplasia in treated infants. In a single-center, randomized trial, Schreiber et al.15 found a decrease in the combined outcome of death or bronchopulmonary dysplasia, as well as improved neurodevelopmental outcome at two years of age16 among infants who received a seven-day course of inhaled nitric oxide. However, a trial by the National Institute of Child Health and Human Development Neonatal Network,17 which used brief exposure to inhaled nitric oxide to treat presumed pulmonary hypertension in newborn infants with severe respiratory failure, found no overall benefit; the rates of complications and death increased with such therapy among infants weighing less than 1000 g. Earlier pilot studies of inhaled nitric oxide treatment for infants with established, severe bronchopulmonary dysplasia suggested improved outcomes and safety.18,19
Methods
We performed a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of inhaled nitric oxide in improving survival without bronchopulmonary dysplasia among infants at 36 weeks of postmenstrual age. Because our target population was infants with developing lung disease, we studied the efficacy of inhaled nitric oxide treatment initiated between 7 and 21 days among preterm infants undergoing mechanical ventilation who were at very high risk for bronchopulmonary dysplasia. The study was approved by the institutional review boards at each participating institution, and written informed consent was obtained from the parents of all enrolled infants.
Eligibility Criteria
Preterm infants born at 32 weeks of gestation or less were eligible if they weighed 500 to 1250 g at birth and were receiving mechanical ventilation for lung disease (not apnea) between 7 and 21 days of age. Infants with a birth weight of 500 to 799 g who were being treated with nasal continuous positive airway pressure were also eligible, since many such infants subsequently require intubation and ventilation. Infants could be enrolled if they had previously been extubated temporarily but required reintubation. All infants underwent ultrasonography of the head before being enrolled, and those with normal findings, grade 1 or 2 intraventricular hemorrhage, or unilateral grade 3 or 4 intraventricular hemorrhage were eligible. Exclusion criteria included life-threatening conditions, such as complex congenital anomalies and other conditions deemed by the attending neonatologist as likely to result in death (see the Supplementary Appendix, available with the full text of this article at www.nejm.org); preexisting bilateral grade 4 intraventricular hemorrhage; or previous receipt of inhaled nitric oxide therapy.
Study Design and Randomization
The trial was conducted at 21 infant intensive care units. Initial visits were made to each hospital by the principal investigator and a study coordinator to reach a consensus on all aspects of the trial and to ensure the hospital's compliance with long-term follow-up. The site investigators agreed to general guidelines for ventilatory management, the treatment of patent ductus arteriosus, and criteria for administration of postnatal corticosteroids. Randomization of infants occurred at the data coordinating center in Philadelphia and was stratified according to birth weight (500 to 799 g and 800 to 1250 g) and site with the use of permuted blocks, with equal assignment to the group receiving nitric oxide or the placebo group within blocks. If more than one infant from a multiple gestation was entered into the trial, only the first sibling enrolled underwent randomization. On the basis of parental requests in previous trials, any additional infants from that pregnancy who met entry criteria were assigned to the same therapy as the randomized sibling with the use of the same blinded delivery system.
Administration of Study Gas
Inhaled nitric oxide (INOmax, INO Therapeutics) and the delivery system (INOvent, Datex-Ohmeda) were provided to all sites by INO Therapeutics. INO Therapeutics was not involved in the study design, safety monitoring, data analysis or interpretation, or manuscript preparation. All of the physicians and nursing staff, as well as the parents, were unaware of infants' treatment assignment; only the respiratory therapist who administered the study gas was aware of infants' gas assignment. The study gas tanks were shrouded to prevent identification of contents (inhaled nitric oxide or nitrogen), and the delivery system had software that prevented the display of actual levels of nitric oxide or nitrogen dioxide on the screen. Infants initially received 20 ppm of study gas for 48 to 96 hours, and the doses were subsequently decreased to doses of 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 days.
Since few of these infants had indwelling arterial catheters for the monitoring of the partial pressure of arterial oxygen (PaO2), it was not possible to use the oxygenation index for an evaluation of the severity of respiratory disease. (The oxygenation index was calculated as the mean airway pressure times the fraction of inspired oxygen [FiO2] times 100, with the result divided by the PaO2.) A simplified severity score consisting of the mean airway pressure multiplied by the FiO2 was used. Infants were treated with an oxygen-saturation goal of 88 to 94 percent and were expected to have a PaO2 range of 40 to 70 mm Hg. Accordingly, a severity score of 3.5 was equivalent to an oxygenation index between 5 and 9.
Hypotheses and Outcomes
We hypothesized that the administration of inhaled nitric oxide to infants would increase survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age (primary outcome). Infants who required ventilatory support or were unable to maintain oxygen saturation above 88 percent while breathing room air were classified as having bronchopulmonary dysplasia. The oxygen requirement at 36 weeks of postmenstrual age was evaluated for infants receiving an effective concentration of less than 30 percent oxygen20 by a stepwise reduction in oxygen delivery to the lowest tolerated oxygen concentration. Secondary outcomes included the duration of oxygen therapy and the duration of hospitalization. In addition, we prospectively evaluated the need for hospitalization and respiratory support, including mechanical ventilation, continuous positive airway pressure, and oxygen supplementation at 40, 44, 52, and 60 weeks of postmenstrual age.
Safety Monitoring
Infants were monitored for complications of prematurity, including sepsis, patent ductus arteriosus, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and retinopathy of prematurity, as well as any other adverse events occurring during their hospitalization. Injury to the central nervous system was evaluated by ultrasonography of the head, which was performed before enrollment and either during or after the administration of study gas. Deaths that occurred while infants were receiving study gas were reported within 72 hours to the institutional review boards, the data coordinating center, and subsequently, to the Food and Drug Administration. Blood methemoglobin concentrations were measured at baseline and within the first 24 hours after the initiation of study gas. Concentrations of nitrogen dioxide were monitored, and the alarm on the delivery system was set to go off if they exceeded 3 ppm. The therapist who administered the study gas regularly calibrated the machine in an unblinded fashion and recorded actual levels of nitric oxide and nitrogen being delivered. The data and safety monitoring board reviewed the safety data after the enrollment of each group of 60 infants. The protocol called for survivors to be followed for pulmonary and neurodevelopmental outcomes through two years of age.
