Number 195 

Inhaled Nitric Oxide in Preterm Infants 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-2007-10061-I 

Prepared by: 

The Johns Hopkins University Evidence-based Practice Center 

Baltimore, MD 

Investigators: 

Marilee C. Allen, M.D.
 

Pamela Donohue, Sc.D.
 

Maureen Gilmore, M.D.
 

Elizabeth Cristofalo, M.D., M.P.H.
 

Renee F. Wilson, M.S. 

Jonathan Z. Weiner, B.A.
 

Karen Robinson, Ph.D.
 

AHRQ Publication No. 11-E001 

October 2010 
 

This report is based on research conducted by the Johns Hopkins University Evidence-based 

Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-2007-10061-I). The findings and conclusions in this document 

are those of the author(s), who are responsible for its content, and do not necessarily represent the 

views of AHRQ. No statement in this report should be construed as an official position of AHRQ 

or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders.

Suggested Citation:

Allen MC, Donohue P, Gilmore M, Cristofalo E, Wilson RF, Weiner JZ, Bass EB, and Robinson 

K. Inhaled Nitric Oxide in Preterm Infants. Evidence Report/Technology Assessment No. 195. 

(Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-

2007-10061-1). AHRQ Publication No. 11-E001. Rockville, MD: Agency for Healthcare 

Research and Quality. October 2010.

No investigators have any affiliations or financial involvement (e.g., employment, 

consultancies, honoraria, stock options, expert testimony, grants or patents received or 

pending, or royalties) that conflict with material presented in this report.
 

Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report was requested and funded by the National 

Institutes of Health (NIH), Office of Medical Applications of Research (OMAR). The reports 

and assessments provide organizations with comprehensive, science-based information on 

common, costly medical conditions and new health care technologies. The EPCs systematically 

review the relevant scientific literature on topics assigned to them by AHRQ and conduct 

additional analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Stephanie Chang, M.D., M.P.H. Christine Chang, M.D. 

Director, EPC Program Task Order Officer 

Agency for Healthcare Research and Quality Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Jennifer M. Croswell, M.D., M.P.H. 

Acting Director, Office of Medical 

Applications of Research 

National Institutes of Health 

iii 
 

Acknowledgments 

The EPC thanks Ritu Sharma, Brandyn Lau, and Rebecca Stainmann for their assistance with 

literature searching, database management, and project organization, and Brenda Zacharko for 

her assistance with budget matters and final preparations of the report. 

We also extend our appreciation to the members of our Technical Expert Panel (TEP) and 

Peer Reviewers: Gerald M. Loughlin, M.D., T. Michael O'Shea, M.D., M.P.H., William Truog, 

M.D., Paul H. Lipkin, M.D., Brian Hanna, MDCM, John Zupancic, M.D., Sc.D., Brian Rogers, 

M.D., Lisa Askie, M.D. 

iv 
Structured Abstract 

Objectives. To systematically review the evidence on the use of inhaled nitric oxide (iNO) in 

preterm infants born at or before 34 weeks gestation age who receive respiratory support. 

Data sources. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled 

Studies (CENTRAL) and PsycInfo in June 2010. We also searched the proceedings of the 2009 

and 2010 Pediatric Academic Societies Meeting and ClinicalTrials.gov. We identified additional 

studies from reference lists of eligible articles and relevant reviews, as well as from technical 

experts. 

Review methods. Questions were developed in collaboration with technical experts, including 

the chair of the upcoming National Institutes of Health Office of Medical Applications of 

Research Consensus Development Conference. We limited our review to randomized controlled 

trials (RCTs) for the question of survival or occurrence of bronchopulmonary dysplasia (BPD) 

and for the question on short-term risks. All study designs were considered for long-term 

pulmonary or neurodevelopmental outcomes, and for questions about whether outcomes varied 

by subpopulation or by intervention characteristics. Two investigators independently screened 

search results, and abstracted data from eligible articles. 

Results. We identified a total of 14 RCTs, reported in 23 articles, and eight observational 

studies. Mortality rates in the NICU did not differ for infants treated with iNO versus those not 

treated with iNO (RR 0.97 (95% CI 0.82, 1.15)). BPD at 36 weeks for iNO and control groups 

also did not differ (RR 0.93 (0.86, 1.003) for survivors). A small difference was found between 

iNO and control infants in the composite outcome of death or BPD (RR 0.93 (0.87, 0.99)). There 

was inconsistent evidence about the risk of brain injury from individual RCTs, but meta-analyses 

showed no difference between iNO and control groups. We found no evidence of differences in 

other short term risks. There was no evidence to suggest a difference in the incidence of cerebral 

palsy (RR 1.36 (0.88, 2.10)), neurodevelopmental impairment (RR 0.91 (0.77, 1.12)), or 

cognitive impairment (RR 0.72 (0.35, 1.45)). Evidence was limited on whether the effect of iNO 

varies by subpopulation or by characteristics of the therapy (timing, dose and duration, mode of 

delivery, or concurrent therapies). 

Conclusions. There was a seven percent reduction in the risk of the composite outcome of death 

or BPD at 36 weeks PMA for infants treated with iNO compared to controls, but no reduction in 

death or BPD alone. Further studies are needed to explore particular subgroups of infants and to 

assess long term outcomes including function in childhood. There is currently no evidence to 

support the use of iNO in preterm infants with respiratory failure outside the context of 

rigorously conducted randomized clinical trials. 

v 
 

 

 

Contents 

Executive Summary.........................................................................................................................1
 

Evidence Report .............................................................................................................................7
 

Chapter 1. Introduction ...................................................................................................................9
 

Background................................................................................................................................9
 

Treatment options ................................................................................................................9
 

Mechanism of action............................................................................................................9
 

FDA approved indications and usage ................................................................................10
 

Utilization of iNO ..............................................................................................................11
 

Purpose of this Evidence Report..............................................................................................11
 

Key Questions..........................................................................................................................12
 

Chapter 2. Methods........................................................................................................................13
 

Topic Development..................................................................................................................13
 

Analytic Framework ................................................................................................................13
 

Search Strategy ........................................................................................................................14
 

Sources...............................................................................................................................14
 

Search terms and strategies................................................................................................14
 

Organization and tracking of the literature search.............................................................14
 

Study Selection ........................................................................................................................16
 

Abstract screen...................................................................................................................16
 

Article screen .....................................................................................................................16
 

Data Abstraction ......................................................................................................................16
 

Quality Assessment of Individual Studies (Risk of Bias Assessment)....................................17
 

Grading of the Body of Evidence ............................................................................................17
 

Data Synthesis..........................................................................................................................18
 

Peer Review .............................................................................................................................18
 

Chapter 3. Results ..........................................................................................................................19
 

Literature Search/Abstract/Article Review..............................................................................19
 

Description of Types of Studies Retrieved ..............................................................................19
 

Risk of Bias..............................................................................................................................19
 

Key Question 1: Does inhaled nitric oxide (iNO) therapy increase survival and/or reduce the 

occurrence or severity of bronchopulmonary dysplasia (BPD) among premature infants 

who receive respiratory support? .......................................................................................23
 

Major findings....................................................................................................................23
 

Detailed analysis ................................................................................................................23
 

Conclusions........................................................................................................................36
 

Key Question 2: Are there short term risks of iNO therapy among premature infants who 

receive respiratory support?...............................................................................................37
 

Major findings....................................................................................................................37
 

Detailed analysis ................................................................................................................37
 

Conclusions........................................................................................................................45
 

vii 
 

 

 

 

 

 

 

 

 

 

 

Key Question 3: Are there effects of iNO therapy on long term pulmonary and/or 

neurodevelopmental outcomes among premature infants who receive respiratory
 

support?..............................................................................................................................46
 

Major findings....................................................................................................................46
 

Detailed analysis ................................................................................................................46
 

Conclusions........................................................................................................................59
 

Key Question 4. Does the effect of iNO therapy on BPD and/or death or 

neurodevelopmental impairment vary across subpopulations of premature infants? ........60
 

Major findings....................................................................................................................60
 

Detailed analysis ................................................................................................................60
 

Conclusions........................................................................................................................68
 

Key Question 5. Does the effect of iNO therapy on BPD and/or death or 

neurodevelopmental impairment vary by timing of initiation, mode of delivery, 

dose and duration, or concurrent therapies? ......................................................................68
 

Major findings....................................................................................................................68
 

Detailed analysis ................................................................................................................69
 

Conclusions........................................................................................................................77
 

Chapter 4. Discussion ....................................................................................................................79
 

Chapter 5. Future Research Needs.................................................................................................87
 

Other Future Research Needs ..................................................................................................87
 

References and Included Studies ...................................................................................................89
 

Figures 

Figure 1: Analytic framework .................................................................................................15
 

Figure 2. Summary of literature search (number of articles) ..................................................20
 

Figure 3. Summary of risk of bias for RCTs ...........................................................................21
 

Figure 4. Meta-analysis of studies describing death at 36 weeks PMA or in the NICU .........28
 

Figure 5. Meta-analysis of studies describing death at 36 weeks PMA or in the NICU 

without Ballard, 2006..........................................................................................................29
 

Figure 6. Meta-analysis of studies describing BPD at 36 weeks PMA among survivors .......31
 

Figure 7. Meta-analysis of studies describing death or BPD at 36 weeks PMA .....................35
 

Figure 8. Meta-analysis of studies describing death or BPD at 36 weeks PMA without
 

Ballard, 2006.......................................................................................................................36
 

Figure 9. Meta-analysis of studies describing brain injury......................................................41
 

Figure 10. Meta-analysis of death at followup after NICU discharge....................................48
 

Figure 11. Meta-analysis of severe CP ..................................................................................50
 

Figure 12. Meta-analysis of cognitive development as measured by the Bayley Scales Mental 

Developmental Index below 70. .......................................................................................51
 

Figure 13. Meta-analysis of visual impairment .......................................................................53
 

Figure 14. Meta-analysis of hearing impairment.....................................................................54
 

Figure 15. Meta-analysis of studies reporting NDI .................................................................56
 

viii 
 

 

 

 

 

 

Figure 16. Meta-analysis for dose-stratified death, including only studies that reported 

death in the NICU at 36 weeks PMA or later .....................................................................73
 

Figure 17: Meta-analysis for dose-stratified BPD at 36 weeks PMA......................................74
 

Figure 18: Meta-analysis for dose-stratified death or BPD .....................................................75
 

Summary Tables 

Table 1. Included articles.........................................................................................................22
 

Table 2. Summary of outcomes for RCTs addressing KQ1 ....................................................24
 

Table 3. Study design of randomized controlled trials of inhaled nitric oxide in preterm 

infants.................................................................................................................................26
 

Table 4. Summary of outcomes for RCTs addressing KQ2 ....................................................38
 

Table 5. Meta-analyses of short-term risks of iNO therapy.....................................................43
 

Table 6. Summary of outcomes for RCTs addressing KQ3 ....................................................47
 

Table 7. Studies addressing death and/or survival beyond the NICU .....................................47
 

Table 8. Studies addressing neurodevelopmental impairment ................................................55
 

Table 9. Summary of outcomes for RCTs addressing KQ4 ....................................................62
 

Table 10. Summary of outcomes for RCTs addressing KQ5 ..................................................70
 

Table 11. Strength of evidence for articles addressing Key Question 1..................................81
 

Table 12. Strength of evidence for articles addressing Key Question 2..................................81
 

Table 13. Strength of evidence for articles addressing Key Question 3 .................................82
 

Table 14. Strength of Evidence for articles being addressed by Key Question 4....................82
 

Table 15. Strength of Evidence for articles being addressed by Key Question 5....................83
 

Table 16. Summary of the meta-analyses................................................................................83
 

Appendixes 

Appendix A: List of Acronyms
 

Appendix B: Detailed Search Strategies
 

Appendix C: Screen and Data Abstraction Forms
 

Appendix D: Excluded Articles
 

Appendix E: Evidence Tables
 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf. 

ix 
 

 

 

 

 

 

Executive Summary 

Background 

Neonatal lung disease is the most common complication of preterm delivery and causes 

significant morbidity and mortality. Disorders of prematurity and respiratory distress are among 

the leading causes of infant mortality in the U.S. 

The use of inhaled nitric oxide (iNO) has been approved by the U.S. Food and Drug 

Administration for respiratory failure of the term and near-term infant and is recommended by 

professional societies, such as the American Academy of Pediatrics. Evidence supporting the use 

of iNO in term or near term infants is summarized by a Cochrane review that found that use of 

iNO therapy reduced the need for extracorporeal membrane oxygenation in term and near term 

(> 34 weeks gestation) infants with respiratory failure, but did not change neurodevelopmental 

outcomes at two to three years of age. There is a need to consider the evidence about the use of 

iNO therapy in preterm infants < 34 weeks of gestation. 

This report summarizes the available evidence on the use of iNO in preterm infants born at or 

before 34 weeks gestation age who receive respiratory support. The report addresses the 

following questions: 

1.	 Does iNO therapy increase survival and/or reduce the occurrence or severity of 

bronchopulmonary dysplasia (BPD) among premature infants who receive respiratory 

support? 

2.	 Are there short-term risks of iNO therapy among premature infants who receive respiratory 

support? 

3.	 Are there effects of iNO therapy on long-term pulmonary and/or neurodevelopmental 

outcomes among premature infants who receive respiratory support? 

4.	 Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary 

across subpopulations of premature infants? 

5.	 Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary 

by timing of initiation, mode of delivery, dose and duration, or concurrent therapies? 

1
 
 

Methods 

We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Studies 

(CENTRAL) and PsycInfo in June 2010. We also searched the proceedings of the 2009 and 2010 

Pediatric Academic Societies Meeting and ClinicalTrials.gov. We identified additional studies 

from reference lists of eligible articles and relevant reviews, as well as from technical experts. 

Questions were developed in collaboration with technical experts, including the chair of the 

upcoming National Institutes of Health Office of Medical Applications of Research Consensus 

Development Conference. We limited our review to randomized controlled trials (RCTs) for the 

question of survival or occurrence of bronchopulmonary dysplasia (BPD) and for the question on 

short-term risks. All study designs were considered for long-term pulmonary or 

neurodevelopmental outcomes, and for questions about whether outcomes varied by 

subpopulation or by intervention characteristics. Two investigators independently screened 

search results, and abstracted data from eligible articles. 

Results 

We identified a total of 14 RCTs, reported in 23 articles, and eight cohort studies addressing 

our questions. Our major findings are summarized by key question. 

Key Question 1. Does iNO therapy increase survival and/or reduce the occurrence or 

severity of bronchopulmonary dysplasia (BPD) among premature infants who receive 

respiratory support? 

●	 There is no statistically significant effect of iNO compared to placebo on survival or 

mortality rates in preterm NICU infants requiring mechanical ventilation. 

●	 There is insufficient evidence to determine whether iNO reduces the rate of 

bronchopulmonary dysplasia (BPD), as defined by requiring supplemental oxygen at 36 

weeks postmenstrual age, in preterm NICU infants requiring mechanical ventilation. 

●	 There is small but statistically significant reduction in the composite variable of death or 

BPD at 36 weeks PMA for infants treatment with iNO compared to infants in control 

groups. 

●	 Preterm infants who required mechanical ventilation and were the subjects of randomized 

controlled trials of inhaled nitric oxide were a high risk population with high mortality 

and BPD rates during NICU hospitalization. 

Fourteen RCTs addressed death or BPD. The definition of outcomes, specifically the time 

outcomes were assessed, differed across studies. Evidence on the outcome of death was 

considered of moderate strength as was BPD at 36 weeks PMA. 

Key Question 2. Are there short-term risks of iNO therapy among premature infants who 

receive respiratory support? 

●	 There is insufficient evidence of a neuroprotective effect of iNO in preterm infants. 

●	 There is no evidence that treatment of preterm infants with iNO influences the rates of 

other complications of prematurity, including patent ductus arteriosus (PDA), sepsis, 

2
 
 

 

 

necrotizing enterocolitis (NEC), severe retinopathy of prematurity (ROP), pulmonary 

hemorrhage, or air leaks. 

●	 No study reported accumulation of toxic levels of methemoglobin or nitrogen dioxide. 

Fourteen RCTs provided data on short term risks of iNO therapy. There was moderate 

strength of evidence on IVH, PVL, PVL, PDA and NEC. 

Key Question 3. Are there effects of iNO therapy on long-term pulmonary and/or 

neurodevelopmental outcomes among premature infants who receive respiratory support? 

●	 There is insufficient evidence to determine whether iNO therapy in preterm infants who 

require respiratory support influences the incidence of cognitive, motor or sensory 

impairments, or neurodevelopmental disability. 

●	 There is evidence suggesting that iNO therapy in preterm infants who require respiratory 

support may decrease the need for respiratory medications at one year of age. 

●	 There is insufficient evidence to determine whether iNO therapy in preterm infants who 

require respiratory support impacts long-term health outcomes such as respiratory 

symptoms, rehospitalization after NICU discharge, and growth. 

Twelve articles reported long term outcomes; nine RCTs and three observational studies. 

Evidence was considered to be of low strength for neurodevelopmental and coginitive outcomes 

and for cerebral palsy. Evidence for death as a long term outcome was moderate. Evidence on all 

of the other long term outcomes was considered low or insufficient. 

Key Question 4. Does the effect of iNO therapy on BPD and/or death or 

neurodevelopmental impairment vary across subpopulations of premature infants? 

●	 There is insufficient evidence to determine whether the effect of iNO therapy on 

mortality, BPD, or motor impairment differs by the birth weight of the treated infants. 

●	 There is insufficient evidence to evaluate the relationship between iNO therapy and infant 

sex, race/ethnic group, gestational age, or socioeconomic status. 

●	 There are no published data available to evaluate the association between iNO therapy 

and, antenatal steroids, chorioamnionitis, multiple birth, or growth restriction. 

●	 There is insufficient evidence concerning the relationship between iNO therapy and the 

severity of illness. 

●	 There is insufficient evidence that iNO therapy improves outcome of infants suffering 

respiratory failure from pulmonary hypoplasia, respiratory distress syndrome or 

pulmonary hypertension. 

●	 There is no consistent pattern of infants that respond to iNO therapy and those that do 

not. 

●	 There is no consistent pattern of infants that respond to iNO therapy and those that do 

not. 

We identified six RCTs with five followup studies, and six other studies, that addressed this 

question. The definition of outcomes varied across studies, and many of the subgroup analyses 

were by post hoc analyses. Death, BPD at 36 weeks PMA and survival without BPD had 

3
 
 

 

moderate strength of evidence. All other outcomes for this question had evidence judged to be 

low strength. 

Key Question 5. Does the effect of iNO therapy on BPD and/or death or 

neurodevelopmental impairment vary by timing of initiation, mode of delivery, dose and 

duration, or concurrent therapies? 

●	 There is insufficient evidence to determine if initiating iNO therapy for acute respiratory 

distress at < 3 days reduces the risk of death or bronchopulmonary dysplasia (BPD) at 36 

weeks PMA, or death and neurodevelopmental disability at 1 year of age, corrected for 

gestational age at birth. 

●	 In infants with developing BPD, there is insufficient evidence to determine if treatment 

with iNO during the second week after birth improves survival without BPD compared 

with treatment during the third week after birth. 

●	 There is insufficient evidence to determine the effect of delivery of iNO by high 

frequency ventilation on either death or BPD, or neurodevelopmental outcome compared 

with conventional ventilation. 

●	 There is insufficient evidence to support an optimal dose of iNO or duration of exposure 

to improve outcome or prevent harm. 

●	 There is insufficient evidence to determine the effect of iNO with concurrent therapy. 

We identified 14 RCTs addressing this question. No studies allowed for assessment of 

duration of therapy. Comparison across studies was limited by differences in definitions of 

outcomes. All but two of the studies provided data based on post hoc analysis, and so should be 

interpreted with caution. Strength of evidence was moderate for survival without BPD and BPD 

at 36 weeks. For all other outcomes, evidence was low strength. 

Future Research 

Current evidence does not support the routine use of iNO to treat premature infants. 

However, we should not abandon the possibility that iNO may someday become a component of 

a treatment strategy for some preterm infants receiving respiratory support. Several factors 

contribute to our recommendation to continue the study of iNO: 1) our finding a small but 

statistically significant difference in death or BPD at 36 weeks PMA, the common primary 

outcome variable of 73% of RCT conducted to-date; 2) the statistically significant finding of a 

diminished need for chronic pulmonary medication at one year corrected age, suggesting less 

severe lung disease in those treated with iNO, and 3) no studies have been powered to detect 

meaningful differences in infant functional outcome or quality of life with iNO treatment 

compared to standard therapy. 

