Nitric oxide, an important signaling molecule with multiple regulatory effects throughout the body, is an important tool for the treatment of full-term and late-preterm infants with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure. Several randomized controlled trials have evaluated its role in the management of preterm infants ≤34 weeks’ gestational age with varying results. The purpose of this clinical report is to summarize the existing evidence for the use of inhaled nitric oxide in preterm infants and provide guidance regarding its use in this population.
Introduction
Nitric oxide (NO) is an important signaling molecule with multiple regulatory effects throughout the body. In perinatal medicine, inhaled nitric oxide (iNO) was initially studied for its pulmonary vasodilating effects in infants with pulmonary hypertension and has since become an important tool for the treatment of full-term and late-preterm infants with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure.1 Inhaled NO also has multiple and complex systemic and pulmonary effects. In animal models of neonatal chronic lung disease, iNO stimulates angiogenesis, augments alveolarization, improves surfactant function, and inhibits proliferation of smooth muscle cells and abnormal elastin deposition.2,–6 Although the evidence for similar benefits in preterm infants is lacking, the off-label use of iNO in this population has escalated.7 A study published in 2010 reported a sixfold increase (from 0.3% to 1.8%) in the use of iNO among infants born at less than 34 weeks’ gestation between 2000 and 2008.7 The greatest increase occurred among infants who were born at 23 to 26 weeks’ gestation (0.8% to 6.6%). The National Institutes of Health convened a consensus panel in October 2010 to evaluate the evidence for safety and efficacy of iNO therapy in preterm infants. After reviewing the published evidence, the panel concluded that the available evidence does not support the use of iNO in early routine, early rescue, or later rescue regimens in the care of infants born at less than 34 weeks’ gestation and that hospitals, clinicians, and the pharmaceutical industry should avoid marketing iNO for this group of infants.8 An individual-patient data meta-analysis of 14 randomized controlled trials reached similar conclusions.9 The purpose of this clinical report is to summarize the existing evidence for the use of iNO in preterm infants and provide guidance regarding its use in this population.
Literature Review
Use of iNO in Preterm Infants With Respiratory Failure
The benefits associated with iNO therapy in full-term and late-preterm infants with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure initiated interest in exploring whether iNO could reduce the rates of death and neonatal morbidities in more immature infants. Pilot studies reported short-term improvement in oxygenation with iNO, but no significant benefit was observed in mortality or other morbidities.10,–15 Subsequently, several randomized clinical trials were undertaken.16,–23 Table 1 outlines the study population, entry criteria, and dose and duration of iNO treatment and summarizes the outcomes for all published randomized controlled trials. Only 1 small trial of 40 patients reported a beneficial effect on survival (Table 1). Subgroup analyses of secondary outcomes have provided conflicting results. Post hoc analysis of the Neonatal Research Network study suggested that iNO therapy was associated with reduced rates of death and bronchopulmonary dysplasia (BPD) in infants with a birth weight greater than 1000 g, but higher mortality and increased risk of severe intracranial hemorrhage in infants weighing 1000 g or less at birth.17 In contrast, another large multicenter US trial reported no significant difference in the primary outcome of death or BPD between treated and control groups; however, infants treated with iNO had fewer brain lesions (eg, grade 3 or 4 intracranial hemorrhage, periventricular leukomalacia, and/or ventriculomegaly) noted on cranial ultrasonography.20 A European multicenter study reported that infants randomized to iNO treatment had longer duration of ventilation, time on oxygen therapy, and length of hospital stay compared with the placebo group, although none of these results were statistically significant.19