Statistical Analysis
Assuming that 50 percent of the eligible infants would survive free of bronchopulmonary dysplasia,21 we estimated that 544 infants would need to undergo randomization for the study to have a statistical power of 80 percent to detect an absolute increase of 12.5 percent in the group given nitric oxide. The protocol included two interim analyses after 25 percent and 60 percent of the outcome data had become available, to detect either the efficacy or futility of the therapy. We conducted the analyses using the O'Brien–Fleming stopping rule and the Lan–DeMets use function, while maintaining an overall alpha of 0.05,22 according to the intention-to-treat principle. Eligible twins and triplets within the same family were assigned to the same treatment. Because outcomes among siblings may be correlated, in analyses of all treated infants it was not appropriate to assume that the outcomes among siblings were independent. The use of generalized estimating equations,23,24 allowing for correlation between siblings, was not appropriate, since estimation of the common correlation was weak (7 percent of the study population included multiple siblings) and because study outcomes were associated with the size of the cluster. Therefore, we analyzed the data with the use of a multiple outputation approach with 1000 repeats.25 Under the null hypothesis, the P values calculated with this approach followed a uniform distribution (0,1). Baseline characteristics were compared with the use of Fisher's exact test for dichotomous variables and the Wilcoxon rank-sum test for continuous outcomes.
Analyses of the primary outcome, complications, and post hoc analyses were done with the use of a chi-square test on the basis of a univariate logistic model. Interaction terms for subgroup analyses were tested in a multiple logistic-regression model. We compared the status of the infants at 40 and 44 weeks with the use of a Monte Carlo simulation of the exact Wilcoxon two-sample rank test.26 We compared the durations of hospitalization and oxygen supplementation with the use of the log-rank test and assumed the maximum possible duration of each in the analysis of death. All reported P values are two-sided. We also analyzed the data after the exclusion of infants who, as part of a multiple gestation did not undergo randomization but, rather, were assigned to the same treatment as a randomized sibling.
Results
Of 5129 infants with a birth weight of 500 to 1250 g who were admitted to participating centers, 465 died (9.1 percent) and 3109 were ineligible (60.6 percent); 253 were transferred to another hospital, 2212 were extubated, 114 had life-threatening conditions, 119 had bilateral grade 4 intraventricular hemorrhage, 121 had previously received inhaled nitric oxide therapy, and 290 had other medical complications. Of 1555 eligible infants between the ages of 7 and 21 days, 587 (37.7 percent) were enrolled between May 2000 and April 2005. Five infants were withdrawn after randomization (three before treatment and two because of the withdrawal of parental consent). The 582 remaining infants had been delivered by 547 mothers (35 infants were assigned to a sibling's treatment).
Table 1Table 1
Baseline Characteristics of the Infants. gives the baseline characteristics and status at entry of the 582 infants in the study. There were no significant differences between groups in gestational age, birth weight, sex, race or ethnic group, or incidence of preexisting conditions, including pneumothorax, pulmonary hemorrhage, sepsis, necrotizing enterocolitis, patent ductus arteriosus, or unilateral grade 3 or 4 intraventricular hemorrhage. The median age at entry was 16 days, and the median respiratory severity score was 3.5 for both groups. There was no significant difference between groups in the number of infants receiving nasal continuous airway pressure, as compared with mechanical ventilation.In the group that was assigned to receive inhaled nitric oxide, 129 of 294 infants survived to 36 weeks of postmenstrual age without bronchopulmonary dysplasia (43.9 percent), as compared with 106 of 288 infants in the placebo group (36.8 percent) (relative benefit, 1.23; 95 percent confidence interval, 1.01 to 1.51; P=0.04) (Table 2Table 2
Incidence of the Primary Outcome.). The number needed to treat for one improved outcome was 14. The rate of survival without bronchopulmonary dysplasia was similar in both birth-weight strata; the study was not powered to detect significant differences within weight groups. The infants who were treated with inhaled nitric oxide were discharged sooner (P=0.04 by the log-rank test) and received supplemental oxygen therapy for a shorter period (P=0.006 by the log-rank test) than did the controls.At 40 and 44 weeks of postmenstrual age, a significantly lower proportion of infants receiving inhaled nitric oxide than of infants in the placebo group remained in the hospital and required mechanical ventilation, nasal continuous positive airway pressure, or supplemental oxygen (P=0.01 at 40 weeks and P=0.03 at 44 weeks); bronchopulmonary dysplasia, when it occurred, was less severe among infants receiving inhaled nitric oxide (Table 3Table 3
Outcome According to the Severity of Disease at 40 and 44 Weeks of Postmenstrual Age.). By 52 weeks, most infants in both groups either no longer needed respiratory support or had been discharged. Of the 582 enrolled infants, 46 died (7.9 percent), with 3 deaths occurring after discharge from the hospital. A total of 21 infants (9 who received inhaled nitric oxide and 12 who received placebo) died while receiving study gas. When the nonrandomized siblings were excluded, differences between groups in the primary outcome remained significant (relative benefit, 1.25; 95 percent confidence interval, 1.01 to 1.53; P=0.035).Among the infants receiving inhaled nitric oxide, none had significant elevations of methemoglobin. There were also no significant differences between groups in the incidence of complications of prematurity (Table 4Table 4
Incidence of Clinical Complications after Study Entry.) — including sepsis, necrotizing enterocolitis, patent ductus arteriosus requiring therapy, retinopathy of prematurity, or the evolution of neurologic findings on ultrasonography — either during or after the administration of study gas.We conducted post hoc analyses on the basis of the age at study entry, the severity of lung disease at study enrollment, and race or ethnic group (Table 5Table 5
Post Hoc Subgroup Analyses of Survival without Chronic Lung Disease at 36 Weeks of Postmenstrual Age.). We observed a significant interaction between the age at study entry and treatment (P=0.006). Nitric oxide treatment yielded a significant benefit in the group of infants between the ages of 7 and 14 days at enrollment, but not in the group of infants between the ages of 15 and 21 days. For the subpopulation of infants who entered the study at 7 to 14 days of age, the group given inhaled nitric oxide and the placebo group were similar with regard to baseline characteristics (data not shown). There was no interaction between the severity score at study entry and treatment (P=0.20). The effect of inhaled nitric oxide appeared to differ according to race or ethnic group (P=0.05 for the interaction between race and treatment). There were no significant differences in the response to inhaled nitric oxide according to sex or exposure to postnatal corticosteroids (data not shown).Discussion
In this multicenter, randomized trial of inhaled nitric oxide among premature infants undergoing mechanical ventilation, we found that treatment for 24 days significantly improved the likelihood of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. As compared with infants who received placebo gas, infants who were treated with inhaled nitric oxide were hospitalized for fewer days, needed supplemental oxygen for a shorter period, and had less severe disease. We found no evidence of short-term deleterious clinical effects of nitric oxide therapy.