Specific considerations for future research are listed below. 

Patients 

RCTs must be adequately powered to assess the effect of iNO on subgroups of preterm 

infants, such as those of varying birth weight. 

4
 
 

Special care must be taken if infants born at the limit of viability are included in RCTs. 

These infants do not yet have alveoli (gas exchange occurs through their terminal 

bronchioles) and their brains do not yet have gyri or sulci. They are most vulnerable to 

organ injury, which may be most evident on long-term follow-up. Every effort must be 

taken to obtain pulmonary, neurodevelopmental and health follow-up for all infants in 

this category. 

There may be a value to viewing the use of iNO in terms of postmenstrual age, which is a 

better measure of degree of maturation and takes into account both gestational age and 

chronologic age in developing preterm infants. 

Intervention 

Since the goal is to support pulmonary and brain development in the NICU, courses of 

iNO given for weeks, not days, should be studied. 

Mode of ventilation should be considered in randomization schemes for trials restricted to 

infants < 1500 grams, those at highest risk for death, BPD and neurodevelopmental 

impairment, to adequately address the question concerning mode of delivery. 

As many of the smallest preterm infants are managed with CPAP or high flow nasal 

cannula alone, without intubation, information concerning iNO delivery with these 

devices is needed. 

Outcomes 

Future RCTs should require neuroimaging by standardized protocols before trial 

enrollment, to detect the occurrence and progression of brain injury during iNO 

treatment. 

Studies should be powered to assess long term neurodevelopmental, pulmonary and other 

health outcomes. 

Outcomes should focus on functional status and quality of life, as well as 

neurodevelopmental disabilities. 

Studies are needed to provide information on resource utilization such as 

rehospitalizations, medications, physicians’ visits. Future focus should be on the real 

pulmonary problems of prolonged hospitalizations, use of supplemental oxygen and 

pulmonary medications after NICU discharge, prevalence of reactive airway disease and 

recurrent hospitalizations. 

Consideration should be given to assess longer term childhood outcomes (e.g., pulmonary 

function tests, school performances). 

Cost benefit analyses should be conducted with multicenter RCTs of iNO. 

5
 
6
 
Evidence Report
 

7
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chapter 1. Introduction 

Background 

Neonatal lung disease is the most common complication of preterm delivery, and results in 

significant morbidity and mortality.1 Preterm infants suffer from both acute and chronic 

respiratory failure as a result of anatomic and biochemical disruption of lung function, lung 

inflammation and oxidative stress, nutritional deficiencies, and arrest of tracheobronchial and 

pulmonary vascular growth (see Appendix Aa

, List of Acronyms). Treatment for acute 

respiratory failure often contributes to evolving bronchopulmonary dysplasia (BPD) and chronic 

respiratory failure, due to barotrauma and oxygen toxicity from prolonged respiratory support, 

deficient nutrition, as well as immaturity of lung growth, vascular development and immunologic 

defenses. Pulmonary hypertension may occur in association with acute and/or chronic respiratory 

failure.2 Multiple etiologies make finding an effective treatment for respiratory failure in preterm 

infants challenging. Disorders related to prematurity and respiratory distress are among the 

leading causes of infant mortality in the U.S.3 

Treatment Options 

Treatment options for respiratory failure in preterm infants include a variety of modalities. 

Prenatal steroids, antibiotics, exogenous surfactant replacement, tidal volume ventilation, 

conventional ventilation, continuous positive airway pressure, high flow oxygen administration, 

and high frequency ventilation are all used as therapeutic modalities. Treatment of preterm 

infants with inhaled nitric oxide (iNO) as a rescue therapy for refractory hypoxemic respiratory 

failure is an extension of the relative success of the treatment of term and near term infants with 

iNO.4 

Mechanism of Action 

Endogenous nitric oxide (NO), produced in vascular endothelial cells, regulates vascular 

tone. 5 NO diffuses into adjacent vascular smooth muscle cells and activates soluble guanylyl 

cyclase, leading to the activation of cGMP-dependent protein kinase.6 The subsequent signal 

6, 7 transduction cascade results in vascular smooth muscle cell relaxation and vasodilatation.

When exogenous nitric oxide is inhaled, it is a selective pulmonary vasodilator decreasing 

pulmonary vascular resistance without affecting systemic vascular tone.8 This occurs because the 

low molecular weight and high lipid solubility of inhaled NO allows rapid diffusion in the 

ventilated lung from the alveoli to direct contact with arterioles.9 In addition, NO has a very short 

5, 10 half-life, and NO is rapidly deactivated by heme in hemoglobin reducing its effect on other 

11, 12 smooth muscle in the body.

Since 1999, iNO has been approved by the U.S. Food and Drug Administration (FDA) for 

the treatment of severe hypoxemia and persistent pulmonary hypertension of the newborn 

a Appendixes and evidence tables for this report can be found at: 

http://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf 

9
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

(PPHN) in term and near term infants.13 PPHN is a syndrome associated with several neonatal 

cardio pulmonary etiologies, and is characterized by high pulmonary vascular resistance (PVR).7 

High PVR causes extrapulmonary shunting of blood right to left across the ductus arteriosus 

7, 14 and/or foramen ovale and may cause critical hypoxemia. In newborns, the use of iNO therapy 

to selectively lower PVR and reduce extrapulmonary shunting accounts for the acute 

improvement in oxygenation observed with PPHN.15 

In severe respiratory failure, hypoxemia may also occur with intrapulmonary shunting, due to 

atelectasis and ventilation/perfusion inequality.7 Thus, inhaled nitric oxide may also benefit 

preterm infants with parenchymal lung disease by redistributing pulmonary blood flow, thereby 

reducing intrapulmonary shunting and ventilation: perfusion mismatching.16 Both mechanisms 

reduce secondary lung injury from barotrauma, volutrauma, and oxygen toxicity by reducing the 

need for prolonged respiratory support. 

Inhaled NO may have other characteristics beneficial to preterm infants. Ballard, 2006 

demonstrated that iNO therapy in a preterm baboon model of evolving BPD increased maximal 

lung volume, decreased the total protein:phospholipid (PL) ratio of surfactant, and had little 

effect on the composition of surfactant PL or proteins, suggesting that iNO may be associated 

with less severe lung injury and improved surfactant function.17 In a companion study, again in a 

premature baboon model, McCurnin, 2005 reported lung growth after iNO therapy mimicked 

that seen in utero.18 Inhaled NO has also been shown to reduce inflammation and oxidant injury 

19, 20 in animal models of hyperoxic lung injury. Furthermore, NO may play a role in early lung 

development. A newborn rat model with both structural and functional characteristics of BPD21 

showed a reduction in pulmonary hypertension and a preservation of lung growth with early 

introduction of iNO therapy.21 Similarly, following exposure to hyperoxia in neonatal rats, Lin, 

2005 found that iNO exposure during recovery restored distal lung growth and alveolarization.22 

Inhaled NO has several potential toxic complications from both direct and indirect effects.23 

The preterm infant is particularly vulnerable to reactive oxidant species induced damage due to 

the relative inadequacy of antioxidant enzymes in the lung.24 In the presence of oxygen, nitric 

oxide forms nitrogen dioxide (NO2), a potent inflammatory agent leading to pulmonary edema 

11, 25 and lung injury, but the formation is slow at low levels of NO2. A NO2 dose of 5 ppm is 

considered the maximum environmentally safe dose, necessitating careful monitoring of infants 

receiving iNO therapy.26 In simulation, delivery of 20 ppm iNO at high oxygen concentrations 

resulted in the formation of < 1 ppm NO2. NO may also adversely affect platelet aggregation and 

27 28 adhesion, although the evidence is conflicting and has not been reported in trials with infants. 

Methemoglobinemia, the resultant reaction of nitric oxide with hemoglobin, reduces oxygen 

carrying capacity at high concentrations. Accumulation of toxic levels of methemogolobin have 

not been demonstrated when iNO is delivered at < 80ppm,29 the range in which most infants are 

treated, but requires constant monitoring during treatment. 

FDA Approved Indication and Usage 

The U.S. FDA approved iNO for use in intubated full term and late preterm infants with 

hypoxemic respiratory failure in 199913 Current labeling of iNO is for use in respiratory failure 

in term and near term infants (> 34 weeks gestation). The initial recommended starting dose for 

these infants is 20 ppm with continued use for 14 days or until improvement in the underlying 

disease process results in normal oxygen saturations. The dose is weaned incrementally with 

improving oxygen saturations beginning as soon as four hours after the initiation of therapy, to 5 

10
 
 

 

 

 

 

 

ppm before discontinuation. For infants that do not respond to initial iNO therapy, the dose may 

be increased to 40 to 80 ppm. Brief exposure to these higher doses appears to be safe, but 

sustained treatment with 80 ppm will increase the risk of methemoglobinemia,7 with little added 

clinical benefit. 

Utilization of iNO 

Since the FDA approval for use of iNO in full term and late preterm infants, a number of 

studies have been conducted on the use of iNO in clinically diverse populations of preterm 

30-40 infants. These studies demonstrate significant variability in their clinical indications for the 

use of iNO, from its prophylactic use in preterm infants with mild acute respiratory distress to 

prevent BPD and chronic lung disease, to its use as a late rescue therapy for preterm infants with 

severe BPD, with resulting wide variations in inclusion and exclusion criteria for study samples. 

There has been considerable variation in dosage and timing of iNO among studies. Differing 

findings regarding pulmonary effects and effects on the most common primary outcome variable, 

death or BPD, raises concerns about gaps in our understanding of physiological effects of iNO in 

the rapidly developing preterm lung. In addition, differences in the direction of effect on the 

developing preterm brain raise questions as to whether treatment of preterm infants with iNO 

increases or decreases the incidence of brain injury. 

This controversy has resulted in wide variations in clinical practice, as reports of the longer 

term pulmonary and neurodevelopmental outcomes at ages two to six years are just emerging. 

Purpose of This Evidence Report 

Inhaled NO has demonstrated efficacy in improving oxygenation and reducing the need for 

extracorporeal membrane oxygenation (ECMO) in late preterm infants born after 34 weeks 

gestation and full term infants with respiratory failure, with no evidence of long term benefits.4 

Despite the approved use of iNO in full term and late preterm infants, the developmentally 

distinct mechanisms of respiratory failure and differing cardiovascular, pulmonary, and 

pharmacokinetic characteristics of more immature infants require systematic study of the short 

and long term outcomes for preterm infants treated with iNO to prevent or treat respiratory 

failure. 

A 2006 meta-analysis included five randomized controlled trials (RCTs) with 808 infants 

born before 34 weeks gestation.32 The authors concluded that while preterm infants treated with 

iNO had reduced treatment failure (death or chronic lung disease (CLD); RR 0.81 (0.70, 0.93)) 

further research was needed on risks and on later neurodevelopmental outcomes. A 2007 

Cochrane review of 11 RCTs analyzed data on 3,251 preterm infants (defined as < 35 weeks 

gestation) in terms of illness severity, dose and timing of iNO. 31 The Cochrane review 

concluded that iNO has no proven efficacy as a rescue therapy to treat very ill ventilated preterm 

infants, and it may increase the incidence of brain injury (one trial was stopped early).31 It did 

not appear to prevent chronic lung disease or BPD in preterm infants. Subgroup analyses in some 

of the multicenter RCTs of iNO in preterm infants suggest that iNO may be beneficial in some 

preterm infants (e.g., those with higher birth weights, milder respiratory illness, or persistent 

32, 40-42 pulmonary hypertension).

The Cochrane review acknowledged very limited data on long term outcomes of preterm 

infants treated with iNO. If iNO is beneficial, the number need to treat would be very large. 

11
 
 

 

 

 

 

Papers published or presented from 2007 to present report conflicting results as to whether, in 

preterm infants, iNO has beneficial, adverse, or no effects on long term neurodevelopmental and 

30, 43-46 pulmonary outcomes.

Despite the ongoing controversy, iNO continues to be used for hypoxemic respiratory failure 

in preterm infants < 34 weeks gestation even with potential harm to the developing lungs and 

brain.47 There is an urgent need to weigh the current evidence as to whether iNO is a safe and 

effective treatment in preterm infants. 

The Office of Medical Applications of Research (OMAR) at the National Institutes of Health 

(NIH) scheduled an NIH Consensus Development Conference: Inhaled Nitric Oxide in Preterm 

Infants to be held in October 2010. The Evidence-based Practice Center at the Johns Hopkins 

University (JHU) was asked by OMAR and the Agency for Healthcare Research and Quality 

(AHRQ) to prepare an evidence report for this conference. 

Key Questions 

We sought to identify and synthesize evidence addressing the following questions: 

1.	 Does inhaled nitric oxide (iNO) therapy increase survival and/or reduce the occurrence or 

severity of bronchopulmonary dysplasia (BPD) among premature infants who receive 

respiratory support? 

2.	 Are there short term risks of iNO therapy among premature infants who receive respiratory 

support? 

3.	 Are there effects of iNO therapy on long term pulmonary and/or neurodevelopmental 

outcomes among premature infants who receive respiratory support? 

4.	 Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary 

across subpopulations of premature infants? 

5.	 Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary 

by timing of initiation, mode of delivery, dose and duration, or concurrent therapies? 

For the purposes of our review, we sought studies that included infants less than or equal to 

34 weeks gestation age. The outcomes of interest are described in detail in Chapter 2. 

12
 
 

 

Chapter 2. Methods 

Our objective was to review and synthesize the evidence on the use of inhaled nitric oxide 

(iNO) in preterm infants born at or before 34 weeks gestation age who require respiratory 

support. This review addresses the short term outcomes bronchopulmonary dysplasia, 

cardiopulmonary risks, infectious risks, neurological risks, as well as short term survival and 

death. Long term outcomes including pulmonary outcomes, neurodevelopmental outcomes, 

growth, chronic medical conditions, and survival to childhood were also assessed. The results of 

this report will be presented to an NIH Consensus Panel in October 2010. 

Topic Development 

The core team worked with technical experts, the NIH Consensus Panel Chair, to develop 

and refine the Key Questions that are presented in Chapter 1 (Introduction). Prior to searching 

for literature, we clarified the definitions of these key questions and the types of evidence which 

we would include in our review. Topic development was facilitated by the results of preliminary 

searches, discussions among team members, and input from our Technical Expert Panel. 

Key Questions 1 and 2 address short term impact of iNO use on preterm infants. Key 

Question 1 addresses the impact of iNO on survival and/or bronchoplulmonary dyplasia. Key 

Question 2 addresses short term risks to preterm infants receiving iNO therapy. Based on 

discussion with our experts, we decided to limit our review to randomized controlled trials for 

these two questions. 

Key Question 3 addresses long term outcomes of iNO use in preterm infants. This question 

focuses on pulmonary and neurodevelopmental outcomes. We did not limit the consideration of 

studies by study design. We identified, and abstracted separately case reports and case series. 

However, we ultimately chose not to include case reports and case series in our formal review as 

the level of detail in these reports was generally insufficient. 

The impact of iNO therapy on bronchopulmonary dyplasia, death, and/or 

neurodevelopmental outcomes across subpopulations of premature infants is addressed in Key 

Question 4, and influence of the timing of initiation, mode of delivery, dose and duration, or 

concurrent therapies is addressed in Key Question 5. Included studies for this question were not 

limited by study design except for the exclusion of case reports and case series, as for Key 

Question 3. 

Analytic Framework 

We developed a framework (Figure 1) to illustrate the components of the key questions, 

including the population, intervention and outcomes. The framework also delineates the 

subgroups; treatment characteristics, such as dose of iNO; and specific short and long term 

outcomes of interest. Short term outcomes were defined as adverse events and clinical outcomes 

associated with iNO treatment that occur during the initial hospitalization after birth. Long term 

outcomes were defined as the effects of iNO treatment on infant health and functional outcome 

in early childhood and include measures of chronic pulmonary disease, growth, developmental 

delay and disability, and survival. 

13
 
 

 

 

 

 

 

 

 

 

Search Strategy
 

Searching the literature involved identifying reference sources, formulating a search strategy 

for each source, and executing and documenting each search. For the searching of electronic 

databases we used controlled vocabulary terms (i.e., MeSH, EMTREE), combined with text 

words for iNO (see Appendix Bb, Detailed Search Strategies) We also looked for eligible studies 

by reviewing the references in pertinent reviews, by scanning conference proceedings, by 

querying our experts, and through knowledge shared at core team meetings. 

Sources 

Our search included electronic and hand searching. On November 9, 2009, we ran searches 

of MEDLINE® (using PubMed), EMBASE®, the Cochrane Central Register of Controlled 

Studies (CENTRAL), and PsycInfo databases. These searches were run again on June 23, 2010. 

We also searched the references of articles included in this study and those tagged as of interest 

during the screening process. As information on long term outcomes for infants treated with iNO 

is just emerging, we also scanned the proceedings of the Pediatric Academic Societies Meetings 

in 2009 and 2010. ClinicalTrials.gov was searched for ongoing or completed trials. Investigators 

of ongoing trials were not contacted for information. We decided that the investigators 

conducting ongoing trials would only be contacted if they were studying outcomes with no 

published information. There were no limits used in the searches, including any based on 

publication date. 

Search Terms and Strategies 

We developed a strategy for MEDLINE, accessed via PubMed, based on an analysis of the 

MeSH terms and text words of key articles identified a priori. The PubMed strategy formed the 

basis for the strategies developed for the other electronic databases (see Appendix B). 

Organization and Tracking of the Literature Search 

The results of the searches were downloaded into ProCite® version 5.0.3 (ISI ResearchSoft, 

Carlsbad, CA). Duplicate articles retrieved from the multiple databases were removed prior to 

initiating the review. From ProCite, the articles were uploaded to Distiller SR © (Evidence 

Partners, Ottawa, Ontario). We used this software to store full articles in portable document 

format (PDF) and to track the results of the abstract screen, article screen, and data abstraction. 

b Appendixes and evidence tables for this report can be found at: 

http://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf 

14
 
Figure 1. Analytic framework 

15 
 

 

 

 

 

 

Study Selection
 

Abstract Screen
 

Each abstract was independently screened by two reviewers. An abstract was excluded at this 

level if it did not reporting any original data, did not include human data, did not include infants 

born at less than or equal to 34 weeks of gestation, did not include preterm infants requiring 

respiratory support, did not include preterm infants treated with inhaled nitric oxide, did not 

address any of the key questions, or addressed Key Question 1 and or 2 but was not a 

randomized controlled trial. An option was provided for reviewers to indicate other reasons for 

exclusion. Articles tagged as non English were reviewed by individuals fluent in the language of 

publication to determine eligibility. (Appendix C, Abstract Review Form). 

Abstracts were promoted to be screened using full text article if both reviewers agreed that 

the abstract could apply to one or more of the key questions. An abstract could be excluded for 

different reasons by the two reviewers. Disagreements about the eligibility of an abstract were 

resolved by discussion between the two reviewers or by adjudication of a third reviewer. 

Article Screen 

Full text articles underwent another independent review by paired investigators to determine 

whether they should be included in the full data abstraction (see Appendix C, Article 

Inclusion/Exclusion Form). If articles were deemed to have applicable information, they were 

included in the data abstraction. Articles could be excluded at this level for the same set of 

reasons used at the abstract screen level with an additional exclusion criterion of no abstractable 

data. Articles that had English language abstracts that were promoted to this level but were 

tagged for exclusion as “not English language” were reviewed by investigators fluent in the 

specific language for eligibility. 

Articles were promoted to data abstraction if both reviewers agreed. An article could be 

excluded for different reasons by the two reviewers. Disagreements about the eligibility of an 

article were resolved by discussion between the two reviewers or by adjudication of a third 

reviewer. 

Data Abstraction 

We used an independent review process to abstract data from the included articles. In this 

process, both a clinical expert and a research assistant completed all relevant data abstraction 

forms independently. Reviewers were not masked to the articles’ authors, institutions, or 

journal.48 Disagreements that could not be resolved between the reviewers were resolved through 

consensus adjudication at team meetings. 

For all articles, reviewers extracted information on general study characteristics: study 

design, whether the study was a followup or additional analysis of another study, location, 

recruitment start and end dates, inclusion and exclusion criteria, description of the study 

intervention, iNO dose and duration, and length of followup (see Appendix C, Study 

16
 
 

 

 

 

 

 

 

 

 

Characteristics Form). Participant characteristics were also abstracted: number of participants, 

gestational age, birth weight, participant age, sex, and relevant background data such as disease 

severity, mode of ventilation, and concurrent medications. Maternal characteristics were also 

collected on this form (see Appendix C, Participant Characteristics Form). 

