Original Article
Low-Dose Nitric Oxide Therapy for Persistent Pulmonary Hypertension of the Newborn
N Engl J Med 2000; 342:469-474February 17, 2000
- Abstract
Background
Inhaled nitric oxide improves gas exchange in neonates, but the efficacy of low-dose inhaled nitric oxide in reducing the need for extracorporeal membrane oxygenation has not been established.
Methods
We conducted a clinical trial to determine whether low-dose inhaled nitric oxide would reduce the use of extracorporeal membrane oxygenation in neonates with pulmonary hypertension who were born after 34 weeks' gestation, were 4 days old or younger, required assisted ventilation, and had hypoxemic respiratory failure as defined by an oxygenation index of 25 or higher. The neonates who received nitric oxide were treated with 20 ppm for a maximum of 24 hours, followed by 5 ppm for no more than 96 hours. The primary end point of the study was the use of extracorporeal membrane oxygenation.
Results
Of 248 neonates enrolled, 126 were randomly assigned to the nitric oxide group and 122 to the control group. Extracorporeal membrane oxygenation was used in 78 neonates in the control group (64 percent) and in 48 neonates in the nitric oxide group (38 percent) (P=0.001). The 30-day mortality rate in the two groups was similar (8 percent in the control group and 7 percent in the nitric oxide group). Chronic lung disease developed less often in neonates treated with nitric oxide than in those in the control group (7 percent vs. 20 percent, P=0.02). The efficacy of nitric oxide was independent of the base-line oxygenation index and the primary pulmonary diagnosis.
Conclusions
Inhaled nitric oxide reduces the extent to which extracorporeal membrane oxygenation is needed in neonates with hypoxemic respiratory failure and pulmonary hypertension.
Media in This Article
Table 1
Base-Line Characteristics of the Study Subjects.Table 2
Base-Line Ventilatory Status of the Study Subjects.Article Activity
- Article
Persistent pulmonary hypertension is common in neonates with respiratory failure.1,2 It is characterized by pulmonary hypertension and extrapulmonary right-to-left shunting across the foramen ovale and ductus arteriosus. In many cases, the disease progressively worsens, becoming refractory to treatment.3-5
When other therapies fail, neonates are treated with extracorporeal membrane oxygenation.3-5 This therapy improves survival in neonates with respiratory failure,6-8 but its administration is labor-intensive and costly and necessitates large amounts of blood products. The mortality rate in neonates treated with extracorporeal membrane oxygenation is 15 to 20 percent, and 10 to 20 percent of the neonates who survive have substantial developmental delay.7-12
Nitric oxide is produced in vascular endothelial cells and plays an important part in increasing blood flow to the lungs after birth.13-17 Exogenously administered nitric oxide causes selective pulmonary vasodilatation in newborn lambs,13 and the administration of low doses of nitric oxide causes sustained improvement in gas exchange in neonates.18 However, the efficacy of low-dose inhaled nitric oxide in reducing the use of extracorporeal membrane oxygenation has not been established. This study was undertaken to determine whether low-dose inhaled nitric oxide reduces the use of extracorporeal membrane oxygenation in neonates with pulmonary hypertension.
Methods
Study Subjects
We studied 248 neonates who were born after 34 weeks' gestation, were 4 days old or younger, required assisted ventilation, and had an oxygenation index of 25 or higher. The oxygenation index was calculated as the mean airway pressure times the fraction of inspired oxygen times 100, divided by the partial pressure of arterial oxygen. The neonates had clinical or echocardiographic evidence of pulmonary hypertension without structural heart disease. Clinical evidence of pulmonary hypertension was defined as a difference of 5 percent between preductal and postductal oxygen saturation or recurrent (more than two) decreases in arterial oxygen saturation (to less than 85 percent) in a period of 12 hours despite optimal treatment of lung disease. Echocardiographic evidence of pulmonary hypertension was defined as an estimated peak systolic pulmonary-artery pressure that was higher than 35 mm Hg or more than two thirds of the systemic systolic pressure as indicated by a tricuspid regurgitant jet, a right-to-left ductus arteriosus shunt, or a right-to-left atrial-level shunt. In addition, we considered as study candidates neonates in whom extreme alkalosis (a pH higher than 7.55) was required to maintain a partial pressure of arterial oxygen of more than 60 mm Hg.
Pre-enrollment treatment with high-frequency ventilation (model 3100A, SensorMedics, Yorba Linda, Calif.) or surfactant was encouraged. Neonates were not eligible for the study if extracorporeal membrane oxygenation was urgently needed for refractory hypotension (a mean blood pressure lower than 35 mm Hg) or profound hypoxemia (a partial pressure of arterial oxygen lower than 30 mm Hg) or if they had a lethal congenital anomaly, a substantial bleeding diathesis, active seizures, or a history of severe asphyxia. The study was approved by the institutional review board at each study site, and written informed consent was obtained from a parent or guardian.
Randomization
To balance the distribution of pulmonary-disease diagnoses in the two treatment groups, each neonate was assigned to one of five diagnostic categories and then randomly assigned to treatment. The diagnostic categories were the meconium aspiration syndrome, which was diagnosed on the basis of a history of meconium-stained amniotic fluid and abnormal results on chest radiography; pneumonia, with two or more risk factors for sepsis and no history that suggested lung immaturity (the risk factors for sepsis were maternal chorioamnionitis, maternal fever, positive vaginal culture for group B streptococcus, a white-cell count of more than 30,000 cells per cubic millimeter or less than 5000 cells per cubic millimeter, a ratio of immature to total neutrophils of more than 0.2, a serum C-reactive protein concentration of more than 2 μg per milliliter, hypotension that required vasopressor support, and coagulopathy); the respiratory distress syndrome, with fewer than two risk factors for sepsis, a history that suggested lung immaturity, and a chest radiograph that had a reticulogranular appearance; lung hypoplasia syndromes, which were diagnosed on the basis of the presence of a congenital diaphragmatic hernia, a history of prolonged oligohydramnios, or hydrops fetalis; and idiopathic persistent pulmonary hypertension, which required a clinical diagnosis of pulmonary hypertension and a chest radiograph showing little or no lung disease.
Cards on which treatment assignments were written were randomly ordered (shuffled by hand three times) at Emory University in Atlanta and placed in sequentially numbered opaque envelopes in blocks of eight for diagnostic-category strata 1, 2, and 3 and in blocks of four for strata 4 and 5; the number in each block reflected the anticipated frequencies of diagnoses. Notebooks in which the numbered envelopes were stored were sent to each study site.
After the attending physician obtained consent, a respiratory therapist was told the neonate's diagnostic stratum and identified the appropriate sequentially ordered envelope. The therapist then set up the system of treatment delivery, completed the basic information on the randomization card, and mailed the card to the center that coordinated the study. The study coordinator at the coordinating center monitored the order in which the treatment cards were used.
Neither the physicians nor the nurses were told the treatment assignments. Respiratory therapists directed treatment and made adjustments to keep the concentration of nitric oxide within the prescribed range (±10 percent of the target dose). In the first 36 neonates enrolled, the delivery systems for the two treatment groups were identical. The neonates assigned to the control group were treated by continuing the flow of oxygen without initiating the administration of nitric oxide. In the remaining 212 neonates, nitrogen (delivered through the INO Delivery System, Ohmeda, Madison, Wis.) was used as the control to improve the masking of the treatment assignment. The gas tank and monitor readouts were covered so that the tank and the monitored values for nitric oxide and nitrogen dioxide could not be seen.