Randomized Controlled Trials of iNO in Preterm Infants
Author, Year . | n . | Gestational Age, wk . | Birth Weight, g . | Age at Enrollment . | Entry Criteria . | iNO Protocol . | Primary Outcome . | Study Results . |
---|---|---|---|---|---|---|---|---|
Subhedar, 199711 | 42 | <32 | — | 96 h | Need for mechanical ventilation and high risk of developing CLD | 20 ppm for at least first 2 h and then 5 ppm for 3–4 d | Death and/or CLD before discharge | No difference in primary outcome |
Kinsella, 199912 | 80 | ≤34 | — | ≤7 d | aAO2 ratio <0.1 on 2 consecutive blood gases in first 7 d of life | 5 ppm for 7–14 d | Survival | No difference in primary outcome; no difference in rate of IVH or CLD |
The French-Belgian iNO Trial, 199913 | 85 | <33 | — | <7 d | OI between 12.5 and 30.0 on 2 consecutive blood gases at least 1 h apart | 10–20 ppm for a minimum of 2 h | OI reduction of ≥33% or at least 10 points | More treated infants achieved primary outcome; no difference in median OI at 2 h; no difference in survival or other outcomes |
Srisuparp, 200215 | 34 | — | <2000 | <72 h | OI ranging from >4 to >12 based on birth wt | 20 ppm for 24–48 h and then 5 ppm for maximum of 7 d | Change in oxygenation | Improved oxygenation with treatment but no difference in survival or IVH |
Schreiber, 200316 | 207 | <34 | <2000 | <72 h | Need for mechanical ventilation | 10 ppm for first day then 5 ppm for 6 d | Death and survival without BPD at 36 wk postmenstrual age | Treatment associated with a decrease in the combined incidence of BPD and death; no difference in mortality alone |
Van Meurs, 200517 | 420 | <34 | 401–1500 | 4–120 h; mean 26–28 h | OI ≥10 on 2 consecutive blood gases between 30 min and 12 h apart | 5–10 ppm for maximum of 14 d | Incidence of death or BPD | No difference in primary outcome; no difference in rate of BPD, severe IVH, or PVL. |
Post hoc analyses: Decrease in primary outcome in cohort with birth weight >1000 g; higher rate of mortality and severe IVH in cohort with birth wt <1000 g | ||||||||
Hascoet, 200518 | 145 | <32 | — | 6–48 h | aAO2 ratio <0.22 | 5 ppm for first h of treatment and further dosage were adjusted based on response; total duration of treatment not clearly defined but varied from 4 h in nonresponders to few days in responders | Intact survival at 28 d | No difference in primary outcome; iNO was an independent risk factor for the combined risk of death or brain lesion |
Field, 200519 | 108 | <34 | — | <28 d; median 1 d | Severe respiratory failure requiring assisted ventilation | 5–40 ppm depending on patient response; total duration of treatment not clearly defined | Death or severe disability at 1 y corrected age; death or CLD | No difference in primary outcome |
Kinsella, 200620 | 793 | ≤34 | 500–1250 | <48 h | Need for mechanical ventilation | 5 ppm for maximum of 21 d | Death or BPD at 36 wk postmenstrual age | No difference in primary outcome but had a decreased risk of brain injury; decreased incidence of BPD in cohort with birth weight ≤1000 g |
Dani, 200621 | 40 | <30 | — | ≤7 d | aAO2 ratio <0.15 | 10 ppm for 4 h then 6 ppm until extubation | Death and BPD | Primary outcome less with iNO treatment |
Ballard, 200624 | 582 | ≤32 | 500–1250 | 7–21 d | Need for mechanical ventilation for lung disease between 7 and 21 d; infants with birth weight 500–799 g were eligible if requiring nasal CPAP | 20 ppm for 48–96 h followed by 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 d | Survival without BPD at 36 wk of postmenstrual age | Improved survival without BPD at 36 wk postmenstrual age; post hoc analysis showed most benefit when iNO treatment was started between 7–14 d of age |
Van Meurs, 200723 | 29 | <34 | >1500 | 4–120 h; mean 24–25 h | OI ≥15 on 2 consecutive blood gases between 30 min and 12 h apart | 5–10 ppm for maximum of 14 d | Incidence of death or BPD | No difference in primary outcome |