Reviewers abstracted data, for all study arms and subgroups, on a predefined set of outcomes 

(see Appendix C, All Outcomes). Case reports were abstracted separately to identify whether 

they included data relevant to this study (see Appendix C, Case report form). These data were 

ultimately not included as the level of detail in these reports was generally insufficient. 

Quality Assessment of Individual Studies 

(Risk of Bias Assessment) 

In order to assess the risk of bias in randomized controlled trials, we used the Cochrane 

Collaboration Tool for Assessing Risk of Bias from the Cochrane Handbook for Systematic 

Reviews of Interventions.49 This tool was used to assess six categories of potential bias; (1) 

sequence generation, (2) allocation concealment, (3) blinding, (4) incomplete data reported, (5) 

selective reporting bias as well as (6) other sources of bias. For each bias category reviewers 

answered one or more questions and entered “Yes” for a low risk of bias, “No” for a high risk of 

bias or “Unclear.” 

For the observational studies we adapted the Newcastle-Ottawa Scale in order to determine 

the risk of bias of the reported data in both cohort and case control studies.50 This form assessed 

possible sources of bias including (1) representativeness of the study cohort, (2) selection of the 

control cohort (if applicable), (3) selection of treated patients, (4) presence of the outcome of 

interest at the start of the study, (5) comparability of the cohorts, (6) reporting bias, (7) whether 

the followup was long enough for outcomes to occur, and (8) incomplete data reported. Similar 

to the risk of bias forms for randomized control trials, we used question based forms where 

reviewers entered “Yes” for a low risk of bias, “No” for a high risk of bias or “Unclear” for 

questions about each source of bias. 

The risk of bias forms were completed independently by paired reviewers. In the case of a 

disagreement, the two original reviewers conferred and agreed upon a single answer. These 

assessment instruments are included in Appendix C, Risk of Bias Forms. 

Grading of the Body of Evidence 

At the completion of our review, we assessed the quantity, quality and consistency of the 

body of available evidence addressing Key Questions 1 through 5. We used an evidence grading 

scheme recommended by the GRADE Working Group, and adapted by AHRQ in their Draft 

51 52 Methods Guide, and recently published in the Journal of Clinical Epidemiology. We 

considered the strength of the study designs with randomized controlled trials as the highest level 

of evidence, followed by observational studies. If an outcome was evaluated by at least one 

randomized controlled trial as well as observational studies our evidence grade was based on the 

randomized controlled trials and followed by the quality of the cohort studies. If an outcome was 

17
 
 

 

 

 

evaluated by one or no randomized controlled trials, our evidence grade was based on the single 

randomized controlled trial in addition to the best available observational study. 

We assessed the quality and consistency of the best available evidence, including assessment 

of the risk of bias in relevant studies, as well as aspects of consistency, directness, and precision 

51 52 as described in the Draft Methods Guide and Owens, 2010.

For each outcome of interest, two investigators graded the major outcomes for each Key 

Question and then the entire team discussed their recommendations and reached consensus. 

Data Synthesis 

We created a set of detailed evidence tables containing information extracted from eligible 

studies. We stratified the tables according to applicable key question. Once evidence tables were 

created, we rechecked selected data elements against the original articles. If there was a 

discrepancy between the data abstracted and the data appearing in the article, this discrepancy 

was brought to the attention of the investigator in charge of the specific data set and the data 

were corrected in the final evidence tables. 

Meta-analyses were completed using MetaAnalyst. The program was developed by the Tufts 

Evidence-based Practice Center under contract with AHRQ.53 The analyses were performed 

using a Der-Simonian Laird random effects model.54 In this program, a Woolf-Haldane 

continuity correction of 0.5 was used when a cell contained zero events.55 In all analyses, we 

examined the risk ratio for each outcome. Sensitivity analyses were performed to determine 

stability of the results. In general, meta-analyses were completed for outcomes reported across 

more than one study where the definition and measurement of the outcome was determined to be 

similar. Where relevant, further details regarding the decision to conduct or not conduct metaanalyses, the inclusion and exclusion of articles from the meta-analysis, and any sensitivity 

analyses, are provided in the results section. 

Peer Review 

We recruited external technical experts from diverse professional backgrounds, including 

neonatology, pulmonology, cardiology, and neurodevelopment. The technical experts were asked 

for input regarding key steps of the process, including development of the analytic framework, 

outcomes, and search strategies. In addition to the technical experts, three peer reviewers were 

recruited from various clinical and methodological settings. 

Throughout the project, the core team sought feedback from the external technical experts 

and the NIH Panel Chair. A draft of the report was sent to the technical experts and peer 

reviewers, as well as to representatives of AHRQ, and the NIH Office of Medical Applications 

Research Panel Chair for this project. In response to the comments from the technical experts 

and peer reviewers, we revised the evidence report and submitted a summary of the comments 

and their disposition. 

18
 
 

 

 

 

 

 

 

 

 

 

Chapter 3. Results 

Literature Search/Abstract/Article Review 

The literature search process identified 3104 unique citations. During the abstract review 

process, we excluded 2650 citations that did not meet one or more of the eligibility criteria (see 

Chapter 2 for details). At article review, we excluded an additional 423 articles that did not meet 

one or more of the eligibility criteria (see Appendix Dc, Excluded Articles). Thirty-one articles 

were eligible for inclusion in the review. There were 14 RCTs described in 23 articles, and eight 

observational studies (Figure 2). 

Description of the Types of Studies Retrieved 

There were 14 articles that applied to Key Question 1. Fourteen articles (all RCTs) applied to 

Key Question 2. Twelve articles applied to Key Question 3; three original RCTs with six 

followup studies, and three observational studies. Seventeen articles applied to Key Question 4; 

six RCTs with four followup studies, and seven cohort studies. Twenty-one articles applied to 

Key Question 5; 14 RCTs with seven followup studies (Table 1). Eight studies containing 13 

case reports were also examined. As mentioned in Chapter 2, we reviewed the case reports and 

determined that the data were not of sufficient detail to be considered further. 

Risk of Bias 

As described in Chapter 2, we assessed each individual study for risk of bias using a study 

design specific tool. (See Appendix E, Evidence Tables 1 and 2.) 

The RCTs and their followup studies were not assessed separately for risk of bias. Six of the 

30, 34, 36, 14 RCTs (along with their five followup studies) were assessed as having low risk of bias.

37, 39, 40, 44, 56, 57, 58, 59 60-62 Three of the RCTs were determined to be at fair risk of bias. The 

63-67 remaining five RCTs were assessed as having a high risk of bias. Figure 3 provides a 

summary of the risk of bias for the RCTs. (Appendix E, Evidence Table 1). 

None of the eight observational studies were considered to have a low risk of bias. Five 

38, 68-71 received a fair risk of bias assessment, and received this score for a variety of reasons.

72-74 Three observational studies were assessed at high risk of bias. (Appendix E, Evidence Table 

2). 

Appendixes and evidence tables for this report can be found at: 

http://www.ahrq.gov/downloads/pub/evidence/pdf/inoinfants/inoinfants.pdf 

19
 

c 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Retrieved 

4672 

Title/Abstract Review 

3104 

Duplicates 

1567 

Excluded 

2650 

Figure 2. Summary of literature search (number of articles) 

* Total may exceed number in corresponding box, as articles excluded by two reviewers at this 

level. 

20 

Electronic Databases 

MEDLINE® (1747) 

Cochrane (260) 

EMBASE® (2464) 

PsycInfo (13) 

PAS-Abstracts (81) 

Reasons for Exclusion at Title/Abstract Review 

Level* 

No original data: 872 

No human data included: 474 

Not written in English and cannot determine eligibility; 

39 

Article does not include infants born at less than 34 

weeks gestation: 843 

Article does not include pre-term infants who required 

respiratory support: 124 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide: 525 

Article does not address any of the Key Questions: 

1008 

Article addresses Key Question 1 or 2 ONLY and is not 

a randomized controlled trial: 15 

Other reasons: 146 

Hand Searching 

(107) 

Reasons for Exclusion at Article Review Level* 

No original data: 101 

No human data included: 5 

Article does not include infants born at less than 34 

weeks gestation: 131 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide: 21 

Article does not address any of the Key Questions: 166 

(included 63 non-English articles) 

Article addresses Key Question 1 or 2 ONLY and is not 

a randomized controlled trial: 18 

Other reasons: 44 

No abstractable data: 42 

Meeting Abstracts (not applicable to any KQ): 9 

Unobtainable: 12 

Article Review 

454 

Excluded 

415 

Case Reports 

8 

Included articles
 

31 (14 RCTs with 9
 

followup studies and 8
 

cohort studies)
 

KQ1- 14 

KQ2- 14 

KQ3- 13 

KQ4- 17 

KQ5- 21 
Figure 3. Summary of risk of bias for RCTs 

21
 
 

Table 1. Included articles 

Author, year Design Followup of KQ1 KQ2 KQ3 KQ4 KQ5 

Ballard, 200634, 75 RCT x x x x 

Banks, 199970 Phase II pilot 

study 

x 

Bennett, 200176 RCT Subhedar, 199764 x x 

Cheung, 199872 Prospective 

cohort 

x 

Chock, 200977 RCT Van Meurs, 2005, 

200739, 40 x 

Clark, 200271 Prospective 

cohort 

x 

Dani, 200667 RCT x x x 

Dewhurst, 201074 Pilot study x 

Franco-Belgium, 199960 RCT x x x 

Field, 200563 RCT x x x x x 

Hamon, 2005 78 RCT Hascoet, 200561 x 

Hascoet, 200561 RCT x x x 

HIbbs, 200744 RCT Ballard, 200634 x 

Hintz, 2007 30 RCT Van Meurs, 200540 x x x 

Huddy, 200835 RCT Field, 200563 x x 

Kinsella, 199959 RCT x x x 

Kinsella, 200637 RCT x x x x 

Kumar, 200768 Retrospective 

cohort 

x 

Mercier, 201062 RCT x x x x 

Mestan, 200556 RCT Schreiber, 200358 x x x 

Schreiber, 200358 RCT x x x x 

Srisuparp, 200266 RCT x x x 

Su, 200865 RCT x x x 

Subhedar, 199764 RCT x x x 

Tanaka, 200738 Retrospective 

cohort 

x x 

Uga, 200469 Retrospective 

cohort 

x 

Van Meurs, 200540 RCT x x x x 

Van Meurs, 200739 RCT x x x x 

Walsh, 201057 RCT Ballard, 200634 x x x 

Watson, 200936 RCT Kinsella, 200637 x x x 

Yadav, 199973 Retrospective 

cohort 

x 

22
 
 

 

 

 

 

 

 

 

 

Key Question 1: Does inhaled nitric oxide (iNO) therapy 

increase survival and/or reduce the occurrence or severity of 

bronchopulmonary dysplasia (BPD) among premature 

infants who receive respiratory support? 

Major Findings 

●		 There is no statistically significant effect of iNO compared to placebo on survival or 

mortality rates in preterm NICU infants requiring mechanical ventilation. 

●		 There is insufficient evidence to determine whether iNO reduces the rate of 

bronchopulmonary dysplasia (BPD), as defined by requiring supplemental oxygen at 36 

weeks postmenstrual age, in preterm NICU infants requiring mechanical ventilation. 

●		 There is a small but statistically significant reduction in the composite variable of death or 

BPD at 36 weeks PMA for infants treated with iNO compared to infants in control groups. 

●		 Preterm infants who required mechanical ventilation and were the subjects of randomized 

controlled trials of inhaled nitric oxide were a high risk population with high mortality and 

BPD rates during NICU hospitalization. 

Detailed Analysis 

We identified 14 RCTs that compared treatment with iNO to standard treatment in preterm 

infants requiring mechanical ventilation (Table 2). They varied as to inclusion and exclusion 

criteria; age of enrollment; dose, timing and duration of iNO; and outcome variables reported. 

Current labeling of iNO is for use in infants born after 34 weeks gestation with respiratory 

59, 79 failure, so we included two RCTs of preterm infants born at or before 34 weeks gestation.

All but one RCT began enrollment and started iNO during the first week after birth; the RCT that 

differed from the others enrolled infants and started iNO at seven to 21 days after birth.34 The 14 

RCTs varied widely as to severity of respiratory illness, birth weight (BW), gestational age, 

chronological age from birth, and postmenstrual age (PMA, gestational age plus chronological 

age, a proxy for degree of prematurity) when treatment was initiated (Table 3). Their study 

designs varied widely in terms of dose (5 to 40 parts per million (ppm)), duration (1 to 24 days), 

and mode of delivery. The 14 RCTs varied so widely that it was difficult to group them together 

in a way that took these important variables into account. For Key Question 1 (and Key Question 

2), we viewed the aggregation of these 14 RCTs as providing data on a continuum of exposures 

to iNO (as listed above). This discussion of death and BPD includes all 14 RCTs that provide 

data for the variables we were charged with systematically reviewing: death or survival, BPD 

and the composite variable of death or BPD at 36 weeks PMA. Key Questions 4 and 5 explore 

data regarding subgroups and variations in administration of iNO, respectively. 

Each of the 14 RCTs reported mortality data (three reported only death at 7 or 28 days), and 

11 reported data on BPD (Table 2). Three studies focused on changes of oxygenation index (OI) 

60, 61, 65 at 2 to 24 hours after starting iNO therapy. Six RCTs reported using placebo gas in the 

34, 37, 39, 40, 58, 62 control group and keeping NICU staff masked as to study arm assignment. There 

were four multicenter RCTs and one single center RCT that had at least 100 infants per study 

23
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2. Summary of outcomes for RCTs addressing KQ1 

Outcomes Number of studies Total Sample size 

Survival / Death 1434, 37, 39, 40, 58-67 4754 

BPD at 36 weeks PMA 1234, 37, 39, 40, 58-60, 62-65, 67 2655 

BPD other measures 1134, 37, 39, 40, 58-60, 62, 63, 65, 67 3315 

Death or BPD 1234, 37, 39, 40, 58-60, 62-65, 67 3301 

BPD = Bronchopulmonary dysplasia; PMA= Postmenstrual age 

37, 62 arm. The findings of the 14 RCTs are discussed below by outcome variable: death/survival, 

BPD rate, severity of BPD and the composite variable of death or BPD (Appendix E, Evidence 

Tables 3 and 4; Table 2 and 3). 

Survival and death. Each of the 14 RCTs reported mortality data, but there was some 

variation as to the time point cutoff they used for reporting death (e.g., 7 days, 28 days, 36 weeks 

PMA, death while in the NICU, or death while in the NICU or in the first 365 days for infants 

who had prolonged NICU stays). We assumed that death occurred in the NICU in the few studies 

that did not specify the time point cutoff they used for reporting death as they reported only 

NICU outcomes. One pilot study for a larger single center RCT focused on toxicity of iNO, and 

reported only death in the first seven days.66 One study that focused on physiologic response to 

iNO reported death at seven and 28 days.61 For the INNOVO RCT, Field, 2005 reported death in 

the first day after birth, at two to six days, at seven to 27 days and at 28 days to one year 

corrected for degree of prematurity.63 We included these three RCTs in the Evidence Table for 

death (Appendix E, Evidence Table 5). No matter how the 14 RCTs defined and reported death 

or survival, none of the 14 RCTs reported a statistically significant difference between iNO and 

control groups. 

Our discussion and meta-analysis focuses on the 11 RCTs that report death by 36 weeks 

PMA or in the NICU, a specified variable we were asked to include in our systematic review. Six 

37, 39, of the RCTs used the composite variable, death or BPD, as their primary outcome variable,

40, 58, 64, 67, and two RCTs used survival without BPD at 36 weeks PMA as their primary outcome 

34, 62 variable. All three RCTs, Su 2008, Hascoet, 2005, and Srisuparp, 2002, that focused on 

immediate physiologic found no significant differences in mortality between the iNO and control 

60, 61, 65 groups. Survival to NICU discharge was the primary outcome in only one study, an early 

multicenter RCT published by Kinsella, 1999.59 A lower than expected recruitment rate, in 

combination with an interim analysis that suggested they were unlikely to find a difference in 

survival, prompted them to terminate this trial early. The survival rates for the iNO group and 

controls were 25 percent versus 20 percent, respectively with a Relative Risk (RR) of 1.11 (95 

percent confidence interval 0.70, 1.80). To make their data comparable to the other RCTs, we 

report not survival to NICU discharge, but their NICU mortality rates (i.e., 75 percent versus 80 

percent) (Appendix E, Evidence Table 5). 

The largest multicenter RCT (the EUNO trial), Mercier, 2010, was conducted at 36 centers in 

nine European countries.62 They enrolled 800 preterm infants born between 24 weeks and 28 6/7 

weeks gestation with a BW at or above 500 g who were treated with surfactant and mechanical 

ventilation or continuous positive airway pressure (CPAP) for respiratory distress syndrome. 

Within 24 hours after birth, infants were enrolled and treated with low dose iNO (5 ppm) or 

placebo gas for a minimum of seven days. There was no statistically significant difference in 

survival at 36 weeks PMA between the iNO group and controls, 86 percent versus 90 percent, 

respectively, RR 0.74 (0.48, 1.15), adjusted for gestational age, baseline severity of illness, mode 

of ventilation and country. For comparison with the other RCTs, we present their data in Table 3 

24
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

and our meta-analyses in terms of death by 36 weeks PMA, 14 percent versus 10 percent for iNO 

and control groups, respectively. 

The second largest multicenter RCT, published by Kinsella, 2006, enrolled 793 preterm 

infants born at or before 34 weeks gestation with birth weight below 1250 g on mechanical 

ventilation in the first two days after birth.37 Study infants were treated with low dose iNO (5 

ppm) or placebo gas for 21 days or until extubation. The NICU mortality rates were 20 percent in 

the iNO group and 25 percent in the placebo group, RR 0.79 (0.61, 10.3) (p-value = 0.08) 

(Appendix E, Evidence Table 5). 

Ballard, 2006, enrolled 582 infants born before 33 weeks gestation or less with birth weight 

below 1250 g who were on positive pressure ventilation (ventilator or CPAP) beyond the first 

week, seven to 21 days after birth.34 Since preterm mortality is highest during the first week after 

birth, this RCT had the lowest mortality rates at 36 weeks PMA of all the RCTs of iNO in 

preterm infants, 5.4 percent in the iNO group and 6.3 percent in placebo controls. Mortality rates 

were only slightly higher after term, at 44 weeks PMA (6.9 percent versus 6.8 percent) 

(Appendix E, Evidence Table 5). 

In the NICHD Neonatal Research Network’s two RCTs of preterm infants born before 34 

weeks gestation (BW 401 to 1500 g in the 2005 study and BW > 1500 g in the 2007 study), Van 

Meurs reported death before discharge to home or 365 days for preterm infants still 

39, 40 hospitalized. For both RCTs, the Data Safety and Monitoring Committee noted higher than 

expected mortality rates, and recommended lowering the OI inclusion criteria. Despite this 

change to include infants with less severe respiratory failure, mortality rates for preterm infants 

with BW 400 to 1500 g were 52 percent for the iNO group versus 44 percent for placebo controls 

(RR 1.16 (0.96, 1.39)), adjusted for study center, BW group, and OI group.40 As might be 

expected, mortality rates were somewhat lower for infants with birth weight above 1500 g, 36 

percent in the iNO group versus 27 percent in controls (RR 1.26 (0.47, 3.41)) when adjusted for 

OI stratum.39 (Appendix E, Evidence Table 5). 

In the largest single center RCT with 207 infants born before 34 weeks gestation with BW 

below 2000 g, Schreiber, 2003 found no differences in death in the NICU or by six months: 15 

percent for iNO versus 23 percent for placebo gas controls (RR 0.68 (0.38, 1.2)), adjusted for 

type of ventilation. 58 There were no statistically significant differences in NICU mortality in the 

Franco-Belgium, 1999 RCT (27 percent in the iNO group and 35 percent in controls), despite 

having an initial OI that was higher in the iNO group (median 20.2, interquartile range (IQR) 

8.3) than in the control group (median 18.0, IQR 7.4) 60 Neither of two small single center RCTs 

that each enrolled 40 to 42 infants found statistically significant differences between the iNO and 

control groups: mortality was 20 percent versus 30 percent, respectively, as reported by Dani, 

2006, and 50 percent versus 32 percent with RR 1.57 (0.76, 3.38) as reported by 

64, 67 Subhedar,1997 (Appendix E, Evidence Table 5). 