Treatment Guidelines and Delivery of Gas
In the first 18 neonates in the treatment group, nitric oxide gas (Scott Medical Products, Plumstead, Pa.) was delivered from a 450-ppm cylinder. Nitric oxide was introduced into the afferent limb of the ventilator circuit near the endotracheal tube, thus mixing with the fixed flow of gas in the ventilator circuit. The flow was adjusted to yield the assigned concentrations of nitric oxide. Nitric oxide and nitrogen dioxide were measured with electrochemical monitors (Pac II nitric oxide monitor and model 190 nitrogen dioxide monitor, Drager, Chantilly, Va.). For the 108 remaining neonates in the nitric oxide group, nitric oxide gas (INO Therapeutics, Port Allen, La.) was delivered from an 800-ppm cylinder. The control subjects received 100 percent nitrogen (Ohmeda, BOC Gases, Murray Hill, N.J.). The study gas (nitrogen or nitric oxide) was delivered (with the INO Delivery System) into the inspiratory flow of the ventilator circuit. The device measured the flow of gas in the ventilator circuit, and a mass-flow controller added study gas to the ventilator circuit to create the desired concentration. The device continuously sampled gas from the endotracheal side-port adapter and measured oxygen, nitric oxide, and nitrogen dioxide with electrochemical monitors. Inhaled nitric oxide and nitrogen had a similar effect on the fraction of inspired oxygen (reducing the value to 0.98).19
The administration of the study gas (nitrogen or nitric oxide) was started at 20 ppm, and this amount was continued for four hours. At four hours, arterial-blood gases and methemoglobin were measured. The dose was decreased to 5 ppm if the neonate's condition was stable, the partial pressure of arterial oxygen was at least 60 mm Hg, and the pH was 7.55 or lower. If these criteria were not met, the administration of study gas was maintained at 20 ppm, and the neonate was evaluated every 4 hours until the criteria were met or the neonate had been treated for 24 hours. During the first 24 hours, the dose of study gas could be returned to 20 ppm if the neonate's partial pressure of arterial oxygen fell below 60 mm Hg when the fraction of inspired oxygen was 1.0. After 24 hours of treatment, the dose was decreased to 5 ppm. Treatment was continued at 5 ppm until the fraction of inspired oxygen was less than 0.7, the neonate had been treated for 96 hours, or the neonate was seven days old, whichever came first.
If the neonate did not tolerate the decreased dose at 24 hours or if at 96 hours the study gas could not be discontinued, the treatment was considered a failure. If a clinical decision was made to proceed with extracorporeal membrane oxygenation, the study gas was continued until it was started.
Methemoglobin was measured at base line and at 4, 24, and 96 hours while the neonate was receiving the study gas. The concentration of study gas was reduced by half if the neonate had a methemoglobin value of more than 4 percent or a nitrogen dioxide concentration of more than 5 ppm, and the administration of the study gas was discontinued if these values did not become normal.
We aimed to achieve the following blood gas values in the neonates: a partial pressure of arterial oxygen of 60 to 100 mm Hg; a partial pressure of arterial carbon dioxide of 25 to 30 mm Hg and a pH of 7.40 to 7.55 in neonates with a response to alkalosis; and a partial pressure of arterial carbon dioxide of 35 to 45 mm Hg and a pH of 7.35 to 7.45 in neonates with no response to alkalosis. The target mean blood pressure was 45 to 60 mm Hg.
Criteria for Discontinuing Treatment in the Study
Treatment was discontinued if the neonate was successfully weaned from the study gas, met the criteria for treatment failure, or met the criteria for extracorporeal membrane oxygenation. Neonates who met the criteria for treatment failure were not automatically treated with extracorporeal membrane oxygenation. The criteria for the use of extracorporeal membrane oxygenation were an oxygenation index of more than 40 on three of five measurements performed at least 30 minutes apart; a partial pressure of arterial oxygen lower than 40 mm Hg for 2 hours; or progressive hemodynamic deterioration (a mean blood pressure below 35 mm Hg). The decision to use extracorporeal membrane oxygenation was made by the attending physician and by the consulting team for extracorporeal membrane oxygenation.
Study End Points
Our primary hypothesis was that the use of extracorporeal membrane oxygenation would be the same in neonates treated with nitric oxide and those not treated with nitric oxide. Our secondary hypotheses were that the two groups would have the same improvement in the ratio of arterial oxygen to alveolar oxygen, the same incidence of short-term complications (hypotension, methemoglobinemia, and deterioration in gas exchange), the same incidence of long-term complications (chronic lung disease and neurologic handicaps), and the same incidence of death. The results presented here are for follow-up at 30 days; the results of follow-up at 1 year are being collected now.
Statistical Analysis
We evaluated categorical variables using two-tailed chi-square and Fisher's exact tests. Continuous variables were compared with use of a two-tailed t-test or the Kruskal–Wallis test. Ranked data were assessed with the two-tailed Kruskal–Wallis test. We compared changes over time in the two groups of neonates with regard to gas exchange, methemoglobin values, and nitrogen dioxide concentrations, using analysis of variance for repeated measures. We used a multivariate logistic-regression analysis to evaluate the independent effects of the following covariates on the use of extracorporeal membrane oxygenation and the occurrence of chronic lung disease: treatment group, sex, surfactant treatment, support with high-frequency ventilation, air leak (pneumothorax, pulmonary interstitial emphysema, or pneumomediastinum) at study entry, age at study entry, primary pulmonary diagnosis, and oxygenation index.
Results
Base-Line Characteristics
Two hundred forty-eight neonates were enrolled in the study; 126 were assigned to the nitric oxide group, and 122 to the control group. The base-line characteristics of the two treatment groups were similar, with the exception of prenatal care before the third trimester and the presence of an air leak before enrollment (Table 1Table 1
Base-Line Characteristics of the Study Subjects.). However, there were no differences in obstetrical complications, and all air leaks were stabilized before enrollment.As compared with the nitric oxide group, the control group had a higher mean (±SD) blood pressure (55±12 mm Hg vs. 51±11 mm Hg, P=0.02) and a lower partial pressure of arterial oxygen (58±42 mm Hg vs. 72±64 mm Hg, P=0.05) (Table 2Table 2
Base-Line Ventilatory Status of the Study Subjects.). However, the mean level of pressor support and the severity of hypoxemia, assessed by the oxygenation index, were similar in the two groups (Table 1 and Table 2). There were no differences between the two groups in the incidence of echocardiographic evidence of pulmonary hypertension.Deviations from the Protocol
Two neonates assigned to the control group were treated with nitric oxide; both were included in the control group in an intention-to-treat analysis. There were 21 deviations from the protocol. In 12 neonates, an oxygenation index higher than 25 at base line was not documented adequately. Three neonates had partial pressures of arterial oxygen that were lower than 30 mm Hg at base line and thus fulfilled the criteria for exclusion because of their urgent need for extracorporeal membrane oxygenation. Two neonates did not have pulmonary hypertension. Four other neonates should not have been enrolled in the study, because they had congenital heart disease, seizures, an estimated gestational age of less than 34 weeks, or a lethal anomaly (an inoperable cystic hygroma).
Primary Outcome
The use of extracorporeal membrane oxygenation was less common in the nitric oxide group than in the control group (38 percent vs. 64 percent, P=0.001) (Table 3Table 3
Outcome Analysis.). This was true in all pulmonary diagnostic groups except neonates with congenital diaphragmatic hernia (Table 4Table 4
Relative Risk of Extracorporeal Membrane Oxygenation According to Diagnosis.). In the neonates treated with extracorporeal membrane oxygenation, the median time from the start of treatment to the start of extracorporeal membrane oxygenation was similar in the two groups (5 hours in the control group [range, 1 to 86] and 9 hours in the nitric oxide group [range, 2 to 150]). Eight neonates (three in the control group and five in the nitric oxide group) met the criteria for extracorporeal membrane oxygenation but did not receive it. All survived to discharge, and chronic lung disease did not develop in any of them. Four neonates who were not treated with extracorporeal membrane oxygenation died. Two died after prolonged assisted ventilation; one of these neonates had adenoviral bronchiolitis obliterans, and the other had severe chronic lung disease. The other two neonates who died had contraindications to treatment with extracorporeal membrane oxygenation: one had uncontrolled bleeding, and the other had an inoperable cystic hygroma.Secondary Outcomes
Twenty-three neonates died before discharge: 13 in the control group and 10 in the nitric oxide group (P=0.82). There were no differences between the two groups in terms of the cause of death.
After one hour of treatment, the ratio of arterial to alveolar oxygen increased more in the nitric oxide group than in the control group (by 0.10±0.14 vs. 0.05±0.13, P=0.02). There was no difference between the two groups with regard to ventilator settings, heart rate, mean blood pressure, or level of dopamine support during the first four hours of treatment.
Thirty neonates had chronic lung disease (as determined by the need for supplemental oxygen at 30 days). Nineteen neonates died before 30 days of age. In the group of 224 survivors for whom data were available, the incidence of chronic lung disease was lower in the neonates treated with nitric oxide than in the neonates in the control group (7 percent vs. 20 percent, P=0.02).
Among the survivors, there was no difference between the two treatment groups with regard to age at discharge, age at extubation, or duration of extracorporeal membrane oxygenation. Neurologic abnormalities occurred at the same rate in the two groups (Table 3).