Su and Chen, 200822 | 65 | <32 | ≤1500 | Mean 2.5 d | OI ≥25 | 5–20 ppm based on patient response; treatment duration at physician discretion (mean duration 4.9 ± 2.3 d) | OI at 24 h after randomization | Improved oxygenation with iNO treatment; no difference in survival, CLD, IVH, PDA, ROP, or duration of intubation |
Mercier, 201025 | 800 | <29 | >500 | First day of life | Need for surfactant or CPAP within 24 h of birth | 5 ppm for minimum of 7 d and maximum of 21 d | Survival without BPD at 36 wk postmenstrual age | No difference in primary outcome; no difference in survival alone; no difference in BPD; no difference in brain injury |
Author, Year . | n . | Gestational Age, wk . | Birth Weight, g . | Age at Enrollment . | Entry Criteria . | iNO Protocol . | Primary Outcome . | Study Results . |
---|---|---|---|---|---|---|---|---|
Subhedar, 199711 | 42 | <32 | — | 96 h | Need for mechanical ventilation and high risk of developing CLD | 20 ppm for at least first 2 h and then 5 ppm for 3–4 d | Death and/or CLD before discharge | No difference in primary outcome |
Kinsella, 199912 | 80 | ≤34 | — | ≤7 d | aAO2 ratio <0.1 on 2 consecutive blood gases in first 7 d of life | 5 ppm for 7–14 d | Survival | No difference in primary outcome; no difference in rate of IVH or CLD |
The French-Belgian iNO Trial, 199913 | 85 | <33 | — | <7 d | OI between 12.5 and 30.0 on 2 consecutive blood gases at least 1 h apart | 10–20 ppm for a minimum of 2 h | OI reduction of ≥33% or at least 10 points | More treated infants achieved primary outcome; no difference in median OI at 2 h; no difference in survival or other outcomes |
Srisuparp, 200215 | 34 | — | <2000 | <72 h | OI ranging from >4 to >12 based on birth wt | 20 ppm for 24–48 h and then 5 ppm for maximum of 7 d | Change in oxygenation | Improved oxygenation with treatment but no difference in survival or IVH |
Schreiber, 200316 | 207 | <34 | <2000 | <72 h | Need for mechanical ventilation | 10 ppm for first day then 5 ppm for 6 d | Death and survival without BPD at 36 wk postmenstrual age | Treatment associated with a decrease in the combined incidence of BPD and death; no difference in mortality alone |
Van Meurs, 200517 | 420 | <34 | 401–1500 | 4–120 h; mean 26–28 h | OI ≥10 on 2 consecutive blood gases between 30 min and 12 h apart | 5–10 ppm for maximum of 14 d | Incidence of death or BPD | No difference in primary outcome; no difference in rate of BPD, severe IVH, or PVL. |
Post hoc analyses: Decrease in primary outcome in cohort with birth weight >1000 g; higher rate of mortality and severe IVH in cohort with birth wt <1000 g | ||||||||
Hascoet, 200518 | 145 | <32 | — | 6–48 h | aAO2 ratio <0.22 | 5 ppm for first h of treatment and further dosage were adjusted based on response; total duration of treatment not clearly defined but varied from 4 h in nonresponders to few days in responders | Intact survival at 28 d | No difference in primary outcome; iNO was an independent risk factor for the combined risk of death or brain lesion |
Field, 200519 | 108 | <34 | — | <28 d; median 1 d | Severe respiratory failure requiring assisted ventilation | 5–40 ppm depending on patient response; total duration of treatment not clearly defined | Death or severe disability at 1 y corrected age; death or CLD | No difference in primary outcome |
Kinsella, 200620 | 793 | ≤34 | 500–1250 | <48 h | Need for mechanical ventilation | 5 ppm for maximum of 21 d | Death or BPD at 36 wk postmenstrual age | No difference in primary outcome but had a decreased risk of brain injury; decreased incidence of BPD in cohort with birth weight ≤1000 g |
Dani, 200621 | 40 | <30 | — | ≤7 d | aAO2 ratio <0.15 | 10 ppm for 4 h then 6 ppm until extubation | Death and BPD | Primary outcome less with iNO treatment |
Ballard, 200624 | 582 | ≤32 | 500–1250 | 7–21 d | Need for mechanical ventilation for lung disease between 7 and 21 d; infants with birth weight 500–799 g were eligible if requiring nasal CPAP | 20 ppm for 48–96 h followed by 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 d | Survival without BPD at 36 wk of postmenstrual age | Improved survival without BPD at 36 wk postmenstrual age; post hoc analysis showed most benefit when iNO treatment was started between 7–14 d of age |