25
 
 

 

Table 3. Study design of randomized controlled trials of inhaled nitric oxide in preterm infants* 

Author, year 

Birth 

Years 

Sample 

Size Age 

GA, 

wks BW, gm Respiratory 

Exclusion 

Criteria†

Placebo/ 

Mask 

Staff 

Start/ 

Max 

iNO, 

ppm 

Duration 

of iNO, 

days Sites, n 

Mercier, 

201062 2005-2008 

800 <24 hr 24-28.9 >500 Inborn, MV, 

surfactant, FiO2>0.3 

FiO2>0.5, lung 

hypoplasia, lethal 

congenital 

anomaly 

Yes/Yes 5/5 7-21 36 

Su, 200865 2000-

2006 

65 Mean 

24-25 

hr 

<32 <1500 RDS, MV + OI>25 Severe IVH or 

IPH 

No/No 5/20 Mean 4.9 1 

Van Meurs, 

200739 2001-2003 

29 24-25 

hr 

<34 >1500 MV, OI>15/12.5 + 

surfactant 

Platelets<50k Yes/Yes 5/10 Max 14 16 

Ballard, 

200634 80 2000-2005 

582 7-21 d <32 500-

1250 

MV (or CPAP if 

BW<800 g) for lung 

disease 

Lethal congenital 

anomaly, 

bilateral IPH, 

prior iNO 

exposure 

Yes/Yes 20/20 Min 24 21 

Kinsella, 

200637 2001-2005 

793 <48 hr <34 500-

1250 

MV Lethal congenital 

anomaly, active 

air leak 

Yes/Yes 5/5 Max 21 16 

Dani, 200667 2001-

2004 

40 <7 d <30 Inborn, RDS, MV, 

surfactant, FiO2> 0.5 

+ a/AO2 <0.15 

Hydrops fetalis, 

major congenital 

anomaly, 

Platelet<50k 

No/No 10/10 Mean 4.1 1 

Hascoet, 

200561 1999-2001 

145 6-48 hr <32 MV, FiO2>40% + 

a/AO2<0.22 

FiO2 1.0 pO2<50 

+ PCO2 <50, 

major congenital 

anomaly, 

platelets<50k 

No/No 5/10 10 

Field, 200563 1997-

2001 

108 <28 d, 

med 1 

d 

<34 MV + severe resp 

failure 

Platelets<50k, 

IPH, lethal 

congenital 

anomaly 

No/No 5/40 Mean 3.5 15 

26
 
 

 

 

 

 

 

 

Table 3. Study design of randomized controlled trials of inhaled nitric oxide in preterm infants (continued)* 

Author, year 

Birth 

Years 

Sample 

Size Age 

GA, 

wks 

BW, 

gm Respiratory Exclusion Criteria†

Placebo/ 

Mask 

Staff 

Start/ 

Max 

iNO, 

ppm 

Duration 

of iNO, 

days 

Sites, 

n 

Van Meurs, 

200540 2001-2003 

420 Mean 

26-28 

hr 

<34 401-

1500 

MV, OI> 

10/7.5 + 

surfactant 

Congenital lung anomaly, 

platelets<50k 

Yes/Yes 5/10 Max 14 16 

Schreiber, 

200358 1998-2001 

207 <72 hr <34 <2000 RDS, MV + 

surfactant 

Hydrops fetalis, major 

congenital anomaly 

Yes/Yes 10/10 7 1 

Srisuparp, 

200266 1997-1998 

34 <72 hr <2000 MV, 

surfactant, 

RDS, + 

OI>4-12 

(based on 

BW) 

Hydrops fetalis, major 

congenital anomaly, no 

arterial catheter 

No/No 20/20 Max 7 1 

Kinsella, 

199959 80 <7 days 

<34 MV, 

a/AO2<0.1 + 

surfactant 

Lethal congenital anomaly No/Yes 5/5 7-14 12 

FrancoBelgian, 

199960 

1995-

1997 

85 <7 

days 

<33 MV + 

OI=12.5-30 

OI>30, severe asphyxia, 

septic shock, IVH, IPH, 

lung or lethal congenital 

anomaly 

No/No 10/20 33 

Subhedar, 

199764 1995-1996 

42 4 days <32 MV, 

surfactant + 

high CLD 

score ‡

Sepsis, IVH with IPH, 

major congenital anomaly, 

platelets<50k 

No/No 20/20 3-4 1 

TOTAL: 14 1995-

2008 

3,425 Birth to 

21 

days 

<34 401-

2000 

6 with 

placebo 

gas 

5-20 

/5-40 

<1 to 21 1-36 

* All included infants were on either on a mechanical ventilator (MV) or continuous positive airway pressure (CPAP). 

†

All RCTs excluded infants with uncorrected bleeding problems, severe congenital heart disease or a decision to not provide full treatment (or contraindication of continuing 

intensive care). 

‡

high CLD score = chronic lung disease score that is composed of risk factors for chronic lung disease.81 

a/AO2 = alveolar/arterial oxygen ratio; BW – birth weight; CLD = chronic lung disease; CPCAP = continuous positive airway pressure; GA = gestational ages; IPH = 

intraparenchymal hemorrhage; MV = mechanical ventilator; OI = Oxygenation index; RDS = Respiratory distress syndrome; severe IVH = Intraventricular hemorrhage with 

ventricular dilation 

27
 
 

 

 

 

 

There were no statistically significant differences (neither increase nor decrease) in NICU 

mortality rates with iNO in any of the individual fourteen RCTs that reported on death or 

survival. A meta-analysis of the 11 RCTS that reported death by 36 weeks PMA or in the NICU 

found no statistically significant differences between the iNO and control groups (RR 0.97 (0.82, 

1.15)) (Figure 4). 

The relatively high mortality rates for infants enrolled in most of these RCTs are striking. 

Regardless of group assignment, seven studies reported mortality rates as high as 25 percent to 

39, 40, 59-61, 63, 64 37, 58, 65, 67
 65 percent, and another four reported mortality rates of 15 to 30 percent.

The Ballard, 2006 RCT reported the lowest mortality rates (5.4 percent for the iNO group and 

6.3 percent for controls).34 Most preterm infants who die in the NICU die during the first week 

after birth. The low mortality rates reported in Ballard, 2006 reflects a difference of study design 

in that they enrolled preterm infants on mechanical ventilation or CPAP at one and to three 

Figure 4. Meta-analysis of 11 studies describing death at 36 weeks PMA or in the NICU 

28
 
 

 

 

Figure 5. Meta-analysis of 10 studies describing death at 36 weeks PMA or in the NICU without Ballard, 2006 

weeks after birth. We therefore removed the data from the Ballard RCT, and repeated the metaanalysis for the remaining ten RCTs. The results did not change: RR 0.98 (0.81, 1.17) (Figure 5). 

This sensitivity analysis confirmed no statistically significant effect of iNO compared to control 

on NICU death or survival to discharge from the NICU in preterm infants requiring positive 

pressure ventilation. 

Bronchopulmonary dysplasia. The term bronchopulmonary dysplasia was introduced in 

1967 when Northway reported a case series of preterm infants with respiratory distress syndrome 

(RDS) who developed a chronic lung disease with characteristic radiographic and pathologic 

features.82 Although it has always been defined clinically, the definition of BPD has evolved 

with neonatal intensive care.83 The clinical, radiographic and pathologic features of BPD have 

changed as new technologies, medications and management strategies have been introduced, 

leading to dramatic reductions in gestational age specific neonatal mortality and a lowering of 

the limit of viability to now 22 to 24 weeks gestation. The evolution of BPD is reflected in its 

various definitions, including definitions based on persistent respiratory symptoms, radiographic 

features, and treatments (e.g., requiring supplemental oxygen at 28 days from birth, or a more 

severe BPD, requiring oxygen at 36 weeks PMA). 

Twelve RCTs provide data on BPD at 36 weeks PMA, but there was some variation in how 

each RCT defined BPD. Six RCTs defined BPD simply as requiring supplemental oxygen at 36 

39, 40, 59, 60, 63, 67 37 58, 64, 65 weeks PMA. One multicenter study and three single center studies refined 

29
 
 

 

 

 

 

 

 

 

 

 

 

the definition of BPD by adding the requirement of radiological evidence of BPD. Although 

there is general agreement that infants on mechanical ventilation or supplemental oxygen above 

30 percent FiO2 at 36 weeks PMA have BPD, some question whether infants on low flow nasal 

cannulas with a FiO2 of 30 percent or less should be included in the BPD at 36 weeks PMA 

category. 

Walsh published in 2003 an algorithm for physiologic BPD at 36 weeks PMA that includes 

an oxygen challenge test for infants on less than 30 percent FiO2.84 Four RCTs used these 

34, 39, 40, 62 criteria for categorizing BPD at 36 weeks PMA. Van Meurs, 2005 and 2007 reported 

that the rate of BPD as defined by Walsh was somewhat lower than the rate of BPD defined as 

39, 40 on supplemental oxygen at 36 weeks PMA. In the NICHD trial of infants born before 34 

weeks gestation with birth weight below 1500 g, physiologic BPD rates, 50 percent in the iNO 

group and 60 percent in controls, RR 0.87 (0.68, 1.10), were lower than rates of BPD defined as 

requiring oxygen at 36 weeks PMA, 60 percent versus 68 percent, RR 0.90 (0.75, 1.08) (both RR 

were adjusted for study center, BW group and OI group).40 In the NICHD RCT of infants with 

birth weight above 1500 g, the physiological definition classified one more infant treated with 

iNO as having BPD, and one less control infant as having BPD, resulting in BPD rates of 36 

percent versus 40 percent respectively, RR 0.74 (0.26, 2.09) adjusted for OI stratum.39 

(Appendix E, Evidence Table 6). Using the physiologic definition at 36 weeks PMA, Mercier, 

201062 reported lower BPD rates, 24 percent in the iNO group compared to 27 percent in 

controls, RR 0.84 (0.58, 1.17), adjusted for gestational age, baseline severity of illness mode of 

ventilation, and country. Their inclusion criteria differed from two RCTs reported by Van 

39, 40 Meurs (Table 3) in their focus on gestational age (i.e., gestational age 24 to 28 6/7 weeks) 

rather than BW and lower severity of initial illness (mechanical ventilation with FiO2 at or above 

30 percent). 

The twelve RCTs also vary as to the denominator used when calculating rate of BPD at 36 

34, 63-65, 67 weeks PMA: Five used the total number of infants in each group, and seven RCTs used 

37, 39, 40, 58-60, 62, 85 the number of survivors in each group. The small single center Subhedar, 1997 

RCT reported BPD rates both for the total group (50 percent for the iNO group versus 64 percent 

for controls) and for survivors (100 percent versus 90 percent).64 

Dani, 2006 noted that infants treated with iNO had half the rate of BPD at 36 weeks PMA 

than the controls (30 percent versus 60 percent, respectively, p-value = 0.067, BPD rate for the 

total group).67 An unplanned interim analysis revealed a statistically significant reduction in their 

primary outcome, death or BPD (p-value = 0.016). On the recommendation of their consulting 

statisticians and two independent observers, the study was terminated early, with enrollment of 

only 40 of the anticipated 52 infants. Another small single center RCT found no statistically 

significant differences in rate of BPD at 36 weeks PMA (31 percent for the total iNO group and 

33 percent for the total control group).65 Field, 2005 reported that 26 of 55 infants in the iNO 

group and 15 of 53 infants in the control group had BPD at 36 weeks PMA, 47 percent versus 28 

percent. Ballard, 2006 reported rates of BPD at 36 weeks PMA for the total iNO group as 

compared with the total placebo gas control group: 50.7 percent versus 56.9 percent, respectively 

(Appendix E, Evidence Table 6). 

In addition to the Mercier and two Van Meurs NICHD Neonatal Research Network RCTs, 

Kinsella, 2006 reported BPD rates using as denominator the number of infants alive at 36 weeks 

37, 39, 40 PMA There was no statistically significant differences between the iNO and placebo gas 

control groups, 65 percent versus 68 percent, respectively, RR 0.96 (0.86, 1.09). Using the 

number of survivors as denominator, Kinsella, 1999 and Schreiber, 2003 reported differences in 

30
 
 

 

 

 

rates of BPD at 36 weeks PMA that were not statistically significant.58 Kinsella, 1999 reported 

that 60 percent of survivors in the iNO group had BPD at 36 weeks PMA as compared with 80 

percent of control survivors.59 Schreiber, 2003 reported that 39 percent of iNO group survivors 

compared to 53 percent of control group survivors had BPD at 36 weeks PMA, RR 0.74 (0.53, 

1.03) (Figure 6).58 (Appendix E, Evidence Table 6). 

Despite variations in how BPD was defined and calculated, there were no statistically 

significant differences in rates of BPD at 36 weeks PMA between the iNO group and controls in 

any of the RCTs. Subhedar, 199764 demonstrated how drastically BPD rates can differ when they 

are calculated using survivors as compared with the total group as denominator. For this reason, 

we did not do a meta-analysis with all 12 RCTs. We included eight studies in a meta-analysis of 

the rate of BPD at 36 weeks PMA in survivors. The small difference was not statistically 

37, 40, 58, 59, 64 significant (RR 0.93 (0.86, 1.003)) (Figure 6) (Appendix E, Evidence Table 6). 

Figure 6. Meta-analysis of eight studies describing BPD at 36 weeks PMA among survivors 

31
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Other measures of severity of bronchopulmonary dysplasia. Although the most accepted 

BPD definition is based on being on supplemental oxygen at 36 weeks PMA, there are other 

measures of severity of lung disease (e.g., duration of mechanical ventilation and oxygen 

supplementation, treatment with medications for lung disease), and other time points for 

reporting the need for mechanical ventilation of supplemental oxygen (e.g., at 40 weeks PMA, 

44 weeks PMA and NICU discharge). We found no RCTs that reported number of infants on 

mechanical ventilation at 36 weeks PMA. 

Ballard, 2006 reported statistically significantly fewer infants in the iNO group than controls 

remained in the hospital, and on mechanical ventilation, nasal continuous positive airway 

pressure (CPAP) or supplemental oxygen at 40 weeks PMA (p-value = 0.01), and at 44 weeks 

PMA (p-value = 0.03).34 At 40 weeks PMA (i.e., full term), six percent in the iNO group and 10 

percent of controls were hospitalized and on mechanical ventilation, and 22 percent versus 29 

percent were hospitalized and on supplemental oxygen. Kinsella, 1999 reported that 54 percent 

of infants in the iNO group were discharged home on oxygen as compared with 80 percent of 

control infants, RR 0.65 (0.41, 1.02).59 In contrast, only nine percent of all infants in each group 

were discharge home on supplemental oxygen in Field, 2005.63 

Kinsella, 2006 reported no differences between the iNO group and controls in proportion of 

infants ever treated with postnatal corticosteroids (60 percent versus 56 percent).37 There were no 

statistically significant differences in proportion of survivors at 36 weeks PMA who were on 

bronchodilators (20 percent versus 20 percent), corticosteroids (15 percent versus 12 percent) or 

diuretics (37 percent versus 38 percent). In Franco-Belgium, 1999 there were also no statistically 

significant differences between the 29 survivors in the iNO group who were treated with steroids 

(54 percent versus 72 percent) or beta-mimetics (21 percent versus 39 percent) than the 29 

control survivors.63 Field, 2006 reported that 40 percent and 34 percent of the iNO versus control 

group were treated with corticosteroids63 (Appendix E, Evidence Table 6). Eight RCTs reported 

39, 40, 58, 60, 62, 63, 65, 67 mean duration of supplemental oxygen, mechanical ventilation or CPAP.

Dani, 2006 reported a statistically significant lower mean duration of supplemental oxygen 

reached statistical significance for all infants in the iNO compared to all in the control group 

(47.3+/-39.4 versus 69.4+/-30.2, p-value = 0.05), but no statistically significant differences in 

mean days of mechanical ventilation or CPAP .67 Two other RCTs found no statistically 

significant differences between the total iNO group and controls in mean duration of mechanical 

60, 65 60 ventilation nor mean duration of supplemental oxygen. (Appendix E, Evidence Table 6). 

The largest multicenter RCT published in 2010 by Mercier reported no statistically significant 

differences in mean duration of mechanical ventilation between the iNO group and controls, 

44+/-26 versus 45+/-29, respectively, p-value = 0.68, but did not specify whether these data were 

for the total groups or survivors.62 Three RCTs reported mean duration of supplemental oxygen 

39,40, 58 or mechanical ventilation in survivors. Van Meurs, 2007 RCT of preterm infants with birth 

weight above 1500 g, the mean duration of mechanical ventilation was 8.7+/-5.4 days for the 

nine survivors in the iNO group and 16.8+/-13.9 for the 11 controls (p-value = 0.08).39 In their 

RCT of preterm infants with birth weight 400 to 1500 g, there were no statistically significant 

differences between the iNO and control groups in mean duration of mechanical ventilation 

(39+/-45 versus 47+/-53) or supplemental oxygen (84+/-63 versus 91+/-61).40 In Schreiber, 

2003, the median duration of mechanical ventilation was 16 days for the iNO group (the 

interquartile range was 8 to 48) and 28.5 days (IQR 8 to 48) for controls p-value = 0.19.58 

(Appendix E, Evidence Table 6). 

32
 
 

 

 

 

 

 

 

 

 

 

 

As a part of their analyses of costs and resource utilization, Field, 2005 reported data 

regarding mechanical ventilation and supplemental oxygen for infants who survived and for the 

total group.63 Median (interquartile range) for days on mechanical ventilation after 

randomization was 7.0 (2.0, 28.0) for all infants in the iNO group versus 4.0 (1.0, 9.0) in all 

controls, and 15.0 (6.0, 28.0) for survivors in the iNO group versus 12.0 (5.0, 36.0) in surviving 

controls. The data for days on supplemental oxygen after randomization were similar.63 

(Appendix E, Evidence Table 6). 

Of the eight RCTs that reported various measures of severity of BPD, only two reported 

differences between the iNO and control groups that approached statistical significance, and both 

favored iNO. Ballard, 2006 reported a statistically significant reduction in hospitalization and 

respiratory support at 40 and 44 weeks PMA with iNO (p-value = 0.01 and p-value = 0.03, 

respectively).34 Dani, 2006 reported a lower duration of supplemental oxygen with iNO (p-value 

= 0.05).67 There are insufficient data to perform a meta-analysis for any measure of severity of 

BPD due to lack of uniformity in definitions used. Although a number of RCTs reported duration 

of mechanical ventilation and/or supplemental oxygen, they varied as to whether they used mean 

+/- standard deviation or median (interquartile range), and whether the data were calculated for 

the total group or only for survivors. 

Death or bronchopulmonary dysplasia at 36 weeks PMA. The composite outcome of 

death or BPD at 36 weeks PMA was reported in 11 RCTs: it was the primary outcome variable 

for six RCTs39; its complement, survival without BPD at 36 weeks PMA, was the primary 

34, 62 outcome variable in the Mercier, 2010 RCT ; in two RCTs the primary variable was OI at a 

60, 65 34, 37, 40, 58, 64 specified time ; in one RCT the primary outcome variable was survival to 

discharge from the NICU59; and for one RCT the primary outcome variable was death or severe 

59, 63 neurodevelopmental impairment. In one multicenter RCT and two single center RCTs, there 

were statistically significant differences between the iNO group and controls in the composite 

34, 58, 67 outcome of death or BPD. All eleven RCTs were included in our meta-analysis. 

(Appendix E, Evidence Table 7). 

Ballard, 2006 found a statistically significant benefit in their primary outcome, survival 

without BPD at 36 weeks PMA, for the iNO group compared to placebo controls, 44 percent 

versus 37 percent, RR 1.23 (1.01, 1.51).34 The number needed to treat was 14. Although their 

study sample was similar to other RCTs (birth before 33 weeks gestation with birth weight at or 

below 1250 g), infants were enrolled later than in other studies (at 7 to 21 days, compared to 

within the first week), and the minimum duration of treatment for the Ballard study was 21 days. 

For comparison with the other RCTs, we used the complement composite variable, rates of death 

or BPD at 36 weeks PMA, 56 percent of the iNO group versus 63 percent of the placebo control 

group) in Appendix E, Evidence Table 7 and Figure 7. 

Schreiber, 2003, the largest single center trial, reported a statistically significant difference in 

rate of death or BPD.58 In the iNO group (n = 105), 49 percent died or developed BPD compared 

to 64 percent in the placebo control group (n = 102), RR 0.76, (0.60, 0.97). This RCT enrolled 

infants born before 34 weeks gestation as other RCTs but with birth weight below 2000 g, and 

they treated study infants with iNO for seven days (Appendix E, Evidence Table 7). 