This trial differed in design from the study by Kinsella et al.,27 which appears elsewhere in this issue of the Journal, and from previously reported trials of inhaled nitric oxide,14,15,17,28,29 which focused on preterm infants with respiratory failure shortly after birth with the intention of treating pulmonary hypertension or reducing inflammation. In our study, therapy was started later (between 7 and 21 days, as compared with during the first 24 to 48 hours after birth14,15,17) and was continued for a longer period (24 days vs. 76 hours to 14 days). We hypothesized that prolonged therapy with inhaled nitric oxide might be needed to prevent increased airway resistance and muscularity,8,9 to attenuate hyperoxic injury,30 and to improve surfactant function,31 lung growth, angiogenesis, and alveolarization, as has been reported in studies in animals.32-34
We delayed enrollment in the study until infants were seven days of age because of concern about a possible interaction between inhaled nitric oxide and brain injury. We did not find any evidence of increased evolution of brain injury in treated infants. We entered infants when they were 7 to 21 days of age in an effort to include all infants at high risk for bronchopulmonary dysplasia. Very preterm infants frequently have initial respiratory disease that improves, often with extubation at approximately days 4 to 7, and later worsens, requiring reintubation. Moreover, our earlier pilot trial demonstrated the benefit of inhaled nitric oxide for infants with severe disease who are older than 28 days of age.18
Infants in the current trial had greater total exposure to inhaled nitric oxide, in terms of both the duration (24 days) and the peak and total dose, than did infants in other trials. In the National Institute of Child Health and Human Development Neonatal Network trial,17 only infants who had a response to treatment (defined as an immediate improvement in oxygenation) continued to receive treatment (mean duration, 76 hours). In that trial, the benefit of treatment was limited to infants weighing more than 1000 g at birth. In a study by Schreiber et al.,15 infants were treated for a maximum of seven days, and only those with less severe disease at enrollment benefited. Kinsella et al.,27 who administered 5 ppm of inhaled nitric oxide and discontinued therapy on extubation, found that this approach had respiratory benefit only among infants with a birth weight of more than 1000 g. In our trial, the effect of inhaled nitric oxide on survival without bronchopulmonary dysplasia appeared to be similar among infants in the birth-weight strata of 500 to 799 g and 800 to 1250 g, although results were not significantly different in individual subgroups; only 55 infants weighed more than 1000 g.
The mechanism of the beneficial effect of inhaled nitric oxide may include a decrease in airway resistance, resulting over time in a decreased need for supplemental oxygen and ventilatory support, with less oxidative stress. Results of post hoc analyses suggest that inhaled nitric oxide may be less beneficial when initiated later (after 14 days), indicating that infants receiving such treatment may already have sustained lung damage secondary to oxidative stress and volutrauma. Inhaled nitric oxide also appeared to have less benefit among white infants, as compared with nonwhite infants; some investigators have suggested the possibility of racial differences in responsiveness to inhaled nitric oxide. However, these results must be viewed as hypothesis-generating; the study was not powered to address such subgroups.35
In conclusion, prolonged inhaled nitric oxide therapy that is initiated between 7 and 21 days of age in preterm infants undergoing mechanical ventilation significantly improved survival without bronchopulmonary dysplasia without short-term adverse effects. Definitive recommendations regarding the use of inhaled nitric oxide among infants at high risk for bronchopulmonary dysplasia await further long-term neurodevelopmental follow-up in the completed trials.
Supported by grants (U01-HL62514, P50-HL56401, P30-HD26979, MRDDRC-P30, and HD26979) from the National Institutes of Health and grants (M01-RR00240, M01-RR00084, M01-RR00425, M01-RR001271, M01-RR00064, and M01-RR00080) from the General Clinical Research Centers Program.
Dr. R. Ballard reports having received grant support from INO Therapeutics for an MRI follow-up study of infants in the trial; Dr. Walsh, support from INO Therapeutics to fund a research nurse coordinator for a follow-up of this trial; Dr. Durand, grant support from Bunnell for a trial of jet ventilation; Dr. Hudak, support from Inhibitex for the Veronate Study follow-up; Dr. Courtney, lecture fees from INO Therapeutics and Viasys; Drs. Golombek and Stewart, lecture fees from INO Therapeutics; and all investigators in the trial, support from the National Heart, Lung, and Blood Institute for enrolling patients in the trial. Dr. Courtney also reports having served on the advisory board of Discovery Labs. No other potential conflict of interest relevant to this article was reported.
This article is dedicated to the memory of Thomas Hazinski, M.D., a distinguished scientist and valued colleague and friend, who served as chairman of the data and safety monitoring board.
We are indebted to Beverly Banks Randall, M.D., Ph.D., for doing the initial pilot trials; to all the neonatal nurses, residents, fellows, and respiratory therapists who made this study possible; to Carol Dennis for help with the manuscript; to INO Therapeutics for providing study equipment and gas; and to the families and infants who participated in the study.