The use of nitric oxide independently affected both the use of extracorporeal membrane oxygenation and the occurrence of chronic lung disease. A high oxygenation index, assignment to the control group, and a diagnosis of congenital diaphragmatic hernia were all associated with the use of extracorporeal membrane oxygenation. The most important factor that affected the development of chronic lung disease was the diagnosis of congenital diaphragmatic hernia. The oxygenation index and the presence of an air leak before enrollment in the study were not independent predictors of chronic lung disease.
Discussion
We found that the administration of low doses of nitric oxide reduced the use of extracorporeal membrane oxygenation and decreased the need for supplemental oxygen at 30 days in neonates with hypoxemic respiratory failure and persistent pulmonary hypertension. We stratified the neonates in both groups according to the diagnosis in order to assess the relative efficacy of treatment across diagnostic groups and to minimize the effect of underlying disease as a confounding variable. Our results confirm the findings of the Neonatal Inhaled Nitric Oxide Study that nitric oxide is effective across a broad range of diagnoses.20 The only exception was neonates with congenital diaphragmatic hernia, in whom nitric oxide did not reduce the use of extracorporeal membrane oxygenation or improve the outcome.21
The most important difference between our trial and previous studies is that we used a low dose of inhaled nitric oxide for a limited amount of time (a maximum of 96 hours). Other trials have used higher doses (80 ppm) for longer periods (as long as two weeks).19,20,22 By limiting the duration of treatment, we hoped to avoid delaying extracorporeal membrane oxygenation beyond the point at which its efficacy might be reduced. Our data, combined with the results of previous studies, suggest that this approach is effective. In the Neonatal Inhaled Nitric Oxide Study, neonates who did not have a response to 20 ppm of nitric oxide rarely had a response to 80 ppm.20 The median duration of successful treatment in our study was 44 hours, and all but two neonates were weaned from nitric oxide by 96 hours.
The potentially toxic effects of inhaled nitric oxide at high doses include decreased platelet aggregation,15 an increased risk of bleeding,23-25 acute lung injury as a result of oxidant injury,26-29 and surfactant dysfunction.30 In our study, none of the neonates had high concentrations of nitrogen dioxide, only two had high methemoglobin values, and nitric oxide was not associated with an increase in the occurrence of intracranial hemorrhages or chronic lung disease. In fact, nitric oxide was associated with a decrease in the occurrence of chronic lung disease.
The strength of the association between treatment with nitric oxide and an improved pulmonary outcome is demonstrated by the fact that the association remained significant in multivariate and subgroup analyses. The reason for this improvement is unclear. One possibility is that inhaled nitric oxide reduces lung inflammation. Studies in animals suggest that inhaled nitric oxide may reduce the accumulation of neutrophils in the lung and the attendant inflammatory cascade that contributes to acute lung injury.31-33 Another possibility is that nitric oxide reduces ventilator-induced lung injury by improving gas exchange and reducing the intensity of required ventilatory support.
In conclusion, low-dose inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation and reduces the occurrence of chronic lung disease in neonates with hypoxemic respiratory failure that does not result from congenital diaphragmatic hernia.
Supported in part by a grant from INO Therapeutics.
Dr. Clark has acted as a consultant to INO Therapeutics regarding the submission of data to the Food and Drug Administration. He is also the principal investigator for the grant that supported this study. Dr. Kinsella has acted as a consultant to INO Therapeutics regarding the submission of data to the Food and Drug Administration. Mrs. Huckaby has acted as a clinical research associate for INO Therapeutics in monitoring this study.
We are indebted to all the parents who agreed to allow their children to participate in this study; to Ms. Barbara Reynolds for her tireless administrative assistance; to Mr. Alex Stenzler for his help with the development of the protocol; to Dr. Richard Straube for his careful review of the manuscript and for statistical evaluation of our data; to Mr. Jared Rhines for coordinating data monitoring, meetings of investigators, and the delivery of drugs to the study sites; and to Dr. George Brumley, Dr. Devn Cornish, and Dr. Steve Abman for their support during the course of the study.
Source Information
From the Department of Pediatrics, Duke University, Durham, N.C. (R.H.C.); the Division of Neonatology, Carolinas Medical Center, Charlotte, N.C. (T.J.K.); the Department of Neonatology, Greenville Hospital System, Greenville, S.C. (M.W.W.); Medical University of South Carolina, Charleston (W.M.S.); Egleston Children's Hospital, Atlanta (J.L.H.); Arnold Palmer Hospital, Orlando, Fla. (J.A.P.); the Department of Pediatrics, Emory University, Atlanta (B.J.R.); the Division of Neonatology, Georgetown University Hospital, Washington, D.C. (M.K.); and the University of Colorado School of Medicine, Denver (J.P.K.).
Address reprint requests to Dr. Clark at Pediatrix Medical Group, 1301 Concord Terr., Sunrise, FL 33323, or at reese_clark@mail.pediatrix.com.
The members of the Clinical Inhaled Nitric Oxide Research Group are listed in the Appendix.
Appendix
In addition to the authors, the following institutions and investigators participated in the Clinical Inhaled Nitric Oxide Research Group: Akron, Ohio — J. Butler, K. Wellendorf; Durham, N.C. — K. Auten; Phoenix, Ariz. — D. Hall, E. Ramthun; Atlanta — L. Jain, I. Seabrook; Washington, D.C. — P. Angelus; Charlotte, N.C. — L. Brucoli; Columbia, S.C. — D. Marsh, A. O'Dell; New Orleans — M. McGettigan, B. Quinn, G. Matranga; St. Petersburg, Fla. — A. Napolitano, R. Williams; San Antonio, Tex. — M. Odom; Orlando, Fla. — J. Ramos; Chicago — M. Rathi, A. Shukla, T. Gardner; Charleston, S.C. — D. Purohit, S. Ballard, M. Nussbaum; Sioux Falls, S.D. — D. Stevens, R. Klinghagen; Greenville, S.C. — V. Jenkinson; Nashville — W. Walsh, S. Steele, B. Canter; Lackland AFB, Tex. — B. Yoder, S. Woodcox.
- References
References
1
Kinsella JP ,Abman SH . Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 1995;126:853-864
CrossRef | Web of Science | Medline2
Morin FC III ,Stenmark KR . Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 1995;151:2010-2032
Web of Science | Medline3
Cornish JD ,Heiss KF ,Clark RH ,Strieper MJ ,Boecler B ,Kesser K . Efficacy of venovenous extracorporeal membrane oxygenation for neonates with respiratory and circulatory compromise. J Pediatr 1993;122:105-109
CrossRef | Web of Science | Medline4
Kanto WP ,Bunyapen C . Extracorporeal membrane oxygenation: controversies in selection of patients and management. Clin Perinatol 1998;25:123-135
Web of Science | Medline5
Kanto WP Jr . A decade of experience with neonatal extracorporeal membrane oxygenation. J Pediatr 1994;124:335-347
CrossRef | Web of Science | Medline6
UK Collaborative ECMO Trial Group
CrossRef | Web of Science | Medline7
UK Collaborative ECMO Trial Group
Web of Science8
O'Rourke PP ,Crone RK ,Vacanti JP , et al. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study. Pediatrics 1989;84:957-963
Web of Science | Medline9
Glass P ,Wagner AE ,Papero PH , et al. Neurodevelopmental status at age five years of neonates treated with extracorporeal membrane oxygenation. J Pediatr 1995;127:447-457
CrossRef | Web of Science | Medline10
Glass P ,Bulas DI ,Wagner AE , et al. Severity of brain injury following neonatal extracorporeal membrane oxygenation and outcome at age 5 years. Dev Med Child Neurol 1997;39:441-448
CrossRef | Web of Science | Medline11
Vaucher YE ,Dudell GG ,Bejar R ,Gist K . Predictors of early childhood outcome in candidates for extracorporeal membrane oxygenation. J Pediatr 1996;128:109-117
CrossRef | Web of Science | Medline12
Walsh-Sukys MC ,Bauer RE ,Cornell DJ ,Friedman HG ,Stork EK ,Hack M . Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes. J Pediatr 1994;125:104-110
CrossRef | Web of Science | Medline13
Abman SH ,Chatfield BA ,Hall SL ,McMurtry IF . Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol 1990;259:H1921-H1927
Web of Science | Medline14
Kinsella JP ,McQueston JA ,Rosenberg AA ,Abman SH . Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. Am J Physiol 1992;263:H875-H880
Web of Science | Medline15
Moncada S ,Palmer RM ,Higgs EA . Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-142
Web of Science | Medline16
Moncada S ,Higgs A . The l-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-2012
Full Text | Web of Science | Medline17
Steinhorn RH ,Morin FC III ,Fineman JR . Models of persistent pulmonary hypertension of the newborn (PPHN) and the role of cyclic guanosine monophosphate (GMP) in pulmonary vasorelaxation. Semin Perinatol 1997;21:393-408
CrossRef | Web of Science | Medline18
Kinsella JP ,Neish SR ,Shaffer E ,Abman SH . Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-820
CrossRef | Web of Science | Medline19
Davidson D ,Barefield ES ,Kattwinkel J , et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics 1998;101:325-334
CrossRef | Web of Science | Medline20
The Neonatal Inhaled Nitric Oxide Study Group
Full Text | Web of Science | Medline21
The Neonatal Inhaled Nitric Oxide Study Group
CrossRef | Web of Science | Medline22
Wessel DL ,Adatia I ,Van Marter LJ , et al. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1997;100:888-888 abstract.