The other single center RCT that found a statistically significant difference between the iNO 

group and controls in the outcome of death or BPD was reported by Dani, 2006.67 This RCT was 

stopped early (n = 40) because an unplanned interim analysis found a statistically significant 

difference (p-value = 0.02) in death or BPD, their primary outcome. Only 50 percent of infants in 

the iNO group died or developed BPD, compared to 90 percent of infants in the control group, 

33
 
 

 

 

 

 

RR 0.11 (0.02, 0.61). In this study, the controls were not treated with placebo gas but received 

standard care and NICU staff was not masked as to study status. The mean duration of treatment 

with iNO was 98.5 +/- 21.4 hours (4.1 days) (Appendix E, Evidence Table 7). 

The largest multicenter RCT published in 2010 by Mercier reported no statistically 

significant difference between 395 infants in the iNO group compared to 400 in the placebo gas 

control group in their primary outcome variable, survival without BPD at 36 weeks PMA.62 They 

used low dose 5 ppm iNO for seven to 21 days and the physiologic definition of BPD, as 

published in 2003 by Walsh.57 Sixty-five percent of the infants in the iNO group and 66 percent 

of infants in the placebo gas control group survived without BPD at 36 weeks PMA, RR 1.05 

(0.78, 1.43). For comparison with other RCTs, we use the complement combined variable death 

or BPD at 36 weeks PMA, 35 percent versus 34 percent, respectively (Appendix E, Evidence 

Table 7 and Figure 7. 

Just as they found no statistically significant differences in mortality or BPD rates, the two 

Van Meurs Neonatal Research Network RCTs, the large multicenter Kinsella, 2006 RCT, and 

Subhedar’s small single center RCT found no statistically significant differences in the 

37, 39, 40, 64 composite variable of death or BPD at 36 weeks PMA. Both NICHD trials were 

terminated at the second interim data analysis of this study, at the recommendation of their data 

safety monitoring committee, based on no statistically significant differences in death or BPD 

and concerns about significantly higher rates of severe intracranial hemorrhage or periventricular 

39, 40 leukomalacia (PVL) in the larger RCT. Rate of death or BPD at 36 weeks PMA was 80 

percent for the iNO group and 82 percent for controls, RR 0.97 (0.86, 1.06) adjusted for study 

center, birth weight group and OI group.40 The NICHD trial of infants birth weight above 1500 g 

reported that rate of death or BPD at 36 weeks PMA was 50 percent for the iNO group and 60 

percent for controls, RR 0.80 (0.43, 1.48) adjusted for OI.39 The rate of death of death or BPD in 

the large Kinsella, 2006 multicenter RCT was 72 percent in the iNO group compared to 75 

percent in controls, RR 0.95 (0.87, 1.03).37 Kinsella, 1999, a trial that included infants with more 

severe respiratory failure, reported much higher rates of death or BPD at 36 weeks PMA, 77 

percent versus 91 percent, RR 0.85 (0.70, 1.03), but no significant differences between groups.59 

Subhedar, 1997 reported even higher rates of death or BPD at 36 weeks PMA, 95 percent in the 

iNO group and 100 percent in controls, RR 1.04 (0.92, 1.19).64 (Appendix E, Evidence Table 7). 

34
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 7. Meta-analysis of studies describing death or BPD at 36 weeks PMA 

Two RCTs focused on early physiologic response to the administration of iNO gas. They both 

had oxygen index (OI) as their primary outcome variable, and differed only as to timing. FrancoBelgium, 1999 found no statistically significant differences in OI at two hours after administration 

of iNO,60 whereas Su, 2008 reported an OI at 24 hrs after administration of iNO that was 

statistically significantly lower in the iNO group.65 Rates of the composite variable, death or BPD 

at 36 weeks PMA, in the iNO versus control groups were 45 percent versus 53 percent, 

respectively, for the Franco-Belgium, 1999 and 50 percent versus 64 percent, respectively, for Su, 

2008. 

Our meta-analysis of pooled data from all 11 RCTs for death or BPD at 36 weeks PMA found 

a small but statistically significant difference in favor of iNO, RR 0.927 (0.870, 0.988) (Figure 7). 

It has been suggested that the study by Ballard, 2006,34 should not be included in meta-analyses as 

it had a very different study design as well as the lowest mortality rates when compared to the 

other RCTs. In a sensitivity analysis, removing Ballard, 2006 from this meta-analysis did not 

change the effect estimate (RR 0.93). However, not surprising given the size of this study, 

removing it from the analysis did influence the confidence intervals; the confidence interval for the 

meta-analysis without Ballard, 2006 included 1 (0.87, 1.000). Running the analysis without 

Ballard, 2006 did not reduce the statistical heterogeneity, as measured by I2 (Figure 8). 

35
 
 

 

 

Figure 8. Meta-analysis of 10 studies describing death or BPD at 36 weeks PMA, without Ballard, 2006 

Conclusion 

Neither our meta-analysis nor any of the fourteen RCTs found any statistically significant 

differences in death in the NICU or survival to NICU discharge with iNO. Similarly, there were 

no statistically significant differences in any of the 12 RCTs that reported rates of BPD at 36 

weeks PMA. Our meta-analysis of eight RCTs that reported rate of BPD at 36 weeks PMA for 

survivors did not find a statistically significant difference between the iNO or control groups, 

though most of these studies favored the iNO group. Two of eight RCTs that reported other 

pulmonary outcomes reflecting severity of BPD reported statistically significant findings in favor 

of iNO: a reduction in rates of hospitalization and respiratory support at 40 and 44 weeks PMA,34 

and a statistically significant reduction in mean duration of supplementary oxygen.67 Three of 11 

RCTs reported a statistically significant reduction of the composite variable, death or BPD at 36 

34, 58, 67 weeks PMA or its complement, improved survival without BPD at 36 weeks PMA. There 

was a small but statistically significant reduction in favor of iNO in our meta-analysis of all 11 

RCTs that reported data for the composite variable, death or BPD at 36 weeks PMA. Ballard, 

2006 is considered by some as different from the other studies in terms of study design (i.e., not 

enrolling or initiating treatment until a week or more after birth, and a minimum treatment 

duration of 21 days), and it had the lowest mortality rate of all 14 RCTs. Excluding data from the 

Ballard, 2006 and rerunning the meta-analysis resulted in the same effect estimate but a wider 

confidence interval that included 1. A meta-analysis with all 11 trials may provide a more 

36
 
 

 

 

 

 

 

 

 

complete picture of the available evidence, when considering the effect of iNO in a continuum of 

exposure at various postmenopausal ages. When death or BPD at 36 weeks PMA is viewed in 

terms of its complement, the pooled estimate of risk favors iNO with a small but statistically 

significant improvement in survival without BPD at 36 weeks PMA by seven percent. This 

finding leads to questions about short term risks, longer term neurodevelopmental, pulmonary 

and other health outcomes, whether iNO is more effective in certain subgroups, and optimal 

doses, and methods of drug administration, which are discussed in Key Questions 2, 3, 4 and 5. 

Key Question 2: Are there short term risks of iNO therapy 

among premature infants who receive respiratory support? 

Major Findings 

●		 There is insufficient evidence of a neuroprotective effect of iNO in preterm infants. 

●		 There is no evidence that treatment of preterm infants with iNO influences the rates of other 

complications of prematurity, including patent ductus arteriosus (PDA), sepsis, necrotizing 

enterocolitis (NEC), severe retinopathy of prematurity (ROP), pulmonary hemorrhage, or air 

leaks. 

●		 No study reported accumulation of toxic levels of methemoglobin or nitrogen dioxide. 

Detailed Analysis 

Preterm birth requires infants to utilize organ systems that are not yet fully mature.86 The 

many complications of prematurity are multifactorial in etiology, but the highest risk factor is 

degree of prematurity. Infants born at 22 to 23 weeks gestation, the lower limit of viability, have 

the highest risks of all the complications of prematurity. Many biologic and environmental risk 

factors have been identified, and often overlap. For example, inflammation is associated with 

preterm birth and the development of BPD, white matter brain injury, necrotizing enterocolitis 

(NEC), and retinopathy of prematurity (ROP). How iNO exposure will influence the incidence of 

these complications of prematurity has been a major concern. Laboratory data suggest iNO may 

increase or decrease inflammation, cause bleeding by interfering with platelet aggregation and 

adhesion, and/or lead to accumulation of toxic substances (e.g., methemoglobin, formed by 

reaction of NO with hemoglobin, or nitrogen dioxide). 

All 14 RCTs that compared treatment with iNO to standard treatment in preterm infants 

reported data regarding short term risks, including methemoglobin levels, and many 

complications of prematurity. The complications of prematurity we review in this section include 

brain injury, patent ductus arteriosus (PDA), sepsis, NEC, ROP, pulmonary hemorrhage, air leak, 

and pulmonary hypertension. Evidence of brain injury, obtained by serial head ultrasounds, 

includes intraventricular hemorrhage (IVH), intraparenchymal hemorrhage (IPH), 

hydrocephalus, periventricular leukomalacia (PVL), and other signs of white matter injury, 

including ventriculomegaly (Appendix E, Evidence Tables 3 and 4; Table 4). Meta-analyses 

were performed for all short term outcomes and are presented in a table at the end of this section. 

Not all RCTs reviewed in the text are included in the meta-analyses because of differences in the 

denominators across studies (e.g., all infants enrolled versus only survivors), and in the definition 

37
 
 

 

 

 

 

 

 

Table 4. Summary of outcomes for RCTs addressing KQ2 

Outcomes Number of studies Total Sample size 

Brain Injury 1365, 34, 37, 39, 40, 58-62, 64, 66, 67 2936 

PDA 11 34,37, 58, 59, 61-67 2870 

Sepsis 834,37, 58, 62, 63, 65-67 2958 

NEC 834, 37, 58, 61, 62, 64, 65, 67 2683 

ROP 834, 37, 39, 40, 58, 59, 63, 64 2025 

Pulmonary hemorrhage 737, 58, 59, 62-65 2089 

Air leak or pneumothorax 1037, 39, 40, 58, 59, 62-66 2361 

Methemoglobinemia 1234, 37, 39, 40, 58, 59, 62-67 3190 

PDA = Patent ductus arteriosus, NEC = Necrotizing enterocolitis, ROP = retinopathy of prematurity, treated 

of the condition (e.g. any air leak versus only new air leak occurring after randomization). We 

grouped trials for analysis of each condition based on similar measurement characteristics, and 

indicate which trials were included in the table. 

Evidence of brain injury. The nomenclature that describes injury to the preterm infant’s 

brain has changed since the publication of the earliest RCTs of iNO in preterm infants in 1997. 

Severity of IVH was often reported using the grading system proposed by Papile, 1978.87 Grade 

1 is a germinal matrix hemorrhage (GMH), grade 2 is blood in the ventricle but not filling or 

dilating the ventricle, grade 3 is a large amount of blood in the ventricle and ventricular dilation, 

and grade 4 is blood in the brain parenchyma, i.e., intraparenchymal hemorrhage (IPH). In terms 

of its association with neurodevelopmental outcome, GMH is the most benign form of IVH, and 

despite the IVH grading system, it does not denote blood in the ventricle. In the very immature 

infant’s brain, the germinal matrix is a rich capillary network adjacent to the lateral ventricles, 

and very vulnerable to injury. Hemorrhage in the germinal matrix can extend into the ventricle, 

causing an intraventricular hemorrhage (IVH). The hemorrhage can also originate in the choroid 

plexus of the ventricle, and extend into the ventricle, causing an IVH. Blood in the ventricle may 

fill the ventricle and dilate it (Papile grade 3 IVH), or blood may be present in the ventricle with 

no ventricular dilation (Papile grade 2 IVH). However, there may be other causes of enlarged 

ventricles (called ventriculomegaly). Resorption of injured brain parenchyma can produce 

ventriculomegaly, as well as cysts in the brain parenchyma. Intraparenchymal hemorrhage (IPH) 

is more often caused by hemorrhagic infarction of brain tissue than by blood from an IVH 

extending into the brain parenchyma (Papile grade 4 IVH). An IPH may be due to blood filling 

the ventricles and compressing the venous network, or may be an injury to the brain that is 

unrelated to IVH. Periventricular leukomalacia (PVL) is seen when injured brain tissue, 

especially white matter, is resorbed and replaced by fluid. PVL manifests as small cysts, large 

cysts, larger ventricles with irregular borders, or any combination of these findings. PVL may be 

in the frontal, parietal or occipital lobes, and it may be on one side (unilateral) or bilateral. Some 

preterm infants who did not have an IVH develop ventriculomegaly due to resorption of injured 

brain. IVH with ventriculomegaly (Papile grade 3 IVH), IPH, PVL with or without 

ventriculomegaly are each associated with a high risk of neurodevelopmental impairment 

(NDI).87 

Thirteen RCTs compared rate of brain injury on serial head ultrasounds in the iNO and 

34, 37, 39, 40, 58-62, 64-67 control groups. Brain injury may occur in utero, during labor and delivery, and 

immediately after birth, and is common in preterm infants on mechanical ventilation. Studies that 

compared head ultrasounds before treatment with head ultrasounds obtained after treatment can 

best determine whether exposure to iNO has a toxic or neuroprotective effect on brain injury. 

Few studies were able to obtain pretreatment head ultrasounds due to logistical problems. Only 

38
 
 

 

 

 

 

 

 

 

 

four RCTs obtained head ultrasounds at or before enrollment, and compared these to serial 

34, 37, 59, 64 ultrasounds obtained during the remainder of the infant’s NICU hospitalization

(Appendix E, Evidence Table 8). The other seven RCTs did not obtain head ultrasounds before 

study entry. 

Kinsella, 2006, enrolled 420 preterm infants born at and before 34 weeks gestation with a 

birth weight (BW) of 500 to 1250 g on mechanical ventilation within the first two days after 

birth, and treated them with low dose iNO (5 ppm) or placebo gas for 21 days. 37 Head 

ultrasounds at study entry revealed no statistically significant differences between the iNO and 

placebo control groups in rates of GMH or IVH without ventriculomegaly (Papile grades 1 or 2 

IVH, 18.4 percent versus 21.9 percent, respectively) or of IVH with ventriculomegaly (Papile 

Grade 3 IVH) or IPH (6.1 percent versus 6.6 percent, p-value = 0.41). Infants with GMH, IVH 

with or without ventriculomegaly or IPH (Papile grades 1 to 4 IVH) at study entry were reported 

in the outcome data if their condition worsened during or after treatment. Ultrasonographers 

were masked as to treatment category. They found no statistically significant differences of IVH 

with ventriculomegaly or IPH between iNO and placebo control groups, 12.3 percent versus 16.0 

percent, RR 0.77 (0.54, 1.09) or of ventriculomegaly, 5.2 percent versus 8.9 percent, RR 0.58 

(0.37, 1.01), p-value = 0.05. There was a statistically significant reduction of PVL in infants in 

the iNO group (5.2 percent) compared to placebo controls (9.0 percent), RR 0.58 (0.33, 1.00), pvalue = 0.048. The infants in the iNO group had a statistically significant reduction in the rate of 

the composite variable of IVH with ventriculomegaly (Papile grade 3 IVH), IPH, PVL or 

ventriculomegaly than placebo controls, 17.5 percent versus 23.9 percent respectively, RR 0.73 

(0.55, 0.98), p-value = 0.03 (Appendix E, Evidence Table 8). 

Ballard, 2006 enrolled infants with a BW at or below 1250 g on ventilator support or CPAP 

at seven to 21 days, and treated them for a minimum of 21 days.34 Most preterm infants develop 

IVH or IPH within the first seven days after birth. Head ultrasounds were performed before 

enrollment and during and/or after administration of iNO or gas placebo. At baseline, there were 

no statistically significant differences in rate of unilateral IVH with ventriculomegaly or IPH, 

11.9 percent versus 15.6 percent respectively; infants with bilateral IVH with ventriculomegaly 

or IPH were excluded. There were no differences between the iNO group and controls in the 

evolution of neurologic findings on head ultrasounds, 5.0 percent versus 4.1 percent, RR 1.21 

(0.53, 2.76). (Appendix E, Evidence Table 8). 

Two smaller RCTs were also able to perform head ultrasounds before initiating treatment. 

Kinsella, 1999 found that at study entry, 15 percent in the iNO group and 19 percent of controls 

had IVH with or without ventriculomegaly or IPH (Papile’s grades 2 to 4 IVH). 59 There were no 

statistically significant differences in rate of IVH or IPH with or without ventriculomegaly in 

survivors in the iNO group compared to controls, 28 percent versus 33 percent. They reported no 

statistically significant differences in rates of new or higher grade of IVH or IPH (44 percent 

versus 42 percent) 59 (Appendix E, Evidence Table 9). In Subhedar, 1997, 42 infants born before 

32 weeks gestation were enrolled at four days after birth and randomized to iNO or a control 

group. 64 They obtained head ultrasounds at baseline and at weekly intervals for a month. No 

infant in either the iNO or the control group had an extension of an existing IVH64 (Appendix E, 

Evidence Table 8). 

The small pilot RCT reported by Srisuparp, 2002 is the only RCT whose primary outcome 

variable was IVH with ventriculomegaly (Papile grade 3 IVH or IPH).66 They were unable to 

obtain head ultrasounds in all infants before study entry, however, as most were enrolled on the 

39
 
 

 

 

 

 

 

 

 

 

 

day of birth. They found no statistically significant differences between the iNO and control 

groups in brain injury, 25 percent versus 28 percent respectively. 

Schreiber, 2003, enrolled 207 infants born before 34 weeks gestation with BW below 2000 g 

on mechanical ventilation for respiratory distress syndrome during the first week after birth.58 

After randomization to the iNO or the gas placebo group, infants in the iNO group were given 

iNO at 10 ppm for 12 to 24 hours then 5 ppm for six days. They did not obtain head ultrasounds 

before study entry; all ultrasounds were interpreted by a pediatric radiologist masked to 

treatment assignments. Infants in the iNO group had statistically significantly lower rates of the 

composite variable, IVH with ventriculomegaly (Papile grade 3 IVH), IPH or PVL than placebo 

controls, 12.4 percent versus 23.5 percent respectively, (RR 0.53 (0.28, 0.98), p-value = 0.04). 

They found no statistically significant differences in the rate of posthemorrhagic hydrocephalus, 

11.4 percent versus 9.8 percent, RR 1.17 (0.53, 2.58). (Appendix E, Evidence Table 8). 

The secondary hypothesis of the Van Meurs 2005 RCT of infants born before 34 weeks 

gestation with BW 401 to 1500 g who had severe respiratory failure was that iNO would not 

increase the incidence of the composite variable, IVH with ventriculomegaly (Papile grade 3 

IVH), IPH or PVL.40 This study was terminated after the second planned analysis because of a 

higher rate of the composite brain injury variable in the iNO group than in controls reached 

statistical significance. However, when outcomes were analyzed for all 420 enrolled infants (the 

plan was for 440 infants) there were no statistically significant differences in rates of the 

composite brain injury variable (Papile grade 3 IVH, IPH or PVL) whether ultrasounds were 

read by each center’s local radiologists, 39 percent in the iNO group and 32 percent in controls, 

RR 1.25 (0.95, 1.66); or when they were read by a central masked reader after the study was 

terminated, 37 percent versus 38 percent, RR 0.97 (0.74, 1.27). Infants enrolled in this RCT had 

37 58 similar BW as in Kinsella 2006, and both RCTs had lower BW than in Schreiber, 2003.

However, infants in Van Meurs, 2005 were sicker than those in either Schreiber, 2003 or 

Kinsella, 2006, with OI 22 to 23 compared to five to seven at enrollment (Appendix E, Evidence 

Table 8). 

34, 37, 39, 40, 58 In a meta-analysis of five RCTs that reported the composite brain injury variable, 

defined by a combination of IVH with ventriculomegaly, IPH, or PVL (Kinsella, 2006 included 

ventriculomegaly as a separate variable), there was no statistically significant difference between 

infants treated with iNO and controls, RR 0.86 (0.58, 1.29). Results were unaffected by removal 

of the Ballard trial,34 a study that enrolled infants much later than the other trials included in the 

analysis and reported only new or worsening brain injury: RR 0.79 (0.50, 1.27) (Figure 9). There 

was a substantial degree of heterogeneity among the five studies in this meta-analysis of brain 

injury (I2 = 0.657). The two RCTs with the lowest RR of brain injury (Van Meurs, 2007 and 

Schreiber, 2003) differed from the other studies by including larger preterm infants, with BW 

39, 58 above 1500 g. Brain injury tends to occur during the first week after birth and is associated 

with cardiovascular instability in sick preterm infants. We can speculate that the larger preterm 

infants derived greater benefit from the effect of iNO on cardiovascular stability, as is seen with 

more mature full term infants. Smaller, more preterm infants may not benefit as much from this 

effect, due to immature autoregulation of their cerebral blood flow. 