Source Information
From Children's Hospital of Philadelphia (R.A.B., A.C., P.L.B., A.M.H., X.L., S.R.W., C.E.C.) and the University of Pennsylvania School of Medicine (J.D.M.) — both in Philadelphia; the University of Missouri, Kansas City (W.E.T.); Case Western Reserve University, Cleveland (R.J.M., M.C.W.); Children's Hospital and Research Center, Oakland, Calif. (D.J.D., J.M.A.); the University of Washington School of Medicine, Seattle (D.E.M.); Harvard Medical School, Boston (E.C.E.); the University of Utah Medical Center, Salt Lake City (D.R.N.); the University of Florida Health Science Center, Jacksonville (M.L.H.); the University of California Los Angeles School of Medicine, Los Angeles (A.R.P.); New York Medical College, Valhalla (S.G.G.); Long Island Jewish Health System, New Hyde Park, N.Y. (S.E.C.); the University of Louisville School of Medicine, Louisville, Ky. (D.L.S.); Ohio State University School of Medicine and Public Health, Columbus (S.E.W.); and the University of California at San Francisco, San Francisco (R.H.P.).
Address reprint requests to Dr. Ballard at Children's Hospital of Philadelphia, 3535 Market St., Suite 1584, Philadelphia, PA 19104, or at ballard@email.chop.edu.
Additional members of the Nitric Oxide (to Prevent) Chronic Lung Disease (NO CLD) Study Group are listed in the Appendix.
Appendix
In addition to the authors, the following members of the NO CLD Study Group participated in this study: Centers — Alta Bates Summit Medical Center, Berkeley, Calif., and Children's Hospital and Research Center Oakland, Oakland, Calif. — L. Pacello, R. Ratcliff, V. Daly, A. Espinosa; Brigham and Women's Hospital and Children's Hospital, Boston — K. Puopolo, A. Hansen, T. Cimini, D. Beadles, C. Pantano, C. Martin; Cedars-Sinai Medical Center, Los Angeles — W. Bunuan, A. Verne, J. Raber, S. Sehgal; Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania, Philadelphia — L. Corcoran, J. Fricko, S. Zirin, A. Hedgman, K. Kelly, B. Hubble, K. Mooney, L. Brown, R. Scarborough, J. Bernbaum, H. Hurt; Children's Hospital and Regional Medical Center and University of Washington Medical Center, Seattle — C. Gleason, S. Jacques, H. Meo, F. Bennett; Children's Mercy Hospital, Kansas City, Mo. — I. Ekekezie, C. Castor, P. Johnson, K. Meinert, D. Taylor, H. Kilbride; Columbus Children's Hospital, Columbus, Ohio — S. Farley, T. Preston, C. Timan; Kosair Children's Hospital, Louisville, Ky. — S. Daugherty, J. Foos, K. Sheeley, S. Polston, S. Wilkerson; North Shore–Long Island Jewish Health System and Schneider Children's Hospital, New Hyde Park, N.Y. — A. Steele, D. Potak, B. Wilkens, S. Pollard, A. Adesman; Primary Children's Medical Center and the University of Utah Hospital and Clinics, Salt Lake City — R. Milley, S. Baker, L. Cole, K. Hillier, L. Hiatt, A. Bodnar; Rainbow Babies and Children's Hospital, Cleveland — A. Zadell, M. Tracy, J. Di Fiore, M. Hack, D. Costello; University of Florida Wolfson Children's Hospital at Baptist Medical Center and Shands Jacksonville Medical Center, Jacksonville — S. Osbeck, A. Kellum, L. Hogans, D. Childers; University of California at San Francisco Medical Center, San Francisco — S. Sehring, J. Imamura-Ching, N. Newton, C. Kelly, R. Piecuch; Westchester Medical Center, Valhalla, N.Y. — L. Parton, N. Dweck, J. Weissleder, J. Kase; Data Coordinating Center — T. Alvarado-Taylor, J. Valliyil, M. Davis, K. Gibbs; Data and Safety Monitoring Committee — Vanderbilt University School of Medicine, Nashville — T. Hazinski (chair, deceased); New York Academy of Medicine, New York — A. Fleischman; Children's Hospital of Buffalo, Buffalo, N.Y. — F. Morin; Women and Infants Hospital, Brown University School of Medicine, Providence, R.I. — B. Vohr; Emmes, Rockville, Md. — S. Carter; National Heart, Lung, and Blood Institute, Bethesda, Md. — M. Berberich, N. Geller, C. Hunt, G. Zheng; Clinical Steering Committee — R. Ballard, W. Truog, R. Martin, P. Ballard, J. Merrill, M. Walsh.