CrossRef | Web of Science23
Gaston B, Keith JF III. Nitric oxide and bleeding time. Pediatrics 1994;94:134-5.
24
George TN ,Johnson KJ ,Bates JN ,Segar JL . The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates. J Pediatr 1998;132:721-724
CrossRef | Web of Science | Medline25
Hogman M ,Frostell C ,Arnberg H ,Sandhagen B ,Hedenstierna G . Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 1994;151:125-129
CrossRef | Medline26
Freeman BA ,Panus PC ,Matalon S ,Buckley BJ ,Baker RR . Oxidant injury to the alveolar epithelium: biochemical and pharmacologic studies. Res Rep Health Eff Inst 1993;54:1-3
Medline27
Freeman B . Free radical chemistry of nitric oxide: looking at the dark side. Chest 1994;105:Suppl:79S-84S
Web of Science | Medline28
Gutierrez HH ,Nieves B ,Chumley P ,Rivera A ,Freeman BA . 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
CrossRef | Web of Science | Medline29
Luperchio S ,Tamir S ,Tannenbaum SR . NO-induced oxidative stress and glutathione metabolism in rodent and human cells. Free Radic Biol Med 1996;21:513-519
CrossRef | Web of Science | Medline30
Hallman M ,Bry K . Nitric oxide and lung surfactant. Semin Perinatol 1996;20:173-185
CrossRef | Web of Science | Medline31
Guidot DM ,Repine MJ ,Hybertson BM ,Repine JE . Inhaled nitric oxide prevents neutrophil-mediated, oxygen radical-dependent leak in isolated rat lungs. Am J Physiol 1995;269:L2-L5
Web of Science | Medline32
Guidot DM ,Hybertson BM ,Kitlowski RP ,Repine JE . Inhaled NO prevents IL-1-induced neutrophil accumulation and associated acute edema in isolated rat lungs. Am J Physiol 1996;271:L225-L229
Web of Science | Medline33
Kinsella JP ,Parker TA ,Galan H ,Sheridan BC ,Halbower AC ,Abman SH . Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease. Pediatr Res 1997;41:457-463
CrossRef | Web of Science | Medline
- Citing Articles (173)
Citing Articles
1
Kazuo Momma. 2012. Newborn Diagnosis and Management. , 254-260.
CrossRef2
George A. Woodward, Roxanne Kirsch, Michael Stone Trautman, Monica E. Kleinman, Gil Wernovsky, Bradley S. Marino. 2012. Stabilization and Transport of the High-Risk Infant. , 341-356.
CrossRef3
Robin H. Steinhorn, Steven H. Abman. 2012. Persistent Pulmonary Hypertension. , 732-740.
CrossRef4
Qi Yang, Hui Hu, Weipeng Chen, Jie Xu, Jinli Zhang, Shuang Wu. (2011) The Main Plasma Chemical Process of Nitric Oxide Production by Arc Discharge. Plasma Science and Technology 13:6, 702-707
CrossRef5
Anke P. C. Top, Can Ince, Patrick H. M. Schouwenberg, Dick Tibboel. (2011) Inhaled nitric oxide improves systemic microcirculation in infants with hypoxemic respiratory failure. Pediatric Critical Care Medicine 12:6, e271-e274
CrossRef6
Stephen Wedgwood, Satyan Lakshminrusimha, Tohru Fukai, James A. Russell, Paul T. Schumacker, Robin H. Steinhorn. (2011) Hydrogen Peroxide Regulates Extracellular Superoxide Dismutase Activity and Expression in Neonatal Pulmonary Hypertension. Antioxidants & Redox Signaling 15:6, 1497-1506
CrossRef7
Xue-Feng Xu, Fen Cheng, Li-Zhong Du. (2011) Epigenetic regulation of pulmonary arterial hypertension. Hypertension Research 34:9, 981-986
CrossRef8
Robin H. Steinhorn. (2011) Therapeutic approaches using nitric oxide in infants and children. Free Radical Biology and Medicine 51:5, 1027-1034
CrossRef9
Kristofer F. Nilsson, Michael Lundgren, Per Agvald, L. Christofer Adding, Dag Linnarsson, Lars E. Gustafsson. (2011) Formation of new bioactive organic nitrites and their identification with gas chromatography–mass spectrometry and liquid chromatography coupled to nitrite reduction. Biochemical Pharmacology 82:3, 248-259
CrossRef10
Peter Oishi, Sanjeev A Datar, Jeffrey R Fineman. (2011) Pediatric pulmonary arterial hypertension: current and emerging therapeutic options. Expert Opinion on Pharmacotherapy 12:12, 1845-1864
CrossRef11
Y.-p. Xu, J.-j. Zhu, F. Cheng, K.-w. Jiang, W.-z. Gu, Z. Shen, Y.-d. Wu, L. Liang, L.-z. Du. (2011) Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3 / -catenin signaling in neonatal rats. Journal of Molecular Endocrinology 47:1, 33-43
CrossRef12
KT Santhosh, O Elkhateeb, N Nolette, O Outbih, AJ Halayko, S Dakshinamurti. (2011) Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes. British Journal of Pharmacology 163:6, 1223-1236
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
I. Sluiter, C.P. van de Ven, R.M.H. Wijnen, D. Tibboel. (2011) Congenital diaphragmatic hernia: Still a moving target. Seminars in Fetal and Neonatal Medicine 16:3, 139-144
CrossRef15
Susan W. Aucott. (2011) Bronchopulmonary Dysplasia: Development and Progression in the Neonatal Intensive Care Unit. Pediatric Allergy, Immunology, and Pulmonology 24:2, 113-118
CrossRef16
Mark A. Lovich, Natalie K. Bruno, Charles P. Plant, Abraham E. Wei, Gregory B. Vasquez, Bryan J. Johnson, David H. Fine, Richard J. Gilbert. (2011) Use of ultra pure nitric oxide generated by the reduction of nitrogen dioxide to reverse pulmonary hypertension in hypoxemic swine. Nitric Oxide 24:4, 204-212
CrossRef17
Warren M. Zapol. (2011) Life at the Frontier. Anesthesiology 114:4, 771-781
CrossRef18
B. S. Zuckerbraun, P. George, M. T. Gladwin. (2011) Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovascular Research 89:3, 542-552
CrossRef19
Jason Gien. 2011. Respiratory distress syndrome. , 296-299.
CrossRef20
Aimee M. Barton, M. Kabir Abubakar, Jennifer Berg, Martin Keszler. (2011) The Effect of Arterial pH on Oxygenation Persists Even in Infants Treated with Inhaled Nitric Oxide. Pulmonary Medicine 2011, 1-6
CrossRef21
Shekhar T. Venkataraman. 2011. Mechanical Ventilation and Respiratory Care. , 657-688.
CrossRef22
Satyan Lakshminrusimha, Vasanth H. Kumar. 2011. Diseases of Pulmonary Circulation. , 632-656.