40
 
 

 

 

 

Figure 9. Meta-analysis of five studies describing brain injury 

Similarly, a meta-analysis of RCTs that reported the incidence of PVL showed no difference 

between the iNO and control groups, RR 0.78 (0.37, 1.62) (Table 5). 

In summary, one large multicenter RCT and one large single center RCT found a lower rate 

of brain injury (IVH with ventriculomegaly, IPH, PVL, +/- ventriculomegaly) in infants treated 

during the first week after birth with iNO compared to placebo controls. Another large 

multicenter RCT was terminated early for concern that the iNO group had a higher rate of IVH 

with ventriculomegaly, IPH or PVL than controls, but on final analyses, there were no 

statistically significant differences between the iNO and control groups. All the other RCTs 

found no statistically significant differences between the iNO and control groups in rates of all 

IVH (Papile grades 1 to 4), IVH with ventriculomegaly IPH, PVL, hydrocephalus, or 

combinations of these variables. What makes these findings important is that these signs of brain 

injury on serial head ultrasounds in the NICU are some of the best predictors for 

neurodevelopmental impairment in preterm infants. Key Question 3 addresses more long term 

outcomes, at a year or more, including cerebral palsy (CP), cognitive abilities, and 

neurodevelopmental impairments. 

Patent ductus arteriosus. In the fetus, the ductus arteriosus allows most of the blood to 

bypass the lungs (and circulate through the placenta). In preterm infants, especially the most 

immature, failure of this duct to close can interfere with their transition to extrauterine life and 

lead to heart failure. By altering pulmonary blood flow, iNO may influence duct closure. Eleven 

34, 37, 58, RCTs described in 12 articles compared incidence of PDA in the iNO group and controls.

41
 
 

 

 

 

 

 

 

59, 61-67, 78 Some trials reported only those infants who underwent surgical ligation of their PDA, 

and others included all infants diagnosed with PDA, whether they were treated medically or 

surgically. Kinsella, 2006 reported rates of symptomatic PDA that were medically treated (54.0 

percent in the iNO group versus 53.7 percent of controls), and rates of PDA treated with surgical 

ligation (21.6 percent versus 21.8 percent).37 None of the eleven RCTs (Appendix E, Evidence 

Table 9) or a meta-analysis (RR 1.01(0.86, 1.19); Table 5) found a statistically significant 

difference in incidence of PDA between the iNO groups or controls. 

Sepsis. Eight RCTs reported data on infants who developed sepsis. Schreiber, 2003 reported 

the incidence of sepsis diagnosed after the first day, to distinguish between infants who were 

septic at birth from those that developed sepsis during their NICU course.58 Some studies 

34, 63, 66, 67 34, reported sepsis only if the infant’s blood culture was positive. None of the eight RCTs

37, 58, 62, 63, 65-67 that reported rate of sepsis found statistically significant differences between their 

iNO and control groups (Appendix E, Evidence Table 9). All eight trials were included in a 

meta-analysis that found no difference in the development of sepsis between infants treated with 

iNO and controls, RR 1.06 (0.95, 1.18) (Table 5). 

Necrotizing enterocolitis. NEC is an acute inflammation of the intestines that can lead to 

intestinal perforation, surgical resection of injured bowel and placement of an ostomy. Bowel 

perforation is generally associated with sepsis, and treatment consists of intravenous antibiotics, 

bowel rest, parenteral nutrition, and cautious refeeding. NEC can therefore have an impact on 

34,37, 58, 61, 62, 64, 65, 67,78 subsequent health and growth. Eight RCTs reported in nine articles

compared the incidence of NEC in iNO and control groups. Ballard, 2006 was the only study to 

distinguish between NEC treated medically and infants who needed surgery. The They found no 

statistically significant differences in incidence of NEC, 7.8 percent in the iNO group versus 6.6 

percent in controls, RR 1.17 (0.64, 2.13) or NEC requiring surgery (3.4 percent in the iNO group 

and 2.8 percent in controls, RR1.20 (0.46, 3.13).34 None of the eight RCTs (Appendix E, 

Evidence Table 9) nor our meta-analysis (RR 1.23 (0.94, 1.62; Table 5)) found any statistically 

significant differences in NEC between iNO and control groups. 

42
 
Table 5. Meta-analyses of short term risks of iNO therapy 

Variable Studies included Pooled RR 95 % CI 

Brain injury, Ballard, 200634 0.86 0.58, 1.29 

IVH, IPH and/or PVL Kinsella, 200639 

Schreiber, 200358 

Van Meurs, 200540 

Van Meurs, 200739 

PVL alone Dani, 200667 

Kinsella, 199959 

Kinsella, 200639 

Mercier,201062 

Su, 200865 

0.78 0.374, 1.62 

PDA, medically or surgically treated* Ballard, 200634 1.01 0.86, 1.19 

Field, 200563 

Kinsella, 199959 

Kinsella, 200639 

Mercier, 201062 

Schreiber, 200358 

Srisuparp, 200266 

Su, 200865 

Subhedar, 199764 

Sepsis, clinical or culture positive Ballard, 200634 1.06 0.95, 1.18 

Dani, 200667 

Field, 200563 

Kinsella, 200639 

Mercier, 201062 

Schreiber, 200358 

Srisuparp, 200266 

Su, 200865 

NEC, medically or surgically treated† Ballard, 200634 

Dani, 200667 

Kinsella, 200639 

Mercier, 201062 

Schreiber, 200358 

Srisuparp, 200266 

Su, 200865 

1.23 0.94, 1.62 

ROP, surgically treated Ballard, 200634 

Field, 200563 

Kinsella, 199959 

Kinsella, 200639 

Schreiber, 200358 

Subhedar, 199764 

Van Meurs, 200540 

Van Meurs, 200739 

1.01 0.82, 1.24 

Pulmonary hemorrhage ‡ Field, 200563 0.89 0.60, 1.33 

Kinsella, 200639 

Mercier, 201062 

Su, 200865 

Air leak or pneumothorax § Field, 200563 

Kinsella, 200639 0.96 0.71, 1.28 

Mercier, 201062 

Schreiber, 200358 

Srisuparp, 200266 

Su, 200865 

Subhedar, 199764 

43
 
 

 

 

 

 

 

 

 

 

 

 

 

 

Table 5. Meta-analyses of short term risks of iNO therapy (continued) 

61 67 *Studies excluded: Hascoet, outcomes measured at 28 days; Dani PDA diagnosed prior to treatment 

† 78 61 Studies excluded: Hamon and Hascoet outcomes measured at 28 days 

‡ Included only studies that excluded infants with bleeding disorders from enrollment. 

§ Included only studies where all enrolled infants were considered in the denominator. 

Retinopathy of prematurity. Retinopathy of prematurity is a neovascular retinal disorder, 

which can result in severe visual impairment. Serial eye examinations determine whether ROP is 

present as the retina is vascularized, and if it is progressing. Visual outcomes are improved for 

severe ROP, especially if there are dilated, tortuous blood vessels in the posterior pole of the eye 

(i.e. plus disease) with laser surgery. Eight RCTs report the incidence of severe ROP treated with 

34, 37, 39, 40, 58, 59, 63, 64 laser surgery. Ballard, 2006 found a high incidence of any degree of ROP in 

their high risk study population, 83.7 percent in the iNO group and 81.9 percent in controls, RR 

1.00 (0.93, 1.07).34 Their incidence of severe ROP requiring treatment was 24.5 percent in the 

iNO group versus 23.6 percent in controls, RR 0.97 (0.72, 1.31). This is similar to the incidence 

of ROP requiring treatment in the other seven RCTs, and none found statistically significant 

differences between iNO and control groups (Appendix E, Evidence Table 9). A meta-analysis 

confirmed no statistically significant difference in ROP between infants treated with iNO and 

controls, RR 1.01 (0.82, 1.24; Table 5). 

Pulmonary complications. In Key Question 1, we addressed the primary pulmonary 

complication of prematurity, BPD. In this section, we report other pulmonary complications: 

pulmonary hemorrhage, air leak or pneumothorax, pulmonary hypertension or right heart failure. 

An important consideration is whether infants were excluded from studies if they had evidence 

of bleeding or air leak before entry into the study. If they were not excluded, the most 

meaningful data are the rate of pulmonary hemorrhage or air leak once entered into the study. 

Five RCTs, described in six articles, excluded infants with low platelets or bleeding problems,40, 

61, 63, 65, 67, 62 34, 37, 60 and four excluded infants with severe intracranial or pulmonary hemorrhage.

Seven RCTs report data on pulmonary hemorrhage. Whether they excluded infants with 

37, 63, 65 ,74 58, 59, 64 bleeding problems or not they did not find any statistically significant differences 

between iNO and control groups in rates of pulmonary hemorrhage (Appendix E, Evidence 

Table 9). Our meta-analysis with trials that excluded infants with bleeding problems showed no 

difference in pulmonary hemorrhage between iNO treated infants and controls, RR 0.89 (0.60, 

1.33) (Table 5). 

Ten RCTs reported rates of air leak or pneumothorax, and none found any statistically 

37, 39, 40, 58, 59, 62-66 significant differences between the iNO and control groups. Schreiber, 2003 

reported pneumothorax and pulmonary interstitial emphysema separately, finding no statistically 

significant differences in rate of pneumothorax (10.5 percent versus 16 percent, respectively) or 

pulmonary interstitial emphysema (27 percent versus 34 percent, respectively).58 The rates of air 

58, 64, 65 40, 63 leak varied from a low of four to six percent to as high as 35 to 38 percent (Appendix 

E, Evidence Table 9). Our meta-analysis with trials that included all infants in the denominator 

also found no difference in the risk of air leak between the iNO treated infants and controls, RR 

0.96 (0.71, 1.28) (Table 5). 

The only trial that reported pulmonary hypertension as an outcome variable documented 50 

percent of infants in the iNO and control group with the condition.67 No study specifically 

documented right heart failure (Appendix E, Evidence Table 8). 

Methemoglobinemia. Twelve RCTs measured methemoglobin levels, and some measured 

34, 37, 39, 40, 58, 59, 62-67 nitrogen dioxide levels in administered gas. Most reported that 

44
 
 

 

 

 

 

 

 

 

 

 

34, 59, 66, 67 65 methemoglobin levels in all infants were not elevated, or were below 2.5 percent,

64 39 three percent, or four percent. The Van Meurs, 2005 RCT of infants born before 34 weeks 

gestation with BW 400 to 1500 g found two infants (1 percent) in each group who had 

methemoglobin levels above four percent.40 One infant in the iNO group had a methemoglobin 

level of at least eight percent, and the nitrogen dioxide level was at or above 3 ppm in two 

percent, and at or above 5 ppm in one percent. The multicenter Kinsella, 2006 trial reported a 

transient mild elevation of methemoglobin level in two of 398 (0.05 percent) infants, but 

elevation was not defined.37 Three infants treated with iNO in the Schreiber, 2003 RCT had 

elevation in methemoglobin level that never rose above seven percent, and nitrogen dioxide was 

never above 2 ppm.58 The Field RCT allowed the highest maximum dose of iNO, up to 40 ppm, 

and as many as eight of 55 (14.5 percent) preterm infants had methemoglobin levels above two 

percent; only one infant (1.8 percent) had nitrogen dioxide above 2 ppm for 30 minutes63 

(Appendix E, Evidence Table 9). 

Conclusion 

Key Question 2 analyzed 14 RCTs of iNO in preterm infants on mechanical ventilation for 

evidence of toxicity or short term risks of iNO. None of the 14 RCTs reported statistically 

significant effects of iNO on rates of PDA, sepsis, NEC, treated ROP, pulmonary hemorrhage, or 

air leaks. No study reported toxic accumulations of methemoglobin. None of the 13 RCTs that 

reported head ultrasound evidence of brain injury reported a statistically significant increase with 

iNO treatment. Two large RCTs, with more than 100 subjects in each group, reported a 

statistically significant reduction of a composite brain injury variable (IVH with 

37, 58 ventriculomegaly, IPH or PVL) in the iNO group compared with placebo gas controls. These 

two RCTs raise the question as to whether iNO has neuroprotective effects. There was no 

statistically significant difference between the iNO and control groups in a meta-analysis that 

pooled data from five RCTs that reported rates of the composite brain injury variable (IVH with 

ventriculomegaly, IPH or PVL). There was also no statistically significant difference in our 

meta-analysis of four RCTs with data on rates of PVL. However, not only do the RCTs vary 

widely in study design, but there is also little uniformity among studies as to when head 

ultrasounds were performed, who interpreted them (locally at each center or at more uniformly at 

one site), categories reported, and criteria used for each category. These RCTs were generally 

powered for death and BPD, and not for short term risks or brain injury. There is insufficient 

evidence for assessing the effect of iNO on the preterm infant’s brain. There is a need for RCTs 

that obtain neuroimaging before initiation of treatment and at regular prespecified intervals, 

provide for uniform interpretation of neuroimaging studies, carefully define categories of types 

of brain injury, and clearly report rates of each type, and composites of brain injury in terms of 

surviving infants. Because they are so vulnerable as they are rapidly maturing, the effects of any 

intervention on the brain should be studied in every RCT involving preterm infants. Key 

Question 3 reviews the evidence of effects of iNO on longer term neurodevelopmental, 

pulmonary, and other health outcomes. 

45
 
 

 

 

 

 

 

 

 

 

Key Question 3: Are there effects of iNO therapy on long 

term pulmonary and/or neurodevelopmental outcomes 

among premature infants who receive respiratory support? 

Major Findings 

●		 There is insufficient evidence to determine whether iNO therapy in preterm infants who 

require respiratory support influences the incidence of cognitive, motor or sensory 

impairments, or neurodevelopmental disability. 

●		 There is evidence suggesting that iNO therapy in preterm infants who require respiratory 

support may decrease the use of respiratory medications at one year of age. 

●		 There is insufficient evidence to determine whether iNO therapy in preterm infants who 

require respiratory support impacts long term health outcomes such as lung growth and 

development, pulmonary morbidity, rehospitalization after NICU discharge, and growth. 

Detailed Analysis 

Nine articles representing six RCTs report long term followup of health and 

neurodevelopmental outcomes at one year corrected for degree of prematurity or later (see Table 

6). Field, 2005 reported on some health and neurodevelopmental outcomes at one year corrected 

for degree of prematurity of the multicenter INNOVO RCT.63 Mestan, 2005 reported 

neurodevelopmental outcomes and growth at two years of the infants enrolled in Schreiber, 

56 58 2003, the largest single center RCT. Hintz, 2007 reported on survival, CP, cognitive abilities 

and neurodevelopmental impairment (NDI) in 18 to 22 month old survivors enrolled in the 

30, 40 NICHD RCT of infants born before 34 weeks gestation with birth weight below 1500 g.

Neurodevelopmental impairment at one year corrected for degree of prematurity is included in 

the Van Meurs, 2007 paper that reported results from the NICHD RCT on infants born before 34 

weeks gestation with birth weight above 1500 g.39 For surviving infants in Ballard, 2006, Walsh, 

2010 reported on neurodevelopmental outcomes and growth at two years of age, corrected for 

degree of prematurity, and Hibbs, 2008 reported on pulmonary and health outcomes at one 

34, 44, 57 year. In a paper focused mostly on economic costs and resource utilization, Watson, 2009 

reported on survival and some neurodevelopmental outcomes at one year of age, corrected for 

36, 37 degree of prematurity, for infants enrolled in Kinsella, 2006. Bennett, 2001 reported on 30 

month survival for all study participants who were discharged from the NICU, and 

neurodevelopmental outcomes for 21 of the 22 children alive at 30 months, corrected for degree 

of prematurity.76 Huddy, 2008 followed the group of infants in Field, 2005 up to four to five 

years, and reported on several health and neurodevelopment related outcomes; this is the longest 

followup for any of the RCTs35 (Appendix E, Evidence Tables 3 and 4; Table 6). 

Trials that reported comparable neurodevelopmental outcomes were included in metaanalyses. There was some variability in the incidence of outcomes among the few trials that 

reported conditions such as CP, vision, and hearing impairment. The variability is likely due to 

the low prevalence of these conditions and small samples, as studies were not powered to detect 

difference in these outcomes. Few trials reported other long term health outcomes in a consistent 

manner, making pooled estimates of risk impossible, with the exception of pulmonary outcomes. 

46
 
 

 

 

 

 

 

Table 6. Summary of outcomes for RCTs addressing KQ3 

Outcomes Number of studies Total Sample size 

Death and Survival 630, 35, 36, 39, 44, 56, 57, 63, 76 2635 

Cerebral palsy 730, 35, 38, 39, 56, 57, 76 914 

Cognitive outcomes 530, 35, 39, 56, 57 896 

Sensory impairment 730, 35, 36, 39, 56, 57, 63, 76 951 

NDI 739, 30, 35, 36, 56, 57, 76 1312 

Death or NDI 430, 36, 39, 76 1236 

Seizures 235, 63 81 

Growth 630, 35, 56, 57, 63, 72 978 

Oral feeding 163 43 

Pulmonary and other health 

outcomes 

635, 36, 44, 63, 71, 72 1344 

Death and survival beyond the NICU. Followup studies of two RCTs reported survival 

35 63 into early childhood. Huddy, 2008 followed children from Field, 2005 until four to five years 

of age. A total of 108 infants were enrolled in the RCT, 44 survived to their first birthday. 

Overall survival to four to five years was 44 percent in the iNO group and 36 percent in controls. 

Mestan, 200556 reported that 85 percent of the iNO group and 77 percent of placebo controls 

from Schreiber, 200358 were alive at two years. Additionally, seven followup studies reported 

long term mortality rates for six RCTs. Study results are displayed in Table 7. None of the 

studies revealed a significant difference in mortality when comparing infants treated with iNO to 

controls. (Appendix E, Evidence Table 10). 

Table 7. Studies addressing death and/or survival beyond the NICU 

Author, Year Original Trial Followup Control, n/N (%) iNO, n/N (%) 

Walsh, 201057 Ballard, 200634 2 years 23/288 (8.9) 24/294 (9.0) 

Watson, 200936 Kinsella, 200637 1 year 98/384 (25.5) 80/385 (20.8) 

Huddy, 200835 Field, 200563 4-5 years 

Hibbs, 200744 Ballard, 200634 1 year 2/230 (0.87) 2/225 (0.89) 

Van Meurs, 200739 18 – 22 months 4/15 (26.7) 5/14 (35.7) 

Hintz, 200730 Van Meurs, 200540 18 – 22 months 98/210 (47) 109/210 (52) 

Mestan, 200556 Schreiber, 200358 2 years 23/102 (22.5) 16/105 (15.2) 

Field, 200563 1 year 30/55 (54.5) 34/53 (64.2) 

Bennett, 200176 Subhedar, 199764 30 months 10/22 (32) 7/20 (50) 

A meta-analysis was conducted with all the trials that reported death at any time after NICU 

discharge, regardless of the age of the children at the time of the measurement. Two studies were 

44 35 excluded (Hibbs and Huddy ) because there was more than one followup study for the Ballard 

and Field trials. The pooled estimate shows no difference in mortality with iNO therapy 

compared to placebo, RR 1.02 (0.86, 1.20) (Figure 10). 

47
 
 

 

 

 

 

Figure 10. Meta-analysis of death at followup after NICU discharge 

Cerebral palsy and motor outcomes. Cerebral palsy is a disorder of movement and posture 

caused by malformation or injury to the developing brain that cannot be diagnosed in the 

neonate, but requires a neurological examination and assessment of motor function at one or 

more years after birth. Cerebral palsy varies in terms of type (spasticity, extrapyramidal or 

mixed), anatomic distribution (diplegia, hemiplegia, etc.) severity, and associated disabilities 

(cognitive and/or sensory impairments). The more severe the CP, the earlier it can be diagnosed; 

diagnosis of mild CP is generally not made until two years or more. Diagnosis of CP requires a 

comprehensive neurodevelopmental examination focusing on abnormalities of muscle tone, deep 

tendon and other reflexes, movement and posture, as well as an assessment of motor function. 