Van Meurs, 200723 | 29 | <34 | >1500 | 4–120 h; mean 24–25 h | OI ≥15 on 2 consecutive blood gases between 30 min and 12 h apart | 5–10 ppm for maximum of 14 d | Incidence of death or BPD | No difference in primary outcome |
Su and Chen, 200822 | 65 | <32 | ≤1500 | Mean 2.5 d | OI ≥25 | 5–20 ppm based on patient response; treatment duration at physician discretion (mean duration 4.9 ± 2.3 d) | OI at 24 h after randomization | Improved oxygenation with iNO treatment; no difference in survival, CLD, IVH, PDA, ROP, or duration of intubation |
Mercier, 201025 | 800 | <29 | >500 | First day of life | Need for surfactant or CPAP within 24 h of birth | 5 ppm for minimum of 7 d and maximum of 21 d | Survival without BPD at 36 wk postmenstrual age | No difference in primary outcome; no difference in survival alone; no difference in BPD; no difference in brain injury |
Dash indicates not part of enrollment criteria.
aAO2, arterial-alveolar oxygen ratio; CLD, chronic lung disease; CPAP, continuous positive airway pressure; IVH, intraventricular hemorrhage; OI, oxygenation index; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity.
Use of iNO in Preterm Infants to Improve the Rate of Survival Without BPD
Lung pathology in preterm infants with BPD is characterized by reduced numbers of large alveoli and abnormal pulmonary vasculature development. Surfactant deficiency, ventilator-induced lung injury, oxygen toxicity, and inflammation appear to play important roles in its pathogenesis.26,27 In animal models of neonatal lung injury, iNO promotes angiogenesis, decreases apoptosis, and reduces lung inflammation and oxidant injury.28,–30 In an early study of iNO use in preterm infants, the incidence of BPD was reduced in treated infants who required ventilator support.16 Of 3 subsequent large randomized trials designed to evaluate the effect of iNO therapy on survival without BPD,20,24,25 2 found no significant benefit20,25 (Table 1). A third trial, which featured late treatment (7–21 days of age), a longer duration of drug exposure (25 days), and a higher cumulative dose, demonstrated a modest but statistically significant beneficial effect (44% iNO vs 37% placebo; P = .042).24 A subgroup analysis showed that the beneficial effect was seen in infants enrolled between 7 and 14 days of age but not those enrolled between the ages of 15 and 21 days.24
Effects of iNO Therapy on Neurodevelopmental Outcome
Studies in animal models suggest that iNO may have direct beneficial effects on the brain through mechanisms involving the cerebral vasculature and/or neuronal maturation.31,32 Other investigators have described a possible role for intravascular NO-derived molecules in conserving and stabilizing NO bioactivity that may contribute to the regulation of regional blood flow and oxygen delivery.33,34 Neurodevelopmental outcome has been reported for 6 clinical trials,35,–40 and of these, 1 noted a more favorable neurodevelopmental outcome at 1 year of age among the preterm cohort treated with iNO but no difference in the rate of cerebral palsy.36
Effects of iNO Therapy on Long-Term Pulmonary Outcome of Survivors
In animal models, iNO decreases baseline airway resistance and may increase the rate of alveolarization.2,–6 To date, only 2 studies have reported respiratory outcomes of preterm infants treated with iNO.41,42 In a telephone survey that included 456 infants in the Nitric Oxide Chronic Lung Disease (NOCLD) study group, the use of bronchodilators, inhaled steroids, systemic steroids, diuretics, and supplemental oxygen during the first year of life was less in the iNO-treated group, but there were no significant differences in the frequency of wheezing or the rate of rehospitalization. In the Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide multicenter trial, follow-up at 1 year of age showed no difference in maximal expiratory flow at functional residual capacity, wheezing, readmission rate, or use of respiratory medications.42
Results of Meta-Analyses of Studies Evaluating the Use of iNO in Preterm Infants