- References
References
1
Northway WH Jr ,Rosan RC ,Porter DY . Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967;276:357-368
Full Text | Web of Science | Medline2
Jobe AH ,Bancalari E . Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729
Medline3
Marlow N ,Wolke D ,Bracewell MA ,Samara M . Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19
Full Text | Web of Science | Medline4
Vohr BWL ,Hack M ,Aylward G ,Hirtz D . Follow-up care of high-risk infants. Pediatrics 2004;114:Suppl:1377-1379
Web of Science5
Laptook AR ,O'Shea TM ,Shankaran S ,Bhaskar B . Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673-680
CrossRef | Web of Science | Medline6
Coalson JJ . Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81
CrossRef | Medline7
Berman W Jr ,Katz R ,Yabek SM ,Dillon T ,Fripp RR ,Papile LA . Long-term follow-up of bronchopulmonary dysplasia. J Pediatr 1986;109:45-50
CrossRef | Web of Science | Medline8
Martin RJ ,Mhanna MJ ,Haxhiu MA . The role of endogenous and exogenous nitric oxide on airway function. Semin Perinatol 2002;26:432-438
CrossRef | Web of Science | Medline9
Bland RD ,Albertine KH ,Carlton DP ,MacRitchie AJ . Inhaled nitric oxide effects on lung structure and function in chronically ventilated preterm lambs. Am J Respir Crit Care Med 2005;172:899-906
CrossRef | Web of Science | Medline10
Martin RJ ,Walsh MC . Inhaled nitric oxide for preterm infants -- who benefits? N Engl J Med 2005;353:82-84
Full Text | Web of Science | Medline11
Roberts JD Jr ,Fineman JR ,Morin FC III , et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997;336:605-610
Full Text | Web of Science | Medline12
Clark RH ,Kueser TJ ,Walker MW , et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000;342:469-474
Full Text | Web of Science | Medline13
The Neonatal Inhaled Nitric Oxide Study Group
Full Text | Web of Science | Medline14
Kinsella JP ,Walsh WF ,Bose CL , et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet 1999;354:1061-1065
CrossRef | Web of Science | Medline15
Schreiber MD ,Gin-Mestan K ,Marks JD ,Huo D ,Lee G ,Srisuparp P . Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003;349:2099-2107
Full Text | Web of Science | Medline16
Mestan KK ,Marks JD ,Hecox K ,Huo D ,Schreiber MD . Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005;353:23-32
Full Text | Web of Science | Medline17
Van Meurs KP ,Wright LL ,Ehrenkranz RA , et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353:13-22
Full Text | Web of Science | Medline18
Banks BA ,Seri I ,Ischiropoulos H ,Merrill J ,Rychik J ,Ballard RA . Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999;103:610-618
CrossRef | Web of Science | Medline19
Clark PL ,Ekekezie II ,Kaftan HA ,Castor CA ,Truog WE . Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002;86:F41-F45
CrossRef | Web of Science | Medline20
Walsh MC ,Yao Q ,Gettner P , et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004;114:1305-1311
CrossRef | Web of Science | Medline21
Ballard RA ,Ballard PL ,Cnaan A , et al. Antenatal thyrotropin-releasing hormone to prevent lung disease in preterm infants. N Engl J Med 1998;338:493-498
Full Text | Web of Science | Medline22
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Boca Raton, Fla.: Chapman & Hall/CRC Press, 2000.
23
EaST, version 3.0, software for advanced clinical trial design, simulation, and monitoring: user's manual. Cambridge, Mass.: Cytel Statistical Software Services, 2003.
24
Liang K-Y ,Zeger SL . Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22
CrossRef | Web of Science25
Follmann D ,Proschan M ,Leifer E . Multiple outputation: inference for complex clustered data by averaging analyses from independent data. Biometrics 2003;59:420-429
CrossRef | Web of Science | Medline26
StatXact 7: statistical software for exact nonparametric inference. Cambridge, Mass.: Cytel, 2005.
27
Kinsella JP ,Cutter GR ,Walsh WF , et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354-364
Full Text | Web of Science | Medline28
Field D ,Elbourne D ,Truesdale A , et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005;115:926-936
CrossRef | Web of Science | Medline29
Hascoet JM ,Fresson J ,Claris O , et al. The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 2005;146:318-323
CrossRef | Web of Science | Medline30
Cotton RB ,Sundell HW ,Zeldin DC , et al. Inhaled nitric oxide attenuates hyperoxic lung injury in lambs. Pediatr Res 2006;59:142-146
CrossRef | Web of Science | Medline31
Ballard PL ,Gonzales LW ,Godinez RI , et al. Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide. Pediatr Res 2006;59:157-162
CrossRef | Web of Science | Medline32
Lin YJ ,Markham NE ,Balasubramaniam V , et al. Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats. Pediatr Res 2005;58:22-29
CrossRef | Web of Science | Medline33
Tang JR ,Markham NE ,Lin YJ , 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-L351
CrossRef | Web of Science | Medline34
McCurnin DC ,Pierce RA ,Chang LY , 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
CrossRef | Web of Science | Medline35
Bloche MG . Race-based therapeutics. N Engl J Med 2004;351:2035-2037
Full Text | Web of Science | Medline
- Citing Articles (86)
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Sonia L. Bonifacio, Fernando Gonzalez, Donna M. Ferriero. 2012. , 869.
CrossRef4
Eric C. Eichenwald. 2012. , 390.
CrossRef5
Roberta L. Keller, Roberta A. Ballard. 2012. , 658.
CrossRef6
K N Farrow, R H Steinhorn. (2012) Sildenafil therapy for bronchopulmonary dysplasia: not quite yet. Journal of Perinatology 32:1, 1-3
CrossRef7
Kristen Tropea, Helen Christou. (2012) Current Pharmacologic Approaches for Prevention and Treatment of Bronchopulmonary Dysplasia. International Journal of Pediatrics 2012, 1-9
CrossRef8
Amir Kugelman, Manuel Durand. (2011) A comprehensive approach to the prevention of bronchopulmonary dysplasia. Pediatric Pulmonology 46:12, 1153-1165
CrossRef9
R. H. Pfister, R. F. Soll. (2011) Pulmonary Care and Adjunctive Therapies for Prevention and Amelioration of Bronchopulmonary Dysplasia. NeoReviews 12:11, e635-e644
CrossRef10
M Nyp, T Sandritter, N Poppinga, C Simon, W E Truog. (2011) Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?. Journal of Perinatology
CrossRef11
J D Merrill, P L Ballard, S E Courtney, D J Durand, A Hamvas, A M Hibbs, K W Lu, R M Ryan, A M Reynolds, K Spence, R H Steinhorn, W E Truog, E C Eichenwald, R A Ballard. (2011) Pilot trial of late booster doses of surfactant for ventilated premature infants. Journal of Perinatology 31:9, 599-606
CrossRef12
Robin H. Steinhorn. (2011) Therapeutic approaches using nitric oxide in infants and children. Free Radical Biology and Medicine 51:5, 1027-1034
CrossRef13
Christie J. Bruno, Todd M. Greco, Harry Ischiropoulos. (2011) Nitric oxide counteracts the hyperoxia-induced proliferation and proinflammatory responses of mouse astrocytes. Free Radical Biology and Medicine 51:2, 474-479
CrossRef14
Jason Gien, John P Kinsella. (2011) Pathogenesis and treatment of bronchopulmonary dysplasia. Current Opinion in Pediatrics 23:3, 305-313
CrossRef15
Athena I Patrianakos-Hoobler, Jeremy D Marks, Michael E. Msall, Dezheng Huo, Michael D Schreiber. (2011) Safety and efficacy of inhaled nitric oxide treatment for premature infants with respiratory distress syndrome: follow-up evaluation at early school age. Acta Paediatrica 100:4, 524-528
CrossRef16
Venkatesh Sampath, Jeffery S. Garland, Min Le, Aloka L. Patel, Girija G. Konduri, Jonathan D. Cohen, Pippa M. Simpson, Ronald N. Hines. (2011) A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia. Pediatric Pulmonologyn/a-n/a
CrossRef17
Keith J Barrington, Neil Finer, Keith J Barrington. 2010. Inhaled nitric oxide for respiratory failure in preterm infants. .