The most common type of CP in preterm infants is spastic diplegia, which involves increased 

muscle tone and reflexes in both lower extremities with little or no involvement of the upper 

extremities. CP prevalence increases with decreasing gestational age and birth weight. Most 

studies reported moderate to severe CP. The functional classification for CP is included in the 

description of each study that reported this outcome. 

30 40 The Hintz, 2007 18 to 22 month followup study of Van Meurs, 2005 RCT of infants with 

birth weight 400 to 1500 g found CP in 20 percent of the iNO group and 11 percent of controls. 

CP functional impairment was defined as the ability to sit independently or with support but not 

ambulate independently (moderate CP), or the inability to sit or walk without support (severe 

CP). The initial RR was not significant at 1.85 (0.93, 3.71). When adjusted for birth weight, OI 

entry criterion strata, sex, BPD, IVH 3 or 4 or PVL, postnatal steroid exposure, study center, and 

48
 
 

 

 

 

 

 

 

length of iNO exposure, the RR was significant at 2.41, indicating a higher rate of CP in iNO 

treated infants, but with a wide 95 percent confidence interval (1.01, 5.75) (Appendix E, 

Evidence Table 11). 

Tanaka, 200738 evaluated a cohort of children at three years of age who had received iNO or 

100 percent oxygen in the neonatal period for hypoxic respiratory failure with pulmonary 

hypertension. Cerebral palsy, defined as abnormal muscle tone in one extremity and abnormal 

control of movement and posture, was diagnosed in 12.5 percent of those treated with iNO 

compared to 46.7 percent who had been treated with 100 percent oxygen (p-value = 0.054) 

(Appendix E, Evidence Table 11). There was also a significantly lower odds of CP in children 

who had received iNO versus 100 percent oxygen (OR=0.16; 0.03, 0.98). This association 

persisted in several multivariate models. 

The other five RCTs that evaluated for CP found no significant differences in the incidence 

of CP in the iNO group compared to controls. The Van Meurs, 2007 RCT of infants with birth 

weight above 1500 g found that none of the 17 infants who were followed to one year corrected 

for degree of prematurity developed CP.39 In the Mestan, 2005 paper that reported two year 

outcomes of survivors of the Schreiber, 2003 RCT, CP rates were virtually the same, nine 

percent in the iNO group and 10 percent in controls.56 They based their diagnoses of CP and its 

type on abnormalities in neuromotor tone, deep tendon reflexes, primitive reflexes, postural 

reactions, movement or coordination, and delay in motor milestones.58 Walsh, 2010 reported 

similar findings from the Ballard, 2006 cohort: six percent of iNO treated infants and five 

34, 57 percent of control infants developed CP by two years. Motor functional impairment for CP 

was determined by Palisano’s Gross Motor Function Classification Scale (at or above 2).88 Of 

the seven infants in the iNO group of Subhedar, 1997 that were followed to 30 months none 

developed CP, compared to two of 14 controls (14 percent), who had significant abnormalities of 

64, 76 tone or movement. In the Huddy, 2008 report of four to five year outcomes of Field 2005, 

the CP rate (moderate to severe disability of motor function) was 13.6 percent in the iNO group 

35, 63 and 12.5 percent in controls.

A meta-analysis of the seven trials that evaluated motor outcome found no statistically 

significant difference in CP among infants treated with iNO compared with controls, RR 1.07 

(0.67, 1.71) (Figure 11). A separate meta-analysis was performed with four trials that used the 

30, 39, 56, 76 Bayley Scales Psychomotor Developmental Index below 70 to define motor delay.

Individually, none of these trials found a statistically significant difference in the incidence of 

motor delay when comparing those who had received iNO to controls. Similarly, the metaanalysis showed no statistically significant difference in the incidence of a motor delay with iNO 

therapy, compared with controls, RR 0.95 (0.66, 1.36) (Figure 11). 

49
 
 

 

 

 

 

Figure 11. Meta-analysis of cerebral palsy 

Cognitive outcomes. There were six RCTs and one cohort study that reported cognitive 

outcomes. The majority used the Bayley Scales of Infant Development Mental Developmental 

Index (MDI) for assessment and defined cognitive impairment as MDI < 70, two standard 

deviations below the mean. The only followup study to report a statistically significant difference 

in cognitive impairment between the iNO group and controls was the followup of Schreiber, 

56, 58 2003 reported by Mestan, 2005. Their followup rate was 82 percent at two years corrected 

for degree of prematurity. They found that only 19 percent of the iNO group had a Bayley MDI 

score more than two standard deviations below the mean compared to 35 percent of controls, pvalue = 0.03. This result must be considered in the context of the significantly lower rate of the 

combined variable of grade 3 IVH, IPH, and PVL in the iNO group compared to controls as 

reported in Schreiber, 2003 (Appendix E, Evidence Table 12). 

Hintz, 2007 evaluated participants with birth weight 400 to 1500 g enrolled in Van Meurs, 

2005 at 18 to 22 months of age. Forty-three percent of infants in the iNO group had MDI scores 

more than two standard deviations below the mean compared to 36 percent of controls, RR 1.2 

(0.84, 1.73).30 Infants in the Van Meurs, 2007 RCT with birth weight above 1500 g were 

followed to one year corrected for degree of prematurity. In the iNO group, 11 percent had MDI 

scores more than two standard deviations below the mean, compared to 25 percent of controls, 

RR 0.44 (0.50, 4.02).39 

A meta-analysis was performed using these three studies in which cognitive impairment was 

defined as MDI < 70. This revealed no statistically significantly difference between those treated 

50
 
 

 

 

 

 

 

 

with iNO therapy and controls, RR 0.78 (0.39, 1.60) (Figure 12). As in the meta-analysis for the 

brain injury, there is substantial heterogeneity, reflecting that many of the same infants are 

39 56 included in this meta-analysis. Again, the Van Meurs, 2007 and Mestan, 2005 (followup of 

Schreiber, 2003) studies included infants with birth weight above 1500 g with a lower risk for 

brain injury and subsequent cognitive impairment than the Hintz30 study (followup of Van 

Meurs, 2005) that restricted enrollment to those with birth weight of 400 to 1500 g. 

In their two year followup of Ballard, 2006, Walsh, 2010 reported cognitive outcomes in 

terms of normal intelligence, defined as MDI score above 85, one standard deviation below the 

34, 57 mean. There was no significant difference in proportion of survivors with MDI above 85; 

there were 39 percent in the iNO group and 35 percent in the placebo control group. Translating 

these data into the proportion with cognitive delay, 61 percent in the iNO group and 65 percent 

in the placebo control group had MDI scores one standard deviation below the mean or lower. 

They also reported mean MDI scores for each group and found no significant difference: 81 +/­

20 versus 79 +/- 22 (Appendix E, Evidence Table 12). Bennett, 2001 reported the incidence of 

cognitive delay, defined as MDI < 85 in survivors from Subhedar, 1997 at 30 months of age 

corrected for prematurity.76 There was no significant difference in the incidence of cognitive 

neurodevelopmental delay when comparing those treated with iNO to controls, RR 0.89 (0.37, 

1.75). 

Figure 12. Meta-analysis of cognitive development as measured by the Bayley Scales Mental Developmental 

Index below 70 

51
 
 

 

 

 

 

 

 

 

 

 

To evaluate cognition at four to five years, the Huddy, 200835 followup of the Field, 2005 

cohort used the British Ability Scales (BAS),89 which has norms similar to the Bayley and other 

intelligence tests, with a standardized mean of 100 and a standard deviation value of 15.35 Three 

children in the iNO group and one control had severe impairments that precluded using the BAS. 

There were no statistically significant differences in mean General Conceptual Ability Score 

(GCAS) between the 19 children in the iNO group and the 15 children in the control group: 91.2 

+/- 21.1 versus 81.3 +/- 22.5. They also found no statistically significant differences in the BAS 

cluster scores for verbal ability, pictorial reasoning, spatial abilities, and the nonverbal composite 

scores. There were six of 22 children (27 percent) in the iNO group with GCAS scores two or 

more standard deviations below the mean, compared with six of 16 controls (38 percent) 

(Appendix E, Evidence Table 12). 

Sensory impairment. There were no significant differences between the iNO and control 

groups in proportion of children with visual impairment or hearing impairment in seven studies 

(representing six original trials) that report these outcomes. Visual impairments occurred in zero 

to four percent of children in the iNO group compared to zero to four percent in controls in the 

six studies that reported this outcome. 63 Our meta-analysis that included trials reporting early 

childhood blindness revealed no significant difference between those treated with iNO therapy 

and controls, RR 1.09 (0.52, 2.30) (Figure 13). Hearing impairments occurred in zero to nine 

percent of children in the iNO group compared to zero to seven percent of controls in the same 

30, 39, 56, 57, 63, 76 six followup studies (Appendix E, Evidence Table 13). The pooled risk ratio for 

hearing loss also showed no significant difference with iNO therapy compared to controls, RR 

1.50 (0.69, 3.27) (Figure 14). 

Neurodevelopmental impairment. Seven studies reported the proportion of children with 

neurodevelopmental impairment (NDI), a combined variable that included cognitive, 

neuromotor, and sensory impairments. Children with moderate to severe CP were included, as 

were children with severe visual or hearing impairments. All studies defined “cognitive 

impairment” as two or more standard deviations below the mean score for the assessment tool 

that was used. Most studies also included children with Psychomotor Developmental Index 

scores two or more standard deviations below the mean from the Bayley Scales of Infant 

30, 36, 39, 56, 57, 76 Development (Appendix E, Evidence Table 14, Table 8). 

52
 
Figure 13. Meta-analysis of visual impairment 

53
 
 

 

 

 

 

 

Figure 14. Meta-analysis of hearing impairment 

Just as they found statistically significant differences in cognitive impairment, the Mestan, 

2005 two year followup study of Schreiber, 2003 found that NDI rates were lower in the iNO 

group compared to placebo controls: 24 percent versus 46 percent, RR 0.53 (0.33, 0.87), p-value 

= 0.01. The six other followup studies revealed no significant differences between the two 

35, 39, 56-58, 76 groups. In two large RCT two year followup studies, as many as half of the survivors 

in both the iNO and control groups had NDI: 45 percent versus 49 percent respectively, RR 0.92 

(0.75, 1.12) reported by Walsh, 2010 using Ballard, 2006 cohort; and 51 percent versus 47 

percent respectively, RR 1.07 (0.8, 1.44) reported by Hintz, 2007 for the Van Meurs, 2005 

57, 30 multicenter RCT. The Van Meurs, 2007 RCT of infants with birth weight above 1500 g 

reported a lower rate of NDI in both iNO and control groups, with no statistically significant 

30, 39 difference between the two groups: 11 percent versus 25 percent, RR 0.44 (0.5, 4.02).

Despite the finding in Kinsella, 2006 of a lower rate of grade 3 IVH, IPH or PVL in infants in the 

iNO group, Watson, 2009 reported no statistically significant differences in the rate of NDI at 

one year corrected for degree of prematurity in infants in the iNO group compared to controls, 35 

36, 37 percent versus 34 percent. Huddy, 2008 reported no significant differences in four to five 

year old children from the Field, 2005 cohort, with NDI in 36 percent of children in the iNO 

35, 63 group and in 44 percent of controls. Bennett, 2001 reported that for 30 month old children in 

the Subhedar, 1997 RCT, none of the seven survivors had NDI compared to 36 percent of 

64, 76 controls (Appendix E, Evidence Table 14). 

54
 
 

 

 

 

 

 

 

 

 

Table 8. Studies addressing neurodevelopmental impairment 

Author, 

Year 

Age Definition Control, n/N (%) iNO 

Walsh, 

201057 2 years MDI or PDI<70, GMLS>2, blind, deaf 

115/234 (49) 109/243 (45) 

Watson, 

200936 1 year CP, blind, severe HI, MDI or PDI<70 

73/218 (33.5) 84/237 (35.4) 

Huddy, 

200835 4-5 years Mod-Sev Disability 7/16 (44) 8/22 (36) 

Hintz, 200730 18-22 

months 

MDI/PDI<70, mod-severe 

CP, VI 

48/102 (47) 45/89 (51) 

Van Meurs, 

200739 18-22 months 

MDI or PDI<70, mod-severe 

CP, blind, deaf 

2/8 (25) 1/9 (11) 

Mestan, 

200556 2 years CP, blind, HI, MDI<70 31/68 (46) 17/70 (24) 

Bennett, 

200176 30 months MDI or PDI<70, CP, blind, HI 5/14 (36) 0/7 (0) 

HI = hearing impairment; VI = visual impairment; GMLS = Palisano gross motor level score; MDI = mental development index; 

PDI = physical development index; CP = cerebral palsy 

Our meta-analysis of trials that measured outcome at 12 to 30 months suggests no 

statistically significant difference in the proportion of infants with NDI between those given iNO 

versus the control group (RR 0.91 (0.77, 1.12)) (Figure 15). 

Two followup studies reported the rate of children in each group who had no impairment. For 

the followup of infants from Kinsella, 2006, Watson, 2009 defined “no impairment” to include 

only those children who had MDI and Bayley Physical Developmental Index (PDI) above 85, 

36, 37 and no CP or severe visual or hearing impairment. They found no statistically significant 

differences in the proportion of children with no impairments at one year corrected for degree of 

prematurity between the iNO group and controls: 38 percent versus 37 percent. In reporting the 

18 to 22 month followup results from Van Meurs, 2005 RCT on preterm infants with birth 

weight 400 to 1500 g, Hintz, 2007 used a similar definition of “unimpaired”: MDI and PDI > 85, 

no moderate to severe CP and not blind or deaf. 30 They found that 23 percent in the iNO group 

and 25 percent in placebo controls were unimpaired. The low proportion of survivors with no 

impairments is an indication of how sick the infants enrolled in the RCTs were. Conversely, 

there was a higher survival rate among infants with NDI. (Appendix E, Evidence Table 13). 

55
 
 

 

 

 

 

 

 

Figure 15. Meta-analysis of studies reporting NDI 

Death or neurodevelopmental impairment. None of the four studies that reported the rate 

of the composite variable, death or NDI, for infants enrolled in four RCTs found any significant 

30, 36, 39, 76 differences between the iNO and control groups. Although Kinsella, 2006 reported 

lower rates of grade 3 IVH, IPH or PVL in infants in the iNO group compared to controls, 

Watson, 2009 reported no significant differences in the rate of death or NDI at one year 

corrected for degree of prematurity: 42.4 percent in the iNO group and 44.5 percent in placebo 

controls.36 Similarly, in the two Van Meurs RCTs, there were no significant differences between 

the iNO groups and placebo controls; Hintz, 2007 reported that 78 percent of preterm infants 

with birth weight 400 to 1500 g in the iNO group died or had NDI compared to 73 percent of 

controls, RR 1.07 (0.95, 1.19)30; while Van Meurs, 2007 reported that 43 percent of preterm 

infants with birth weight above 1500 g in the iNO group died or had NDI compared to 50 percent 

of placebo controls, RR 0.86 (0.37, 1.96).39 In the Bennett, 2001 followup of Subhedar, 1997, 63 

64, 76 percent in the iNO group and 59 percent in the control group died or had NDI at 30 months

(Appendix E, Evidence Table 14). 

Long term health outcomes. 

Seizures. Seizures can accompany complications that occur in the antenatal period or in the 

NICU, including perinatal asphyxia, hypoxia, hypoglycemia and other electrolyte abnormalities, 

intraventricular hemorrhage and meningitis. Seizures in premature infants that persist beyond the 

NICU are usually a result of brain injury and associated with other neurodevelopmental sequelae. 

Field, 200563 included “on anticonvulsants” and “fits in previous four weeks” with neuromotor 

outcomes at one year corrected age. These outcomes are based on available pediatrician 

56
 
 

 

 

 

 

 

 

 

 

 

 

assessments. In the iNO group, three of the 25 infants, and one of the 18 control infants with 

available reports were being treated with anticonvulsants. Three infants in the iNO group and 

none of the 18 control infants had experienced a fit or seizure in the four weeks prior to the 

assessment. Seizures were included in the General Health domain of the four to five year 

assessments of infants enrolled in the Field, 2005 RCT performed by Huddy, 2008.35 Children 

could be categorized as normal, impaired, or mildly, moderately, or severely disabled with 

regard to seizures. Of the five children who had seizures in the 12 months prior to assessment (3 

of 22 iNO, 2 of 16 controls), three iNO and one control were on regular seizure medications, and 

considered to be impaired. One iNO child had more than one seizure per month and was 

classified as mildly disabled (Appendix E, Evidence Table 15). 

Growth. There are five RCTs and one cohort study in which growth parameters were 

included with early childhood outcomes. Cheung, 1998 evaluated the 10 survivors from a cohort 

of 24 infants who received rescue iNO therapy for severe hypoxemic respiratory failure. One or 

more anthropometric measures (weight, length, head circumference) of four of the 10 (40 

percent) infants evaluated at 13 to 40 months were below the third percentile on a standard 

growth curve when plotted at their corrected age.72 In the followup of survivors from the Van 

Meurs, 2005 RCT at 18 to 22 months,30 Hintz, 2007 measured weight and head circumference. 

When comparing the infants who had received iNO to controls, there was no difference in the 

measures of weight and head circumference, or percentage of infants with weight or head 

circumference below the fifth percentile for corrected age, based on CDC growth charts90 

(Appendix E, Evidence Table 15). 

Infants enrolled in the Field, 2005 trial had growth parameters reported at one year corrected 

63 35 age, and four to five years chronologic age. At one year, there were pediatrician reports on 

25 infants who had received iNO, and 18 controls.63 Infants were categorized by the number of 

standard deviations their length and weight were from a standardized height and weight.91 There 

was no reported analysis to determine whether this distribution was different between the two 

groups. The actual measure of head circumference was reported. The mean head circumference 

was similar in the two groups, within one standard deviation: iNO 45.5 cm (1.8), control 45.2 cm 

(1.6). In the followup study by Huddy, 2008, weight, length, and head circumference were 

measured in 22 participants from the iNO group and 15 controls at four to five year of age.35 

There were no differences in the standardized mean values91 for any of the three parameters 

between the iNO and control groups. It was noted that values were lower in both groups than 

57 56 those of normal population. Walsh, 2010 and Mestan, 2005 both evaluated infants at two 

years of age corrected for prematurity from Ballard 2006 multicenter RCT, and Schreiber 2003 

single center RCT, respectively. In the former, there were no significant differences in measures 

of weight, length or head circumference. Mestan, 200556 reported the measures and generated zscores using the CDC growth charts,90 which revealed that both the iNO and control groups were 

smaller than the reference population for all measures. Unlike the others who reported growth 

measures, Mestan, 200556 found that those in the iNO group were significantly heavier than 

participants in the control group (median weights 11.7 kg versus 10.8 kg, p-value = 0.04; zscores -0.49 versus -1.07, p-value = 0.02); and measures of length and head circumference were 

not different (Appendix E, Evidence Table 15). Participants lost to followup had a higher birth 

weight and greater gestational age at delivery, which could influence followup weight if they 

were not equally distributed among the iNO and control groups. 

Oral feeding. Successful oral feeding requires the coordination of basic reflexes, more 

complicated motor skills, and effective breathing. Infants must coordinate these efficiently in 

57
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

order to take in enough to support the energy expenditure required for this task, as well as 

growth. Any of the required skills can be adversely affected by premature birth and associated 

complications. Lung disease can increase the required energy expenditure that is necessary for 

maintenance and catch up growth. Only Field, 200563 reported oral feeding and did so as a 

secondary outcome measure. Reports from pediatricians revealed that three of 25 infants who 

received iNO had a stoma for feeding. Of these infants, only one was limited to feeding through 

the stoma only; two infants also took some pureed feeds orally. One infant who did not receive 

iNO (of 18) was limited to liquid feeds through a tube but did not have a surgical ostomy placed 

for feeding. Five iNO infants and four controls could only manage pureed foods. The remainder 

(17 iNO and 13 control infants) could also manage eating lumps (Appendix E, Evidence Table 

15). 

Pulmonary and other health outcomes. There were two cohort studies and four randomized 

controlled trials that reported pulmonary outcomes beyond NICU hospitalization. The reported 

markers of pulmonary health varied among studies and included the use of supplemental oxygen 

or respiratory medications, asthma or wheezing, respiratory disability, feeding tube, and 

recurrent aspiration. 