Two published meta-analyses found no overall significant effect of iNO on the rate of mortality, BPD, intraventricular hemorrhage, or neurodevelopmental impairment.43,44 In view of the limitations of meta-analysis using aggregate data from different trials and to identify any patient or treatment characteristics that might predict benefit, Askie et al9 conducted an individual-patient data meta-analysis. Data from 3298 infants in 11 trials that included 96% of published data showed no statistically significant effect of iNO on the rate of death or chronic lung disease (relative risk 0.96; 95% confidence interval 0.92–1.01) or severe brain lesions on cranial imaging (relative risk 1.12; 95% confidence interval 0.98–1.28). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested; however, the authors cautioned that they could not exclude the possibility of a small reduction in the combined outcome of death or chronic lung disease if a higher dose of iNO (20 ppm) was used after >7 days of age, as observed in the NOCLD study.9,24
Cost-Benefit Analyses of Routine Use of iNO in Preterm Infants
Treatment with iNO is expensive and can add significantly to health care costs.8 A retrospective economic evaluation using patient-level data from the NOCLD trial (the only trial showing clinical benefit) reported that the overall mean cost per infant for the initial hospitalization was similar in the treated and placebo groups; however, when iNO therapy was initiated between 7 and 14 days of age, there was a 71% probability that the treatment decreased costs and improved outcomes.45 Cost-benefit analysis from 2 other studies failed to show any cost-benefit.37,39 Among preterm infants in the Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide trial, there was no difference in resource use and cost of care through the 4-year assessment.37 Using more robust research methodology, including data on postdischarge resource utilization and health-related quality of life evaluations, Watson et al39 found that costs of care did not vary significantly by treatment arm through 1 year of age. Although quality-adjusted survival was slightly better with iNO therapy, the estimated incremental cost-effectiveness ratio was $2.25 million per quality-adjusted life year, with only a 12.9% probability that the incremental cost-effectiveness ratio would be less than $500 000 per quality-adjusted life year. Additionally, in subgroup analysis, total costs were significantly higher for the iNO-treated group in the smallest birth weight stratum (500–749 g).
Safety of iNO Use in Preterm Infants
Summary
The results of randomized controlled trials, traditional meta-analyses, and an individualized patient data meta-analysis study indicate that neither rescue nor routine use of iNO improves survival in preterm infants with respiratory failure (Evidence quality, A; Grade of recommendation, strong).50
The preponderance of evidence does not support treating preterm infants who have respiratory failure with iNO for the purpose of preventing/ameliorating BPD, severe intraventricular hemorrhage, or other neonatal morbidities (Evidence quality, A; Grade of recommendation, strong).
The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive impairment in preterm infants treated with iNO is similar to that of control infants (Evidence quality, A).
The results of 1 multicenter, randomized controlled trial suggest that treatment with a high dose of iNO (20 ppm) beginning in the second postnatal week may provide a small reduction in the rate of BPD. However, these results need to be confirmed by other trials.
An individual-patient data meta-analysis that included 96% of preterm infants enrolled in all published iNO trials found no statistically significant differences in iNO effect according to any of the patient-level characteristics, including gestational age, race, oxygenation index, postnatal age at enrollment, evidence of pulmonary hypertension, and mode of ventilation.
There are limited data and inconsistent results regarding the effects of iNO treatment on pulmonary outcomes of preterm infants in early childhood.