CrossRef23
Kathryn N. Farrow, Stephen Wedgwood, Keng Jin Lee, Lyubov Czech, Sylvia F. Gugino, Satyan Lakshminrusimha, Paul T. Schumacker, Robin H. Steinhorn. (2010) Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn. Respiratory Physiology & Neurobiology 174:3, 272-281
CrossRef24
Edward P. Armstrong, Rahul Dhanda. (2010) Cost-effectiveness of early compared to late inhaled nitric oxide therapy in near-term infants. Current Medical Research and Opinion 26:12, 2795-2800
CrossRef25
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
CrossRef26
T. F. Yeh. (2010) Core Concepts: Meconium Aspiration Syndrome: Pathogenesis and Current Management. NeoReviews 11:9, e503-e512
CrossRef27
T. Schaible, D. Hermle, F. Loersch, S. Demirakca, K. Reinshagen, V. Varnholt. (2010) A 20-year experience on neonatal extracorporeal membrane oxygenation in a referral center. Intensive Care Medicine 36:7, 1229-1234
CrossRef28
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
CrossRef29
Chris Dewhurst, Hafis Ibrahim, Sylvia Göthberg, Baldvin Jónsson, Nimish Subhedar, . (2010) Use of inhaled nitric oxide in the new born period: results from the European inhaled nitric oxide registry. Acta Paediatrica 99:6, 854-860
CrossRef30
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
CrossRef31
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
CrossRef32
MATTHEW A. BOEGEHOLD. (2010) Endothelium-Dependent Control of Vascular Tone during Early Postnatal and Juvenile Growth. Microcirculation
CrossRef33
Irene W.J.M. van der Horst, Beverly Morgan, Farah Eaton, Irwin Reiss, Dick Tibboel, Bernard Thébaud. (2010) Expression and function of phosphodiesterases in nitrofen-induced congenital diaphragmatic hernia in rats. Pediatric Pulmonology 45:4, 320-325
CrossRef34
Robin H. Steinhorn. (2010) Neonatal pulmonary hypertension. Pediatric Critical Care Medicine 11, S79-S84
CrossRef35
Steven H. Abman. (2010) Pulmonary hypertension in children: A historical overview. Pediatric Critical Care Medicine 11, S4-S9
CrossRef36
Gerald S. Zavorsky, Arlin B. Blood, Gordon G. Power, Lawrence D. Longo, Raul Artal, Emanuel J. Vlastos. (2010) CO and NO pulmonary diffusing capacity during pregnancy: Safety and diagnostic potential. Respiratory Physiology & Neurobiology 170:3, 215-225
CrossRef37
MELISSA J. ROSE, MICHAEL R. STENGER, MANDAR S. JOSHI, STEPHEN E. WELTY, JOHN ANTHONY BAUER, LEIF D. NELIN. (2010) Inhaled Nitric Oxide Decreases Leukocyte Trafficking in the Neonatal Mouse Lung During Exposure to >95% Oxygen. Pediatric Research 67:3, 244-249
CrossRef38
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
CrossRef39
John W. Calvert, David J. Lefer. (2010) Clinical translation of nitrite therapy for cardiovascular diseases. Nitric Oxide 22:2, 91-97
CrossRef40
David A. Paul, Amy Mackley, Erika M. Yencha. (2010) Thyroid Function in Term and Late Preterm Infants with Respiratory Distress in Relation to Severity of Illness. Thyroid 20:2, 189-194
CrossRef41
Csaba Szabo. 2010. Medicinal Chemistry and Therapeutic Applications of the Gasotransmitters NO, CO, and H 2 S and their Prodrugs. .
CrossRef42
Kate L. Brown, Sudhir Sriram, Deborah Ridout, Jane Cassidy, Hitesh Pandya, Morag Liddell, Carl Davis, Allan Goldman, David Field, Ann Karimova. (2010) Extracorporeal membrane oxygenation and term neonatal respiratory failure deaths in the United Kingdom compared with the United States: 1999 to 2005. Pediatric Critical Care Medicine 11:1, 60-65
CrossRef43
Ji-Yeon Sim. (2010) Nitric oxide and pulmonary hypertension. Korean Journal of Anesthesiology 58:1, 4
CrossRef44
So Young Kim. (2010) Neonatal respiratory distress: recent progress in understanding pathogenesis and treatment outcomes. Korean Journal of Pediatrics 53:1, 1
CrossRef45
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
CrossRef46
Robin H. Steinhorn, John P. Kinsella, Christine Pierce, Ghazwan Butrous, Maria Dilleen, Michael Oakes, David L. Wessel. (2009) Intravenous Sildenafil in the Treatment of Neonates with Persistent Pulmonary Hypertension. The Journal of Pediatrics 155:6, 841-847.e1
CrossRef47
M J Pabalan, S P Nayak, R M Ryan, V H Kumar, S Lakshminrusimha. (2009) Methemoglobin to cumulative nitric oxide ratio and response to inhaled nitric oxide in PPHN. Journal of Perinatology 29:10, 698-701
CrossRef48
L. Hout, I. Sluiter, S. Gischler, A. Klein, R. Rottier, H. Ijsselstijn, I. Reiss, D. Tibboel. (2009) Can we improve outcome of congenital diaphragmatic hernia?. Pediatric Surgery International 25:9, 733-743
CrossRef49
David J Henderson-Smart, Antonio G De Paoli, Reese H Clark, Tushar Bhuta, Diane Haughton. 2009. High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term. .
CrossRef50
Jan A. Deprest, Eduardo Gratacos, Kypros Nicolaides, Elise Done, Tim Van Mieghem, Leonardo Gucciardo, Filip Claus, Anne Debeer, Karel Allegaert, Irwin Reiss, Dick Tibboel. (2009) Changing Perspectives on the Perinatal Management of Isolated Congenital Diaphragmatic Hernia in Europe. Clinics in Perinatology 36:2, 329-347
CrossRef51
Deepak K. Tempe, Suruchi Hasija, Vishnu Datt, A.S. Tomar, Sanjula Virmani, Amit Banerjee, Bhuvan Pande. (2009) Evaluation and Comparison of Early Hemodynamic Changes After Elective Mitral Valve Replacement in Patients With Severe and Mild Pulmonary Arterial Hypertension. Journal of Cardiothoracic and Vascular Anesthesia 23:3, 298-305
CrossRef52
G. Ganesh Konduri, U. Olivia Kim. (2009) Advances in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn. Pediatric Clinics of North America 56:3, 579-600
CrossRef53
R F Soll. (2009) Inhaled nitric oxide in the neonate. Journal of Perinatology 29, S63-S67
CrossRef54
Anthony S. Buys Roessingh, Anh Tuan Dinh-Xuan. (2009) Congenital diaphragmatic hernia: current status and review of the literature. European Journal of Pediatrics 168:4, 393-406
CrossRef55
Nandini Arul, G. Ganesh Konduri. (2009) Inhaled Nitric Oxide for Preterm Neonates. Clinics in Perinatology 36:1, 43-61
CrossRef56
Peter M. Mourani, Marci K. Sontag, D. Dunbar Ivy, Steven H. Abman. (2009) Effects of Long-Term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease. The Journal of Pediatrics 154:3, 379-384.e2
CrossRef57
Shigeharu Hosono, Tutomu Ohno, Hirofumi Kimoto, Masaki Shimizu, Shigeru Takahashi, Kensuke Harada. (2009) Developmental outcomes in persistent pulmonary hypertension treated with nitric oxide therapy. Pediatrics International 51:1, 79-83
CrossRef58
A Mukherjee, T Dombi, B Wittke, R Lalonde. (2009) Population Pharmacokinetics of Sildenafil in Term Neonates: Evidence of Rapid Maturation of Metabolic Clearance in the Early Postnatal Period. Clinical Pharmacology & Therapeutics 85:1, 56-63
CrossRef59
S Fredly, G Aksnes, KO Viddal, R Lindemann, D Fugelseth. (2009) The outcome in newborns with congenital diaphragmatic hernia in a Norwegian region. Acta Paediatrica 98:1, 107-111
CrossRef60
B L Short. (2008) Extracorporeal membrane oxygenation: use in meconium aspiration syndrome. Journal of Perinatology 28, S79-S83
CrossRef61
R H Steinhorn. (2008) Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. Journal of Perinatology 28, S67-S71
CrossRef62
A Bin-Nun, M D Schreiber. (2008) Role of iNO in the modulation of pulmonary vascular resistance. Journal of Perinatology 28, S84-S92
CrossRef63
Jeremy D. Marks, Michael D. Schreiber. (2008) Inhaled Nitric Oxide and Neuroprotection in Preterm Infants. Clinics in Perinatology 35:4, 793-807
CrossRef64
John P. Kinsella. (2008) Inhaled nitric oxide in the term newborn. Early Human Development 84:11, 709-716
CrossRef65
E W Coates, M E Klinepeter, T M O'Shea. (2008) Neonatal pulmonary hypertension treated with inhaled nitric oxide and high-frequency ventilation. Journal of Perinatology 28:10, 675-679
CrossRef66
GEORGE R. CONAHEY, GORDON G. POWER, ANDREW O. HOPPER, MICHAEL H. TERRY, LAURA S. KIRBY, ARLIN B. BLOOD. (2008) Effect of Inhaled Nitric Oxide on Cerebrospinal Fluid and Blood Nitrite Concentrations in Newborn Lambs. Pediatric Research 64:4, 375-380
CrossRef67
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
CrossRef68
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
CrossRef69
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
CrossRef70
IWJM van der Horst, I Reiss, D Tibboel. (2008) Therapeutic targets in neonatal pulmonary hypertension: linking pathophysiology to clinical medicine. Expert Review of Respiratory Medicine 2:1, 85-96
CrossRef71
A.H.L.C. van Kaam. 2008. Neonatal Mechanical Ventilation. , 529-551.