CrossRef18
R H Clark, R L Ursprung, M W Walker, D L Ellsbury, A R Spitzer. (2010) The changing pattern of inhaled nitric oxide use in the neonatal intensive care unit. Journal of Perinatology 30:12, 800-804
CrossRef19
ARUL VADIVEL, JUDY L. ASCHNER, GLORIA J. REY-PARRA, JORDAN MAGARIK, HENG ZENG, MARSHALL SUMMAR, FARAH EATON, BERNARD THÉBAUD. (2010) l-Citrulline Attenuates Arrested Alveolar Growth and Pulmonary Hypertension in Oxygen-Induced Lung Injury in Newborn Rats. Pediatric Research 68:6, 519-525
CrossRef20
I Hamon, H Gauthier-Moulinier, E Grelet-Dessioux, L Storme, J Fresson, JM Hascoet. (2010) Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatrica 99:10, 1467-1473
CrossRef21
Sergio G. Golombek, William E. Truog, Roberta A. Ballard, Philip L. Ballard. (2010) Re: ‘The use of iNO in the newborn period: results from the European iNO registry’. Acta Paediatrica 99:9, 1283-1283
CrossRef22
Jean-Christophe Mercier, Helmut Hummler, Xavier Durrmeyer, Manuel Sanchez-Luna, Virgilio Carnielli, David Field, Anne Greenough, Bart Van Overmeire, Baldvin Jonsson, Mikko Hallman, James Baldassarre. (2010) Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. The Lancet 376:9738, 346-354
CrossRef23
Ilene RS Sosenko, Eduardo Bancalari. (2010) NO for preterm infants at risk of bronchopulmonary dysplasia. The Lancet 376:9738, 308-310
CrossRef24
Michael R. Stenger, Melissa J. Rose, Mandar S. Joshi, Lynette K. Rogers, Louis G. Chicoine, John Anthony Bauer, Leif D. Nelin. (2010) Inhaled Nitric Oxide Prevents 3-Nitrotyrosine Formation in the Lungs of Neonatal Mice Exposed to >95% Oxygen. Lung 188:3, 217-227
CrossRef25
A González, J Fabres, I D'Apremont, G Urcelay, M Avaca, C Gandolfi, J Kattan. (2010) Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension. Journal of Perinatology 30:6, 420-424
CrossRef26
Sylvie Joriot-Chekaf, Rony Sfeir, Yvon Riou, Pierre Gressens, Louis Vallée, Régis Bordet, Joseph Vamecq. (2010) Evaluation of inhaled NO in a model of rat neonate brain injury caused by hypoxia–ischaemia. Injury 41:5, 517-521
CrossRef27
Michele C. Walsh, Anna Maria Hibbs, Camilia R. Martin, Avital Cnaan, Roberta L. Keller, Eric Vittinghoff, Richard J. Martin, William E. Truog, Philip L. Ballard, Arlene Zadell, Sandra R. Wadlinger, Christine E. Coburn, Roberta A. Ballard. (2010) Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide. The Journal of Pediatrics 156:4, 556-561.e1
CrossRef28
M A Posencheg, A J Gow, W E Truog, R A Ballard, A Cnaan, S G Golombek, P L Ballard. (2010) Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. Journal of Perinatology 30:4, 275-280
CrossRef29
Keith J Barrington, Neil Finer. (2010) Cochrane review: Inhaled nitric oxide for respiratory failure in preterm infants. Evidence-Based Child Health: A Cochrane Review Journal 5:1, 301-336
CrossRef30
Anna Maria Hibbs, Dennis Black, Lisa Palermo, Avital Cnaan, Xianqun Luan, William E. Truog, Michele C. Walsh, Roberta A. Ballard. (2010) Accounting for Multiple Births in Neonatal and Perinatal Trials: Systematic Review and Case Study. The Journal of Pediatrics 156:2, 202-208
CrossRef31
A A Rosenberg, N R Lee, K N Vaver, D Werner, L Fashaw, K Hale, N Waas. (2010) School-age outcomes of newborns treated for persistent pulmonary hypertension. Journal of Perinatology 30:2, 127-134
CrossRef32
Csaba Szabo. 2010. Medicinal Chemistry and Therapeutic Applications of the Gasotransmitters NO, CO, and H 2 S and their Prodrugs. .