Lead Author
Praveen Kumar, MD, FAAP
Committee on Fetus and Newborn, 2012–2013
Lu-Ann Papile, MD, FAAP, Chairperson
Richard A. Polin, MD, FAAP
Waldemar A. Carlo, MD, FAAP
Rosemarie Tan, MD, FAAP
Praveen Kumar, MD, FAAP
William Benitz, MD, FAAP
Eric Eichenwald, MD, FAAP
James Cummings, MD, FAAP
Jill Baley, MD, FAAP
Liaisons
Tonse N. K. Raju, MD, FAAP – National Institutes of Health
CAPT Wanda Denise Barfield, MD, FAAP – Centers for Disease Control and Prevention
Erin Keels, MSN – National Association of Neonatal Nurses
Anne Jefferies, MD – Canadian Pediatric Society
Kasper S. Wang, MD, FAAP – AAP Section on Surgery
George Macones, MD – American College of Obstetricians and Gynecologists
Staff
Jim Couto, MA
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.
All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
Comments
Response to Kumar on behalf of the AAP Committee on Fetus and Newborn
We read with interest the review of the use of iNO in premature infants recently published by Dr. Kumar on behalf of the AAP Committee on Fetus and Newborn1. Along with the recent NIH Consensus opinion2, this article provides practicing neonatologists with direction on the use of iNO in premature infants, a population in which well-performed clinical trials have failed to produce consensus about its overall efficacy.
We believe, however, that in recommending that iNO not be offered to premature infants at all, the Committee has done a significant disservice to premature infants in two ways:
First, the Committee has recommended that iNO not be offered to premature infants with documented pulmonary hypertension. We strongly disagree. While the efficacy of iNO has not been explicitly studied in this group of infants, case series3, 4 and retrospective reviews5 have demonstrated the efficacy of iNO in treating pulmonary hypertension in these patients. In fact, there are no data to suggest that the pulmonary vasculature in these infants reacts any differently to iNO compared with that of term and near-term infants. This issue was specifically addressed by the NIH Consensus statement2:
There are rare clinical situations, including pulmonary hypertension or hypoplasia that have been inadequately studied, in which iNO may have benefit in infants of 34 weeks gestation [and earlier]. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.
A randomized controlled trial of iNO in premature infants to treat documented pulmonary hypertension would best address whether these infants should receive iNO. However, we believe that neonatologists, by now experienced in iNO use, no longer possess the equipoise to participate in such a trial. After all, the responsiveness of the acutely constricted pulmonary vasculature to iNO in these infants is hardly in doubt. Furthermore, such a study would encounter significant barriers to funding and patient enrollment, since pulmonary hypertension affects only 2% of all premature births. As important, the strong safety profile of iNO, as demonstrated in iNO-treated survivors as old as school age6, indicates that the chance of adverse effects with iNO treatment is very low. Thus, the favorable risk:benefit ratio of iNO strongly indicates that allowing these babies to die or suffer the pulmonary and neurodevelopmental complications of prolonged ventilation without a trial of iNO is unwise.
We believe that in cases like this, when faced with insufficient evidence but where the benefit-harm equilibrium is positive, clinicians should follow the AAP's 2004 Classifying Recommendations for Clinical Practice Guidelines7. These recommend that "guideline developers generally should not constrain the clinician's discretion by making a recommendation but instead should designate acceptable alternatives as options."
Second, in declaring that the "evidence does not support treating premature infants who have respiratory failure for the purpose of preventing/ameliorating BPD", the Committee appears to have concluded that research on iNO and BPD is complete. In fact, study of iNO effects on BPD and other co-morbidities of prematurity continues apace. While the meta- analyses cited by the Committee indicate that iNO has no consistent effect across all premature infants, there are persistent signals from sub-group analyses within large trials8-13 that iNO may have clinically important effects in specific groups of infants, such as those of African-American race. Race-specific differences in endogenous NO production have already led to the development of BiDil?, a drug combination therapy for hypertension targeted specifically to African-American adults14. Accordingly, additional studies to delineate sub-groups, such as African Americans and Hispanics, for whom iNO treatment should be reserved, are in progress.