CrossRef72
Steven H. Abman. 2008. Cor Pulmonale and Pulmonary Complications of Cardiac Disease. , 735-757.
CrossRef73
Paul D. Robinson, Dominic A. Fitzgerald. (2007) Congenital diaphragmatic hernia. Paediatric Respiratory Reviews 8:4, 323-335
CrossRef74
Carlo Dani, Vittorio Pavoni, Iuri Corsini, Mariangela Longini, Gabriele Gori, Lara Giannesello, Avio Perna, Gaetano Gritti, Ferdinando Paternostro, Annalisa Forestieri, Giuseppe Buonocore, Firmino F. Rubaltelli. (2007) Inhaled nitric oxide combined with prostacyclin and adrenomedullin in acute respiratory failure with pulmonary hypertension in piglets. Pediatric Pulmonology 42:11, 1048-1056
CrossRef75
Calvin G. Lowe, Johnn G. Trautwein. (2007) Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure. European Journal of Pediatrics 166:10, 1025-1031
CrossRef76
Amr I El Shahed, Peter A. Dargaville, Arne Ohlsson, Roger Soll, Amr I El Shahed. 2007. Surfactant for meconium aspiration syndrome in full term/near term infants. .
CrossRef77
William E Truog. (2007) Inhaled nitric oxide for the prevention of bronchopulmonary dysplasia. Expert Opinion on Pharmacotherapy 8:10, 1505-1513
CrossRef78
W E Truog, G Kurth, B Haney, H W Kilbride. (2007) Hypoxic respiratory failure: etiology and outcomes at one referral center 2000 through 2005. Journal of Perinatology 27:6, 371-374
CrossRef79
K P Van Meurs, S R Hintz, R A Ehrenkranz, J A Lemons, M B Ball, W K Poole, R Perritt, A Das, R D Higgins, D K Stevenson. (2007) Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure. Journal of Perinatology 27:6, 347-352
CrossRef80
Hui Hu, Haiyan Liang, Jin Li, Quanzhong Zhao, Junjia He. (2007) Study on Production of Inhaled Nitric Oxide for Medical Applications by Pulsed Discharge. IEEE Transactions on Plasma Science 35:3, 619-625
CrossRef81
NN Finer, KJ Barrington. (2007) Cochrane review: Nitric oxide for respiratory failure in infants born at or near term. Evidence-Based Child Health: A Cochrane Review Journal 2:2, 769-807
CrossRef82
J. Wells Logan, C. Michael Cotten, Ronald N. Goldberg, Reese H. Clark. (2007) Mechanical ventilation strategies in the management of congenital diaphragmatic hernia. Seminars in Pediatric Surgery 16:2, 115-125
CrossRef83
G. Ganesh Konduri, Betty Vohr, Charlene Robertson, Gregory M. Sokol, Alfonso Solimano, Joel Singer, Richard A. Ehrenkranz, Nalini Singhal, Linda L. Wright, Krisa Van Meurs, Eileen Stork, Haresh Kirpalani, Abraham Peliowski, Yvette Johnson. (2007) Early Inhaled Nitric Oxide Therapy for Term and Near-Term Newborn Infants with Hypoxic Respiratory Failure: Neurodevelopmental Follow-Up. The Journal of Pediatrics 150:3, 235-240.e1
CrossRef84
Guido Boerrigter, John C. Burnett. (2007) Nitric Oxide-Independent Stimulation of Soluble Guanylate Cyclase with BAY 41-2272 in Cardiovascular Disease. Cardiovascular Drug Reviews 25:1, 30-45
CrossRef85
Xiaowei Hu, Chunbao Guo, Bo Sun. (2007) Inhaled nitric oxide attenuates hyperoxic and inflammatory injury without alteration of phosphatidylcholine synthesis in rat lungs. Pulmonary Pharmacology & Therapeutics 20:1, 75-84
CrossRef86
Leah Leibovitch, Ilan Matok, Gideon Paret. (2007) Therapeutic Applications of Sildenafil Citrate in the Management of Paediatric Pulmonary Hypertension. Drugs 67:1, 57-73
CrossRef87
Andrea Donti, Roberto Formigari, Luca Ragni, Alessandra Manes, Nazzareno Galiè, Fernando M Picchio. (2007) Pulmonary arterial hypertension in the pediatric age. Journal of Cardiovascular Medicine 8:1, 72-77
CrossRef88
Caroline Stephens, Tonks N Fawcett. (2007) Nitric oxide and nursing: a review. Journal of Clinical Nursing 16:1, 67-76
CrossRef89
Golde G. Dudell, Lucky Jain. (2006) Hypoxic Respiratory Failure in the Late Preterm Infant. Clinics in Perinatology 33:4, 803-830
CrossRef90
Ryan W. Kobs, Naomi C. Chesler. (2006) The Mechanobiology of Pulmonary Vascular Remodeling in the Congenital Absence of eNOS. Biomechanics and Modeling in Mechanobiology 5:4, 217-225
CrossRef91
Neil Finer, Keith J Barrington, Neil Finer. 2006. Nitric oxide for respiratory failure in infants born at or near term. .
CrossRef92
Shigeharu Hosono, Tutomu Ohno, Hirofumi Kimoto, Masaki Shimizu, Shigeru Takahashi, Kensuke Harada. (2006) Inhaled nitric oxide therapy might reduce the need for hyperventilation therapy in infants with persistent pulmonary hypertension of the newborn. Journal of Perinatal Medicine 34:4, 333-337
CrossRef93
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 Text94
Ballard, Roberta A., Truog, William E., Cnaan, Avital, Martin, Richard J., Ballard, Philip L., Merrill, Jeffrey D., Walsh, Michele C., Durand, David J., Mayock, Dennis E., Eichenwald, Eric C., Null, Donald R., Hudak, Mark L., Puri, Asha R., Golombek, Sergio G., Courtney, Sherry E., Stewart, Dan L., Welty, Stephen E., Phibbs, Roderic H., Hibbs, Anna Maria, Luan, Xianqun, Wadlinger, Sandra R., Asselin, Jeanette M., Coburn, Christine E., . (2006) Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation. New England Journal of Medicine 355:4, 343-353
Full Text95
ANDY J. PETROS, CHRISTINE M. PIERCE. (2006) The management of pulmonary hypertension. Pediatric Anesthesia 0:0, 060706013023002-???
CrossRef96
Erika Haase, David L. Bigam, Olga Cravetchi, Po-Yin Cheung. (2006) DOSE RESPONSE OF INTRAVENOUS SILDENAFIL ON SYSTEMIC AND REGIONAL HEMODYNAMICS IN HYPOXIC NEONATAL PIGLETS. Shock 26:1, 99-106
CrossRef97
K Sekar. (2006) Inhaled nitric oxide in term and preterm infants. Journal of Perinatology 26, S4-S7
CrossRef98
John P. Kinsella. (2006) Inhaled nitric oxide therapy in premature newborns. Current Opinion in Pediatrics 18:2, 107-111
CrossRef99
Gabriel J. Escobar, Reese H. Clark, John D. Greene. (2006) Short-Term Outcomes of Infants Born at 35 and 36 Weeks Gestation: We Need to Ask More Questions. Seminars in Perinatology 30:1, 28-33
CrossRef100
2006. Nitric oxide. , 2538-2542.
CrossRef101
(2006) Treatment Evolution in High-Risk Congenital Diaphragmatic Hernia. Transactions of the ... Meeting of the American Surgical Association 124, 170-178
CrossRef102
ROBERT B. COTTON, H??KAN W. SUNDELL, DARRYL C. ZELDIN, JASON D. MORROW, L JACKSON ROBERTS, TOM A. HAZINSKI, AMY B. LAW, STEVEN STEELE. (2006) Inhaled Nitric Oxide Attenuates Hyperoxic Lung Injury in Lambs. Pediatric Research 59:1, 142-146
CrossRef103
Matthew Bizzarro, Ian Gross, Matthew Bizzarro. 2005. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. .