CrossRef33
Lindsay C. Johnston, Linda W. Gonzales, Richard T. Lightfoot, Susan H. Guttentag, Harry Ischiropoulos. (2010) Opposing regulation of human alveolar Type II cell differentiation by nitric oxide and hyperoxia.. Pediatric Research1
CrossRef34
Fernando F. Gonzalez, Donna M. Ferriero. (2009) Neuroprotection in the Newborn Infant. Clinics in Perinatology 36:4, 859-880
CrossRef35
Win Tin, Thomas E. Wiswell. (2009) Drug therapies in bronchopulmonary dysplasia: debunking the myths. Seminars in Fetal and Neonatal Medicine 14:6, 383-390
CrossRef36
Matthew M. Laughon, P. Brian Smith, Carl Bose. (2009) Prevention of bronchopulmonary dysplasia. Seminars in Fetal and Neonatal Medicine 14:6, 374-382
CrossRef37
Linda J. Van Marter. (2009) Epidemiology of bronchopulmonary dysplasia. Seminars in Fetal and Neonatal Medicine 14:6, 358-366
CrossRef38
RICHARD L. AUTEN, JONATHAN M. DAVIS. (2009) Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details. Pediatric Research 66:2, 121-127
CrossRef39
CLYDE J. WRIGHT, PHYLLIS A. DENNERY. (2009) Manipulation of Gene Expression by Oxygen: A Primer From Bedside to Bench. Pediatric Research 66:1, 3-10
CrossRef40
Anne Greenough, Vadivelam Murthy. (2009) Respiratory problems in the premature newborn. Pediatric Health 3:3, 241-249
CrossRef41
R F Soll. (2009) Inhaled nitric oxide in the neonate. Journal of Perinatology 29, S63-S67
CrossRef42
Nandini Arul, G. Ganesh Konduri. (2009) Inhaled Nitric Oxide for Preterm Neonates. Clinics in Perinatology 36:1, 43-61
CrossRef43
Jean-Christophe Mercier, Paul Olivier, Gauthier Loron, Romain Fontaine, Laure Maury, Olivier Baud. (2009) Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates. Seminars in Fetal and Neonatal Medicine 14:1, 28-34
CrossRef44
Ah-Fong Hoo, Caroline S. Beardsmore, Rosemary A. Castle, Sarath C. Ranganathan, Keith Tomlin, David Field, Diana Elbourne, Janet Stocks, . (2009) Respiratory function during infancy in survivors of the INNOVO trial. Pediatric Pulmonology 44:2, 155-161
CrossRef45
Bryce RH Robinson, Krishna P Athota, Richard D Branson. (2009) Inhalational therapies for the ICU. Current Opinion in Critical Care 15:1, 1-9
CrossRef46
Kushal Y. Bhakta, James M. Adams, Ann R. Stark. 2009. Chronic Lung Disease of Infancy. , 1-27.
CrossRef47
Jeremy D. Marks, Michael D. Schreiber. (2008) Inhaled Nitric Oxide and Neuroprotection in Preterm Infants. Clinics in Perinatology 35:4, 793-807
CrossRef48
Stephanie S. Miller, William D. Rhine. (2008) Inhaled nitric oxide in the treatment of preterm infants. Early Human Development 84:11, 703-707
CrossRef49
Nicolas F.M. Porta, Robin H. Steinhorn. (2008) Inhaled NO in the experimental setting. Early Human Development 84:11, 717-723
CrossRef50
John P. Kinsella. (2008) Inhaled nitric oxide in the term newborn. Early Human Development 84:11, 709-716
CrossRef51
Fernando F. Gonzalez, Donna M. Ferriero. (2008) Therapeutics for neonatal brain injury. Pharmacology & Therapeutics 120:1, 43-53
CrossRef52
Esther Rieger-Fackeldey, Roland Hentschel. (2008) Bronchopulmonary dysplasia and early prophylactic inhaled nitric oxide in preterm infants: current concepts and future research strategies in animal models. Journal of Perinatal Medicine 36:5, 442-447
CrossRef53
Anne Greenough. (2008) Emerging drugs for the prevention of bronchopulmonary dysplasia. Expert Opinion on Emerging Drugs 13:3, 537-546
CrossRef54
ANNE GREENOUGH, VADIVELAM MURTHY. (2008) RESPIRATORY DISTRESS SYNDROME. Fetal and Maternal Medicine Review 19:03,
CrossRef55
Christiana W. Davis, Linda W. Gonzales, Roberta A. Ballard, Philip L. Ballard, Changjiang Guo, Andrew J. Gow. (2008) Expression of nitric oxide synthases and endogenous NO metabolism in bronchopulmonary dysplasia. Pediatric Pulmonology 43:7, 703-709
CrossRef56
Niranjan Kissoon, Peter C. Rimensberger, Desmond Bohn. (2008) Ventilation Strategies and Adjunctive Therapy in Severe Lung Disease. Pediatric Clinics of North America 55:3, 709-733
CrossRef57
N Ambalavanan, K P Van Meurs, R Perritt, W A Carlo, R A Ehrenkranz, D K Stevenson, J A Lemons, W K Poole, R D Higgins. (2008) Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure. Journal of Perinatology 28:6, 420-426
CrossRef58
John Granton, Jakov Moric. (2008) Pulmonary Vasodilators—Treating the Right Ventricle. Anesthesiology Clinics 26:2, 337-353
CrossRef59
Eichenwald, Eric C., Stark, Ann R., . (2008) Management and Outcomes of Very Low Birth Weight. New England Journal of Medicine 358:16, 1700-1711
Full Text60
Marilee C Allen. (2008) Neurodevelopmental outcomes of preterm infants. Current Opinion in Neurology 21:2, 123-128
CrossRef61
M. Jeeva Sankar, Ramesh Agarwal, Ashok K. Deorari, Vinod K. Paul. (2008) Chronic lung disease in newborns. The Indian Journal of Pediatrics 75:4, 369-376
CrossRef62
Laura Cerny, John S. Torday, Virender K. Rehan. (2008) Prevention and Treatment of Bronchopulmonary Dysplasia: Contemporary Status and Future Outlook. Lung 186:2, 75-89
CrossRef63