Accordingly, we ask that the Committee modify its position on the use of iNO for premature infants. First, we urge the AAP Committee on Fetus and Newborn to remove its "No iNO" recommendation for premature infants with pulmonary hypertension, allowing neonatologists to use their clinical judgment as to its best use. Second, we ask that the Committee explicitly identify the importance of additional study to determine whether iNO may benefit African-American or other vulnerable populations of premature infants.
Jeremy D. Marks1, PhD, MD
Roberta Ballard2, MD
John Kinsella3, MD
Krista P. Van Muers4, MD
Robin Steinhorn5, MD
Bradley Yoder6, MD
Michael D. Schreiber1, MD
The University of Chicago1, University of California, San Francisco2, University of Colorado, Denver3, Stanford University5, University of California, Davis5, University of Utah6
1. Kumar P, Committee on Fetus and Newborn 2012-2013. Use of Inhaled Nitric Oxide in Preterm Infants. Pediatrics. 2014;133(1):164-170.
2. Cole FS, Alleyne C, Barks JDE, Boyle RJ, Carroll JL, Dokken D, et al. NIH Consensus Development Conference Statement: Inhaled Nitric-Oxide Therapy for Premature Infants. Pediatrics. 2011;127(2):363-369.
3. Peliowski A, Finer NN, Etches PC, Tierney AJ, Ryan CA. Inhaled nitric oxide for premature infants after prolonged rupture of the membranes. The Journal of Pediatrics. 1995;126(3):450-453.
4. Geary C, Whitsett J. Inhaled nitric oxide for oligohydramnios- induced pulmonary hypoplasia: a report of two cases and review of the literature. Journal of perinatology : official journal of the California Perinatal Association. 2002;22(1):82-85.
5. Chock VY, Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Kendrick DE, et al. Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia. Amer J Perinatol. 2009;26(EFirst):317-322.
6. Patrianakos-Hoobler AI, Marks JD, Msall ME, Huo D, Schreiber MD. Safety and efficacy of inhaled nitric oxide treatment for premature infants with respiratory distress syndrome: follow-up evaluation at early school age. Acta paediatrica. 2011;100(4):524-528.
7. Steering Committee on Quality Improvement and Management. American Academy of Pediatrics Classifying Recommendations for Clinical Practice Guidelines. Pediatrics. 2004;114(3):874-877.
8. Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. New England Journal of Medicine. 2003;349:2099-2107.
9. Mestan KL, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. New England Journal of Medicine. 2005;353(1):23-32.
10. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled Nitric Oxide in Preterm Infants Undergoing Mechanical Ventilation. N Engl J Med. 2006;355(4):343-353.
11. Yoder B. Inhaled NO for Prevention of BPD: Update on the NEWNO Trial. Hot Topics in Neonatology, Washington, DC, 2013.
12. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354-364.
13. Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353(1):13-22.
14. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, et al. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. New England Journal of Medicine. 2004;351(20):2049- 2057.
Conflict of Interest:
Several authors have received research grants from Ikaria and have been on scientific advisory boards of Ikaria.
Use of inhaled Nitric Oxide in preterm infants
I read the recent Clinical Report on the "use of inhaled Nitric Oxide in Preterm infants"with great interest. Although it supports the recommendations of the NIH Consensus published in October 2010(1), it fails to address the possible benefit of inhaled nitric oxide in preterm infants with pulmonary hypoplasia and/or severe PPHN. Although there is scant published data(2,3) that supports this pratice, nitric oxide is being widely used in these critically ill infants in many NICUs and it is important that the Committee acknowledges this fact as done in the NIH Consensus. Mike Sukumar MD
1. NIH consensus State Sci 2010 October 29;27(5) 1-34 2. Inhaled NO in oligohydramnios induced pulmonary hypoplasia Geary C, Whitsett J Perinatol 2002 Jan 22 (1) 82-5 3. Inhaled NO for PPROM, oligohydramnios and pulmonary hypoplasia Chock VY et al NICHD Network Am J Perinatol 2009 April 26 ( 4) 317-22
Conflict of Interest:
None declared