CrossRef104
Cage S. Johnson. (2005) The Acute Chest Syndrome. Hematology/Oncology Clinics of North America 19:5, 857-879
CrossRef105
Amadu E. Juliana, Filomena C. B. Abbad. (2005) Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. European Journal of Pediatrics 164:10, 626-629
CrossRef106
Robert P. Jankov, Patrick J. McNamara. (2005) Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn: when is it enough?. Journal of Critical Care 20:3, 294-295
CrossRef107
Harun Fakioglu, Balagangadhar R. Totapally, Dan Torbati, Andre Raszynski, Jeffrey B. Sussmane, Jack Wolfsdorf. (2005) Hypoxic respiratory failure in term newborns: clinical indicators for inhaled nitric oxide and extracorporeal membrane oxygenation therapy. Journal of Critical Care 20:3, 288-293
CrossRef108
John P. Kinsella, Steven H. Abman. (2005) Inhaled nitric oxide therapy in children. Paediatric Respiratory Reviews 6:3, 190-198
CrossRef109
MICHAEL D. BRANDLER, STEVEN C. POWELL, DAMIAN M. CRAIG, GEORGE QUICK, TIMOTHY J. MCMAHON, RONALD N. GOLDBERG, JONATHAN S. STAMLER. (2005) A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension. Pediatric Research 58:3, 531-536
CrossRef110
Ricardo G. Branco, Pedro Celiny R. Garcia, Jefferson P. Piva, Carlos H. Casartelli, Vanessa Seibel, Robert C. Tasker. (2005) Glucose level and risk of mortality in pediatric septic shock*. Pediatric Critical Care Medicine 6:4, 470-472
CrossRef111
Krisa P Van Meurs, Toby L Cohen, Guang Yang, Marco Somaschini, Pavani Kuruma, Phyllis A Dennery. (2005) Inhaled NO and Markers of Oxidant Injury in Infants with Respiratory Failure. Journal of Perinatology 25:7, 463-469
CrossRef112
Robert Lindwall, Mats Blennow, Mats Svensson, Baldvin Jonsson, Eva Berggren-Boström, Martino Flanby, Per-Arne Lönnqvist, Claes Frostell, Mikael Norman. (2005) A pilot study of inhaled nitric oxide in preterm infants treated with nasal continuous positive airway pressure for respiratory distress syndrome. Intensive Care Medicine 31:7, 959-964
CrossRef113
Anne Greenough, Babita Khetriwal. (2005) Pulmonary hypertension in the newborn. Paediatric Respiratory Reviews 6:2, 111-116
CrossRef114
Erika Berman Rosenzweig, Robyn J Barst. (2005) Idiopathic pulmonary arterial hypertension in children. Current Opinion in Pediatrics 17:3, 372-380
CrossRef115
(2005) Guías de Práctica Clínica sobre el diagnóstico y tratamiento de la hipertensión arterial pulmonar. Revista Española de Cardiología 58:5, 523-566
CrossRef116
John P. Kinsella, D. Dunbar Ivy, Steven H. Abman. (2005) Pulmonary Vasodilator Therapy in Congenital Diaphragmatic Hernia: Acute, Late, and Chronic Pulmonary Hypertension. Seminars in Perinatology 29:2, 123-128
CrossRef117
Lars J. Bjertnaes, Roy McGuire, Jeffery Jodoin, Andrew L. Salzman, Lillian D. Traber, Daniel J. Passerini, Daniel J. Smith, Csaba Szabo, Daniel L. Traber. (2005) Nebulized nitric oxide/nucleophile adduct reduces pulmonary vascular resistance in mechanically ventilated septicemic sheep*. Critical Care Medicine 33:3, 616-622
CrossRef118
Karen P. Harrington, Alan P. Goldman. (2005) The role of extracorporeal membrane oxygenation in congenital diaphragmatic hernia. Seminars in Pediatric Surgery 14:1, 72-76
CrossRef119
Dan Waisman, Vera Brod, Ronit Dickstein, Amir Abramovich, Avi Rotschild, Haim Bitterman. (2005) EFFECTS OF INHALED NITRIC OXIDE ON LUNG INJURY AFTER INTESTINAL ISCHEMIA-REPERFUSION IN RATS. Shock 23:2, 150-155
CrossRef120
K. Rais Bahrami, Krisa P. Van Meurs. (2005) ECMO for neonatal respiratory failure. Seminars in Perinatology 29:1, 15-23
CrossRef121
Heidi J. Dalton, Peter T. Rycus, Steven A. Conrad. (2005) Update on extracorporeal life support 2004. Seminars in Perinatology 29:1, 24-33
CrossRef122
Kathryn N. Farrow, Paola Fliman, Robin H. Steinhorn. (2005) The diseases treated with ECMO: Focus on PPHN. Seminars in Perinatology 29:1, 8-14
CrossRef123
Roberta A. Ballard, Thomas N. Hansen, Anthony Corbet. 2005. Respiratory Failure in the Term Infant. , 705-722.
CrossRef124
Xiaowei Hu, Lei Cao, Li Kuei Lam, Liewei Zhu, Chunbao Guo, Bo Sun. (2005) Mitigation of Meconium-Induced Lung Injury by Surfactant and Inhaled Nitric Oxide Is Associated with Suppression of Nuclear Transcription Factor Kappa B. Biology of the Neonate 87:2, 73-81
CrossRef125
Claire Westrope, Neil Roberts, Sanjiv Nichani, Carmel Hunt, Giles J Peek, Richard Firmin. (2004) Experience with mobile inhaled nitric oxide during transport of neonates and children with respiratory insufficiency to an extracorporeal membrane oxygenation center. Pediatric Critical Care Medicine 5:6, 542-546
CrossRef126
Jessica D. de Rooij, M
nnever H
CrossRef127
Christian J Hunter, André Dejam, Arlin B Blood, Howard Shields, Daniel B Kim-Shapiro, Roberto F Machado, Selamawit Tarekegn, Neda Mulla, Andrew O Hopper, Alan N Schechter, Gordon G Power, Mark T Gladwin. (2004) Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nature Medicine 10:10, 1122-1127
CrossRef128
BEENA G. SOOD, VIRGINIA DELANEY-BLACK, JACOB V. ARANDA, SEETHA SHANKARAN. (2004) Aerosolized PGE1: A Selective Pulmonary Vasodilator in Neonatal Hypoxemic Respiratory Failure Results of a Phase I/II Open Label Clinical Trial. Pediatric Research 56:4, 579-585
CrossRef129
LARA S. SHEKERDEMIAN, DANIEL J. PENNY, PIA K. RYHAMMER, JAYNE A. READER, HANNE B. RAVN. (2004) Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome. Pediatric Research 56:3, 353-358
CrossRef130
SCOTT A. LORCH, DAVID MUNSON, RICHARD T. LIGHTFOOT, HARRY ISCHIROPOULOS. (2004) Oxygen Tension and Inhaled Nitric Oxide Modulate Pulmonary Levels of S-Nitrosocysteine and 3-Nitrotyrosine in Rats. Pediatric Research 56:3, 345-352
CrossRef131
Erika Berman Rosenzweig, Allison C. Widlitz, Robyn J. Barst. (2004) Pulmonary arterial hypertension in children. Pediatric Pulmonology 38:1, 2-22
CrossRef132
Felicia A Ivascu, Ronald B Hirschl. (2004) New approaches to managing congenital diaphragmatic hernia. Seminars in Perinatology 28:3, 185-198
CrossRef133
Stephan Thelitz, Janine M Bekker, Boaz Ovadia, Regan B Stuart, Michael J Johengen, Stephen M Black, Jeffrey R Fineman. (2004) Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs. The Journal of Thoracic and Cardiovascular Surgery 127:5, 1285-1292
CrossRef134
Crystal B Evig, Eric E Kelley, Christine J Weydert, Yi Chu, Garry R Buettner, C Patrick Burns. (2004) Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts. Nitric Oxide 10:3, 119-129
CrossRef135
M Bizzarro, I Gross. 2004. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. .