Aparna U. Hoskote, Rosemary A. Castle, Ah-Fong Hoo, Sooky Lum, Sarath C. Ranganathan, Quen Q. Mok, Janet Stocks. (2008) Airway function in infants treated with inhaled nitric oxide for persistent pulmonary hypertension. Pediatric Pulmonology 43:3, 224-235
CrossRef64
Win Tin, Thomas E. Wiswell. (2008) Adjunctive therapies in chronic lung disease: Examining the evidence. Seminars in Fetal and Neonatal Medicine 13:1, 44-52
CrossRef65
P H Su, J Y Chen. (2008) Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. Journal of Perinatology 28:2, 112-116
CrossRef66
Chang Won Choi, Beyong Il Kim, Hyun Ju Lee, Kyoung Eun Joung, Gyu Hong Shim, In Suk Lim, Jin-A Lee, Ee-Kyung Kim, Han-Suk Kim, Jung-Hwan Choi. (2008) Clinical characteristics of severe meconium aspiration syndrome. Korean Journal of Pediatrics 51:7, 713
CrossRef67
J.A. Stockman. (2008) Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation. Yearbook of Pediatrics 2008, 400-402
CrossRef68
J M Di Fiore, A M Hibbs, A E Zadell, J D Merrill, E C Eichenwald, A R Puri, D E Mayock, S E Courtney, R A Ballard, R J Martin. (2007) The effect of inhaled nitric oxide on pulmonary function in preterm infants. Journal of Perinatology 27:12, 766-771
CrossRef69
L. Gortner, S. Meyer. (2007) Die bronchopulmonale Dysplasie Frühgeborener. Intensivmedizin und Notfallmedizin 44:8, 475-485
CrossRef70
Phillip V Gordon, Andrew C Herman, Marek Marcinkiewicz, Benjamin M Gaston, Victor E Laubach, Judy L Aschner. (2007) A Neonatal Mouse Model of Intestinal Perforation: Investigating the Harmful Synergism Between Glucocorticoids and Indomethacin. Journal of Pediatric Gastroenterology and Nutrition 45:5, 509-519
CrossRef71
Ballard, Roberta A., . (2007) Inhaled Nitric Oxide in Preterm Infants — Correction. New England Journal of Medicine 357:14, 1444-1445
Full Text72
DANIELE TREVISANUTO, NICOLETTA Doglioni, MASSIMO MICAGLIO, VINCENZO ZANARDO. (2007) Feasibility of nitric oxide administration by neonatal helmet-CPAP: a bench study. Pediatric Anesthesia 17:9, 851-855
CrossRef73
Anne Greenough, Atul Sharma. (2007) What is new in ventilation strategies for the neonate?. European Journal of Pediatrics 166:10, 991-996
CrossRef74
Keith J Barrington, Neil Finer, Keith J Barrington. 2007. Inhaled nitric oxide for respiratory failure in preterm infants. .
CrossRef75
John P. Kinsella, Steven H. Abman. (2007) Inhaled Nitric Oxide in the Premature Newborn. The Journal of Pediatrics 151:1, 10-15
CrossRef76
Susan R. Hintz, Krisa P. Van Meurs, R. Perritt, W. Kenneth Poole, Abhik Das, David K. Stevenson, Richard A. Ehrenkranz, James A. Lemons, Betty R. Vohr, Roy Heyne, David O. Childers, Myriam Peralta-Carcelen, Anna Dusick, Yvette R. Johnson, Brenda Morris, Robert Dillard, Yvonne Vaucher, Jean Steichen, Ira Adams-Chapman, Ganesh Konduri, Gary J. Myers, Marissa de Ungria, Jon E. Tyson, Rosemary D. Higgins. (2007) Neurodevelopmental Outcomes of Premature Infants with Severe Respiratory Failure Enrolled in a Randomized Controlled Trial of Inhaled Nitric Oxide. The Journal of Pediatrics 151:1, 16-22.e3
CrossRef77
William E Truog. (2007) Inhaled nitric oxide for the prevention of bronchopulmonary dysplasia. Expert Opinion on Pharmacotherapy 8:10, 1505-1513
CrossRef78
W Thomas, C P Speer. (2007) Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects. Journal of Perinatology 27, S26-S32
CrossRef79
Robin H Steinhorn, Nicolas FM Porta. (2007) Use of inhaled nitric oxide in the preterm infant. Current Opinion in Pediatrics 19:2, 137-141
CrossRef80
SANDRA M. REES, EMILY J. CAMM, MICHELLE LOELIGER, SARAH CAIN, SANDRA DIENI, DONALD MCCURNIN, PHILIP W. SHAUL, BRADLEY YODER, CATRIONA MCLEAN, TERRIE E. INDER. (2007) Inhaled Nitric Oxide: Effects on Cerebral Growth and Injury in a Baboon Model of Premature Delivery. Pediatric Research PAP,
CrossRef81
Cynthia Price. (2007) INHALED NITRIC OXIDE THERAPY IN PRETERM INFANTS. AJN, American Journal of Nursing 107:2, 35
CrossRef82
Silvia Brunelli, Patrizia Rovere-Querini, Clara Sciorati, Angelo A Manfredi, Emilio Clementi. (2007) Nitric oxide: emerging concepts about its use in cell-based therapies. Expert Opinion on Investigational Drugs 16:1, 33-43
CrossRef83
Virender K. Rehan. (2006) Prevention of bronchopulmonary dysplasia: Finally, something that works. The Indian Journal of Pediatrics 73:11, 1027-1032
CrossRef84
Charlene Laino. (2006) INHALED NITRIC OXIDE MAY BENEFIT SELECT PRETERM INFANTS, RISK OF BRAIN INJURY LOW. Neurology Today 6:17, 12-13
CrossRef85
Kinsella, John P., Cutter, Gary R., Walsh, William F., Gerstmann, Dale R., Bose, Carl L., Hart, Claudia, Sekar, Kris C., Auten, Richard L., Bhutani, Vinod K., Gerdes, Jeffrey S., George, Thomas N., Southgate, W. Michael, Carriedo, Heather, Couser, Robert J., Mammel, Mark C., Hall, David C., Pappagallo, Mariann, Sardesai, Smeeta, Strain, John D., Baier, Monika, Abman, Steven H., . (2006) Early Inhaled Nitric Oxide Therapy in Premature Newborns with Respiratory Failure. New England Journal of Medicine 355:4, 354-364
Full Text86
Stark, Ann R., . (2006) Inhaled NO for Preterm Infants — Getting to Yes?. New England Journal of Medicine 355:4, 404-406
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