CrossRef136
Marshall L Summar, Lynn Hall, Brian Christman, Frederick Barr, Heidi Smith, Asha Kallianpur, Nancy Brown, Meeta Yadav, Alecia Willis, Angela Eeds, Emma Cermak, Samantha Summar, Ann Wilson, Molly Arvin, Allison Putnam, Melissa Wills, Gary Cunningham. (2004) Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Molecular Genetics and Metabolism 81, 12-19
CrossRef137
INGRAM SCHULZE-NEICK, ANDREW N. REDINGTON. (2004) Sildenafil, Nitric Oxide, and Acute Lung Injury: Pathophysiology Beats Pharmacotherapy?. Pediatric Research 55:3, 370-371
CrossRef138
LARA S. SHEKERDEMIAN, HANNE B. RAVN, DANIEL J. PENNY. (2004) Interaction between Inhaled Nitric Oxide and Intravenous Sildenafil in a Porcine Model of Meconium Aspiration Syndrome. Pediatric Research 55:3, 413-418
CrossRef139
Naoki Uga, Tetsuya Ishii, Yasuhiro Kawase, Hiroko Arai, Hiroshi Tada. (2004) Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios. Pediatrics International 46:1, 10-14
CrossRef140
Yasuo Sekine, Thomas K Waddell, Andrea Matte-Martyn, Andrew F Pierre, Marc de Perrot, Stefan Fischer, John Marshall, John Granton, Michael A Hutcheon, Shaf Keshavjee. (2004) Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters. The Journal of Heart and Lung Transplantation 23:1, 96-104
CrossRef141
Peter Oishi, Jeffrey R. Fineman. (2004) Pharmacologic therapy for persistent pulmonary hypertension of the newborn: As ???poly??? as the disease itself *. Pediatric Critical Care Medicine 5:1, 94-96
CrossRef142
Larry N. Cook. (2004) Update on extracorporeal membrane oxygenation. Paediatric Respiratory Reviews 5, S329-S337
CrossRef143
Leslie J. Williams, Thomas H. Shaffer, Jay S. Greenspan. (2004) Inhaled Nitric Oxide Therapy in the Near-Term or Term Neonate with Hypoxic Respiratory Failure. Neonatal Network: The Journal of Neonatal Nursing 23:1, 5-13
CrossRef144
Gilbert Blaise, David Langleben, Bernard Hubert. (2003) Pulmonary Arterial Hypertension. Anesthesiology 99:6, 1415-1432
CrossRef145
Schreiber, Michael D., Gin-Mestan, Karen, Marks, Jeremy D., Huo, Dezheng, Lee, Grace, Srisuparp, Pimol, . (2003) Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome. New England Journal of Medicine 349:22, 2099-2107
Full Text146
Jennifer Sokol, Susan Elizabeth Jacobs, Desmond Bohn. (2003) Inhaled Nitric Oxide for Acute Hypoxic Respiratory Failure in Children and Adults: A Meta-analysis. Anesthesia & Analgesia989-998
CrossRef147
Gregory M Sokol, Richard A Ehrenkranz. (2003) Inhaled nitric oxide therapy in neonatal hypoxic respiratory failure: insights beyond primary outcomes. Seminars in Perinatology 27:4, 311-319
CrossRef148
Richard A. Ehrenkranz, Linda L. Wright. (2003) NICHD neonatal research network: contributions and future challenges. Seminars in Perinatology 27:4, 264-280
CrossRef149
Hao Zhang, Robert Lindwall, Liewei Zhu, Claes Frostell, Bo Sun. (2003) Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets. Pulmonary Pharmacology & Therapeutics 16:3, 163-169
CrossRef150
Lisa A. Brennan, Stephen Wedgwood, Janine M. Bekker, Stephen M. Black. (2003) Nitric Oxide Activates p21 ras and Leads to the Inhibition of Endothelial NO Synthase by Protein Nitration. DNA and Cell Biology 22:5, 317-328
CrossRef151
Jenni Sokol, Susan E Jacobs, Desmond Bohn, Jenni Sokol. 2003. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. .
CrossRef152
William E. Hurford. (2003) Inhaled Nitric Oxide: Current Concepts. ASA Refresher Courses in Anesthesiology 31:1, 81
CrossRef153
William E. Hurford. (2003) Chapter 8 Inhaled Nitric Oxide: Current Concepts. ASA Refresher Courses in Anesthesiology 31:1, 81-91
CrossRef154
Kevin P. Lally. (2002) Congenital diaphragmatic hernia. Current Opinion in Pediatrics 14:4, 486-490
CrossRef155
J. Gianetti, S. Bevilacqua, R. De Caterina. (2002) Inhaled nitric oxide: more than a selective pulmonary vasodilator. European Journal of Clinical Investigation 32:8, 628-635
CrossRef156
Ronald B. Hirschl. (2002) Support of respiratory failure in the pediatric surgical patient. Current Opinion in Pediatrics 14:4, 459-469
CrossRef157
R. Lindwall, C.G. Frostell, P.A. Lonnqvist. (2002) Delivery characteristics of a combined nitric oxide nasal continuous positive airway pressure system. Pediatric Anesthesia 12:6, 530-536
CrossRef158
William E. Hurford, Luca M. Bigatello. (2002) NO-bodyʼs Perfect. Anesthesiology 96:6, 1285-1287
CrossRef159
Habib M. Razavi, Robert Werhun, Jeremy A. Scott, Sean Weicker, Le Feng Wang, David G. McCormack, Sanjay Mehta. (2002) Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury*. Critical Care Medicine 30:4, 868-873
CrossRef160
Xizhong Cui, Zenaide M. N. Quezado, Peter Q. Eichacker. (2002) Inhaled nitric oxide: Is systemic host defense at risk? *. Critical Care Medicine 30:4, 945-946
CrossRef161
Joesph Fawke, John McIntyre. (2002) Recent advances in neonatology. Current Opinion in Obstetrics and Gynecology 14:2, 153-158
CrossRef162
NN Finer, KJ Barrington, Neil Finer. 2001. Nitric oxide for respiratory failure in infants born at or near term. .
CrossRef163
Alfred P. Fishman. (2001) CLINICAL CLASSIFICATION OF PULMONARY HYPERTERNSION. Clinics in Chest Medicine 22:3, 385-391
CrossRef164
Pearson, DeLinda L., Dawling, Sheila, Walsh, William F., Haines, Jonathan L., Christman, Brian W., Bazyk, Amy, Scott, Nathan, Summar, Marshall L., . (2001) Neonatal Pulmonary Hypertension. New England Journal of Medicine 344:24, 1832-1838
Full Text165
Ching Tzao, Peter A. Nickerson, James A. Russell, Sylvia F. Gugino, Robin H. Steinhorn. (2001) Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs. Pediatric Pulmonology 31:2, 97-105
CrossRef166
Tushar Bhuta, Reese H Clark, David J Henderson-Smart, Tushar Bhuta. 2001. Rescue high frequency oscillatory ventilation vs conventional ventilation for infants with severe pulmonary dysfunction born at or near term. .
CrossRef167
Martin F. Krause, Cornelia J??kel, J??rg Haberstroh, J??rgen Schulte-M??nting, Thomas Hoehn. (2001) Functional residual capacity determines the effect of inhaled nitric oxide on intrapulmonary shunt and gas exchange in a piglet model of lung injury. Pediatric Critical Care Medicine 2:1, 82-87
CrossRef168
Tine L.M. De Backer, Jan-Peter Smedema, St??phane G. Carlier. (2001) Current Management of Primary Pulmonary Hypertension. BioDrugs 15:12, 801-817
CrossRef169
John P. Kinsella, Steven H. Abman. (2000) Inhaled nitric oxide: Current and future uses in neonates. Seminars in Perinatology 24:6, 387-395
CrossRef170
A.A. Hislop, C.M. Pierce. (2000) Growth of the vascular tree. Paediatric Respiratory Reviews 1:4, 321-328
CrossRef171
S Jaillard. (2000) Effects of inhaled nitric oxide on gas exchange and acute lung injury in premature lambs with moderate hyaline membrane disease. European Journal of Cardio-Thoracic Surgery 18:3, 334-341
CrossRef172
Tim Higenbottam, Tom Siddons, Eric Demoncheaux. (2000) A therapeutic role for chronic inhaled nitric oxide?. The Lancet 356:9228, 446-447
CrossRef173
Anne Greenough. (2000) Inhaled nitric oxide in the neonatal period. Expert Opinion on Investigational Drugs 9:7, 1601-1609
CrossRef