The safety and efficacy study by Clark, 200271 included infants < 1250 grams birth weight, 

on mean airway pressure of > 7cm H20 and FiO2 > 40 percent at 10 to 30 days of age. The focus 

of the study was safety and short term efficacy. However, records of 25 of the 29 survivors were 

available at six months of age and revealed that 10 of the infants continued to require 

supplemental oxygen (40 percent) (Appendix E, Evidence Table 15). 

Cheung, 1998 reported on the ten survivors from the cohort of 24 infants who received iNO 

as rescue therapy for severe hypoxemic respiratory failure. Eight were diagnosed with 

bronchopulmonary dysplasia; all had supplemental oxygen discontinued by 10 months corrected 

age. Other pulmonary issues reported at followup that occurred in the range of 13 to 40 months 

corrected age include recurrent aspiration pneumonia (1/10), and chronic lung disease requiring 

bronchodilator therapy on a regular basis (1/10). Four of the 10 children had recurrent wheezing 

episodes and used bronchodilator therapy intermittently72 (Appendix E, Evidence Table 15). 

Hibbs, 2007 reported the pulmonary outcomes at one year of 85 percent of the survivors 

34, 44 enrolled in Ballard, 2006. The control group had a greater prevalence of reported pulmonary 

morbidity at one year of age when compared to the iNO group, based on respiratory symptoms 

(56.4 percent versus 49.6 percent ; OR 0.70 (0.48–1.03)), use of diuretics (28.4 percent versus 

18.6 percent; OR 0.54 (0.34, 0.85)), systemic (17.7 percent versus 11 percent; OR 0.56 (0.32, 

0.97)), and inhaled steroids (32.4 percent versus 19.8 percent; OR 0.50 (0.32, 0.77)), inhaled 

bronchodilators (54.1 percent versus 40.1 percent; OR 0.53 (0.36, 0.78)), and supplemental 

oxygen (9.4 percent versus 3.0 percent; OR 0.30 (0.13, 0.73)) at time of followup. Similarly, a 

greater percentage of the control infants had received supplemental home oxygen at some time 

since NICU discharge when compared to infants who had received iNO (49.5 percent versus 

38.4 percent; OR 0.65 (0.44, 0.95)). However, there was no difference between the two groups in 

the percent who were rehospitalized for respiratory complications, or for any reason (21.9 

percent versus 22.6 percent; OR 1.03 (0.65, 1.62)) (Appendix E, Evidence Table 15). 

Field, 200563 reported respiratory outcomes from assessments by pediatricians in the first 

year of life for 25 of 55 who had received iNO and 18 of 53 infants who had not. Three iNO 

infants required respiratory support day or night, and three required supplemental oxygen. Ten 

used bronchodilators since discharge, and five used steroids. Respiratory symptoms in the three 

months prior to assessment included coughing at night (8 infants) and wheezing day or night (13 

58
 
 

 

 

 

 

 

 

infants). Nine iNO infants had respiratory signs and symptoms on exam by the pediatrician. Two 

control infants required respiratory support day or night, and one required supplemental oxygen. 

Seven had used bronchodilators since discharge and five had used steroids. Respiratory 

symptoms in the three months prior to assessment included coughing at night (5 infants) and 

wheezing day or night (11 infants). Four control infants had respiratory signs and symptoms on 

exam by the pediatrician (Appendix E, Evidence Table 15). 

Watson, 200936 assessed the outcomes of premature infants with respiratory failure who were 

randomized to receive iNO versus standard therapy. One year outcomes for these infants focused 

on health resource utilization and neurodevelopment. Use of supplemental oxygen at home was 

not a primary outcome variable but was reported as: 1) percentage of infants using supplemental 

oxygen prior to one year corrected age; 2) percentage on oxygen at one year of age; 3) duration 

of supplemental home oxygen. There were no significant differences in any of these measures by 

study arm when the entire group was evaluated. However, when stratified into birth weight 

categories, the smallest infants (500 to 749 g) who did not receive iNO had an advantage; fewer 

required supplemental oxygen at one year corrected age (4 percent versus 11.7 percent, p-value < 

0.04). 

Our meta-analysis including the trials of Field, 2005 and Hibbs, 2007, showed a statistically 

significant lower risk for those receiving iNO therapy compared to controls in the need for 

bronchodilator, RR 0.75 (0.62, 0.91), and steroid therapy, RR 0.62 (0.46, 0.85), but not in 

wheezing, RR 1.14 (0.56, 2.32). 

Respiratory health was one of the domains assessed at four to five year followup by Huddy, 

2008.35 Twenty of 22 iNO infants and 15 of 16 control infants were reported to have no 

respiratory disability. The remaining infants in each group (2 iNO, 1 control) had mild 

respiratory disability (Appendix E, Evidence Table 15). 

Conclusion 

Our search identified twelve articles that included outcomes into early childhood. Six 

randomized controlled trials provided the baseline population for nine followup studies. Only 

Field, 2005 includes any post NICU followup among primary outcome measures, and this study 

included just over half of the planned sample size for this outcome. We also identified three 

cohort studies addressing long term outcomes. The two prospective cohort studies do not include 

controls for comparison. The controls in the retrospective cohort study are chosen from an earlier 

time period when practice standards other than just iNO use may have differed. Therefore, 

evidence to definitively answer any facet of this key question is not adequate. 

Few individual studies and none of the meta-analyses revealed a significant association 

between neonatal iNO exposure and any neurodevelopmental outcome up to five years of age. 

For CP the two studies that did show associations conflicted in the direction of association. 

Tanaka, 2007 reports a decreased incidence of CP in the iNO group and Hintz reports an increase 

in CP in the iNO group. Both studies also had design or statistics issues that limit interpretation 

of the results. Mestan, 2005 reported a lower incidence of MDI < 70, NDI and the composite 

variable, death or NDI in those treated with iNO from Schreiber, 2003. This provides 

consistency, as the latter found a lower rate of CLD or death, and significant perinatal brain 

injury in the iNO treated infants. Of the studies that report growth parameters, Mestan, 2005 also 

reported the only difference in any anthropometric measure; the iNO treated infants were heavier 

at the time of followup. This set of results provides an incentive to pursue additional randomized 

59
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

controlled trials of iNO in premature infants with primary outcomes, such as neurodevelopment, 

that extend into early childhood. 

Of the studies that reported pulmonary outcomes after NICU discharge, only Hibbs, 200844 

found significant associations that favor iNO use in the NICU; iNO treated infants from Ballard, 

2006 were less likely to use bronchodilators and steroids at one year of age corrected for 

prematurity than controls. Field, 2005 provided the only other comparable data for metaanalyses. This study increased total sample in the meta-analyses by only 10 percent and the 

addition of this study to the meta-analysis did not have any significant influence on the results. 

Meta-analyses found statistically significantly lower use of bronchodilators and steroids in the 

iNO treated infants at followup. Ballard, 2006 treated infants with iNO or study gas at a later 

chronological age than most RCTs (at 7 to 21 days) and for the longest duration, a minimum of 

24 days. This is compelling evidence, but it is not sufficient to recommend routine use of iNO 

for protection against chronic respiratory illnesses of childhood. It does, however, warrant 

directing focus to additional RCTs of iNO use in premature infants in the NICU and considering 

that the timing of initiation and duration of therapy may play an important role in outcome. 

Design of future studies should focus on early childhood outcomes, with definitive and objective 

outcome measures. 

Key Question 4. Does the effect of iNO therapy on BPD 

and/or death or neurodevelopmental impairment vary 

across subpopulations of premature infants? 

Major Findings 

●		 There is insufficient evidence to determine whether the effect of iNO therapy on mortality, 

BPD, or motor impairment differs by the birth weight of the treated infants. 

●		 There is insufficient evidence to evaluate the relationship between iNO therapy and infant 

sex, race/ethnic group, gestational age, or socioeconomic status. 

●		 There are no published data available to evaluate the association between iNO therapy and, 

antenatal steroids, chorioamnionitis, multiple birth, or growth restriction. 

●		 There is insufficient evidence concerning the relationship between iNO therapy and the 

severity of illness. 

●		 There is insufficient evidence that iNO therapy improves outcome of infants suffering 

respiratory failure from pulmonary hypoplasia, respiratory distress syndrome or pulmonary 

hypertension. 

●		 There is no consistent pattern of infants that respond to iNO therapy and those that do not. 

Detailed Analysis 

34, 37, 40, 58, 63, 62	 30, 36, 56, 57 Six randomized controlled trials, four with long term followup, and 

38, 68, 69, 70, 73, 74, 77 seven other studies addressed one or more subpopulations of interest in this Key 

Question (Table 9). 

37, 40, 58, Four RCTs investigated whether iNO therapy has a differential effect by birth weight

34 34, 37, 40	 30, 36, 57 ; three of the trials reported long term followup. Birth weight subgroup analyses 

60
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

34, 37, 58 40, 58 were planned a priori in two trials and were done post hoc for the other two trials.

40, 58, 92 Three trials enrolled infants at < three days of age, while the fourth RCT enrolled infants 

at seven to 21 days of age. 34 

Only small numbers of trials have addressed the effect of iNO therapy on other 

subpopulations including the severity of infant illness, as measured by the oxygenation index 

40, 58, 63 34 34, 37, 57, 62 34, 57, 62 62 (OI) or respiratory severity score, race, sex, gestational age, 

38 69, 77 pulmonary hypertension, and pulmonary hypoplasia.

Descriptions of studies that evaluate iNO therapy in subgroups of infants by demographic 

characteristics are reviewed first below. Studies that evaluated iNO therapy by severity of illness 

indicators and causes for respiratory failure follow (Appendix E, Evidence Tables 3 and 4; Table 

9). 

Birth weight. The evidence for the effect of iNO is presented in standard birth weight 

groupings: < 750 g, 750 to 999 g, 1000 to 1250 g, < 1000 g, > 1000 g, and others. For individual 

studies, the birth weight stratum may vary slightly from the category heading. For instance, 

results for a study using the stratum < 750 g are included under the heading < 750 g. Ballard, 

200634 is an exception as infants were categorized into birth weight groups of 500 to 799 g and 

800 to 1250 g. This trial has been reviewed in the birth weight category of < 750 grams and 1000 

to 1250 grams birth weight 

30, 71 Birth weight < 750 g. In two trials, including one with 384 infants with birth weight 

between 500 g and 749 g, there was no difference in mortality in the NICU,37 or survival without 

58 40 chronic lung disease between those treated with iNO and controls. In followup to a third trial,

mortality at 18 to 22 months was significantly higher in the iNO group compared with the 

30 34 controls (73 percent versus 56 percent; p-value = 0.01). A fourth trial, Ballard 2006 , reported 

no significant difference between infants treated with iNO and controls in survival without CLD 

at 36 wks PMA (RR 1.26 (0.98, 1.62)) or death (RR 1.02 (0.96, 1.08)), among infants with birth 

weight of 500 to 799 g80 (Appendix E, Evidence Table 16). 

No difference was reported in the incidence of BPD at 36 weeks PMA between groups for 

34, 37, 40 36 the three trials that reported the outcome. At one year corrected age, Watson 2009

reported more infants treated with iNO in Kinsella, 2006 37 remained on oxygen compared with 

control infants (11.7 percent versus 4 percent, p-value = 0.04). (Appendix E, Evidence Tables 

16). 

61
 
 

 

 

 

Table 9. Summary of outcomes for RCTs addressing KQ4 

Subanalysis Outcome Number of Studies Total sample 

size 

Birth weight < 750 g Death 330 573 

BPD at 36 weeks PMA 534, 36, 37, 40, 44 1464 

Death or BPD 437,34, 36, 58 1355 

Survival without BPD 234, 58 601 

NDI 230, 36 254 

Death or NDI 130 94 

Birth weight 750-999 g Death 237, 40 388 

BPD at 36 weeks PMA 137, 40 380 

Death or BPD 236, 37, 40 865 

Survival without BPD 158 57 

NDI 236, 37, 40 384 

Death or NDI 136 273 

Birth weight <1000 g Death 130, 40 316 

BPD at 36 weeks PMA 140 155 

Death or BPD 140 316 

Birth weight 1000-1250 g Death 136, 37 129 

BPD at 36 weeks PMA 137 129 

Death or BPD 236, 37 251 

NDI 136 77 

Other Birth weight 

categories 

Death 334 ,*

58 , 

†40 , 

‡30 343 

BPD at 36 weeks PMA 334 , 

§58 , 

†40‡ 343 

Death or BPD 140‡ 104 

Survival without BPD 234 , 

§58† 239 

Survival with BPD 234 , 

§58† 239 

Gestational age Survival without BPD 162 795 

Sex Survival without BPD 162 795 

Race Survival without BPD 134 582 

Death, ICH, and PVL 137 793 

Socioeconomic status NDI 157 396 

OI Risk of Death 140, 63 108 

BPD and Death or BPD 340, 58, 63 726 

NDI 156 138 

Death or disability 163 108 

Respiratory severity 

score 

Survival w/o BPD 134 582 

NDI 157 477 

RDS BPD at 36 weeks PMA 163 108 

Death or NDI 163 108 

Pulmonary hypoplasia Death 269, 77 30 

BPD at 36 weeks PMA 269, 77 25 

Death or BPD 177 12 

NDI 177 4 

Pulmonary HTN Cerebral Palsy 138 31 

Responders vs. 

nonresponders 

Death 368, 70, 73, 74 169 

BPD, ventilator dependant 

survivors 

170, 74 105 

Survival to discharge 173 41 

* Birth weight 500-799g 

† Birth weight 1000-1500g 

‡

Birth weight >1000g 

§

Birth weight 800-1250g 

BPD = Bronchopulmonary Dysplasia; PMA = Post menstrual age; NDI = Neurodevelopmental impairment; IVH = 

Intraventricular hemorrhage; ICH: Intracranial Hemorrhage; PVL = Periventricular leukomalacia; CP = Cerebral palsy 

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No meta-analyses were conducted for this Key Question because of the differences in the 

definitions of subgroups across studies and the reported outcomes measured. 

Similar rates of the composite outcome death or BPD at 36 weeks PMA were reported for 

34, 37, 58 iNO treated infants and controls in all three studies that reported this outcome. In one 

followup study, the combined outcome of death or an oxygen requirement to one year of age 

occurred in 37 percent of infants in each group36 (Appendix E, Evidence Tables 16). 

Inhaled nitric oxide therapy did not improve neurodevelopmental outcome in this birth 

weight category. Neurodevelopmental impairment (NDI) was similar between iNO treated 

infants and controls when measured by Hintz 2007 at 18 to 22 months corrected age (NDI 

defined as including any of the following: moderate to severe CP, blind, deaf, MDI < 70, or PDI 

< 70),36 by Walsh, 2010 at 24 months corrected age (NDI defined as moderate or severe CP, 

bilateral blindness, bilateral hearing loss requiring amplification, or score <70 on the Bayley 

Scales MDI or PDI) (RR 0.85 (0.67, 1.08))57, and by Watson 2009 at one year of age corrected 

for gestational age at birth (NDI defined as including any of CP, blindness, severe hearing loss, 

30 30, 36 MDI < 70 or PDI < 70). In two followup studies the composite outcome death or NDI was 

similar between the groups. The composite death or moderate to severe CP occurred more 

frequently in the iNO treated infants than controls (81 percent versus 62 percent, p-value = 

0.0039), in one study. 30 (Appendix E, Evidence Table 16). 

Birth weight 750 to 999 g. No differences were reported between iNO and control infants in 

this subgroup with respect to mortality, BPD, the combined outcome of death or BPD, 

37, 40 58 neurodevelopmental impairment (NDI), or survival without BPD in the three studies. 

Watson, 2009 reported that iNO treated infants had lower rates of death or NDI at one year 

compared with controls (32.1 percent versus 44.4 percent, p-value=0.04), as well as a decreased 

rate of the combined outcome of death, on oxygen, or NDI at one year corrected age (32.9 

percent versus 45.1 percent, p-value = 0.04)36 (Appendix E, Evidence Table 16). 

Birth weight <1000 g. Only one study examined this birth weight subgroup, using post hoc 

analyses. The iNO treated infants had a higher mortality rate than the control group (62 percent 

versus 48 percent, RR 1.28 (1.06, 1.54)), but they also had a higher rate of severe (Grade 3 or 4) 

IVH (43 percent versus 33 percent, RR 1.40 (1.03, 1.88)). No difference was found in the 

incidence of BPD, or the composite outcome death or BPD40 (Appendix E, Evidence Table 16). 

At followup to 18 to 22 months corrected age, the iNO group had a higher rate of death 

(98/152, 64 percent) than the control group (79/152, 52 percent; p-value=0.04). Those treated 

with iNO also had a 22 percent greater rate of death or moderate to severe CP at 74 percent 

(111/151) compared to 59 percent (89/152) in the control group (RR 1.22 (1.05, 1.43) p-value = 

0.01) 30 (Appendix E, Evidence Table 16). 

Birth weight 1000 to 1250 g. The largest RCT that described birth weight subgroups and 

outcomes is Kinsella, 2006.37 For this higher birth weight stratum, Kinsella reported a significant 

reduction in the combined outcome of death or BPD for the iNO treated infants (38.5 percent 

versus 64.1 percent, RR 0.60 (0.42, 0.86)), as well as a lower rate of BPD alone (29.8 percent 

versus 59.6 percent, RR 0.50 (0.32, 0.79)), although there was no difference in death alone. In 

followup at one year corrected age, there were no significant differences in the incidence of NDI, 

death, subjects on oxygen, or any composite outcomes36 (Appendix E, Evidence Table 16). 

In the Ballard, 2006 RCT,34 which stratified infants across the wider birth weight category of 

800 to 1250 g, there was no significant difference for iNO treated infants compared with controls 

for death (RR 1.00 (0.95, 1.06)) or survival without BPD at 36 wks PMA (RR 1.25 (0.88, 

1.79)).80 There was also no significant difference between iNO treated infants and controls for 

63
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

BPD alone (51.5 percent versus 61.5percent) nor death or survival with BPD (54.6 percent 

80 57 versus 64.8 percent). In followup at two years corrected age, there was no difference between 

groups in the incidence of NDI (RR 1.07 (0.76, 1.50)). 

Other birth weight groups including infants larger than 1250 g. No differences were reported 

40, 58 58 for any outcome in studies that reported birth weights of 1000 to 1500 g or >1500 g.

However, in post hoc analyses for the subgroup of infants with birth weight > 1000g, Van 

Meurs, 200540 found a lower rate of the composite outcome of death or BPD for the iNO treated 

group compared to controls (50 percent versus 69 percent, p-value = 0.03; RR 0.72 (0.54, 0.96)), 

but no difference in death or BPD alone (Appendix E, Evidence Table 16). 

We determined that meta-analyses of trials reporting outcomes by birth weight subgroups 

would not be performed due to the differences in definitions of birth weight categories, the 

marked variability in iNO administration and differences in outcomes reported in these few 

trials. 

Gestational age. Mercier, 201062 assessed the relationship between iNO and gestational age 

at birth in infants born at less than 29 weeks. A similar incidence in survival without BPD at 36 

weeks PMA was reported for infants treated with iNO therapy and controls resulting in a risk 

ratio for those with gestational age <26 weeks of RR 1.14 (0.71, 1.82), and for those with 

gestational age ≥26 weeks of RR 0.94 (0.64, 1.38) (Appendix E, Evidence Table 16). 

Sex. Two RCTs commented on the association of iNO therapy and an infant’s sex. In post 

hoc analysis, Ballard, 200634 stated that there was no difference in the response to iNO according 

to sex, but no data were shown. In the two year followup to Ballard, 2006, Walsh, 2010 reported 

there was no interaction between treatment with iNO and infant sex for the composite outcome 

NDI.57 

Mercier, 201062 also showed no treatment effect by sex with similar relative risks of survival 

without BPD at 36 weeks PMA among girls treated with iNO compared with controls, RR 1.18 

(0.76, 1.83), and boys treated with iNO compared with controls, RR 0.85 (0.58, 1.26) (Appendix 

E, Evidence Table 16). 

Race/ethnicity. Kinsella, 200637 performed post hoc analyses and found no significant effect 

of race or ethnic group on the composite outcome of death, ICH or PVL following iNO 

treatment. In a post hoc analysis by Ballard, 200634 the effect of iNO did not differ significantly 

according to race or ethnicity (p-value = 0.06).75 The risk ratios for survival without BPD at 36 

weeks PMA by individual race follow: whites RR 1.06 (0.76, 1.47), blacks RR 1.72 (1.20, 2.47), 

Hispanics RR 1.66 (1.06, 2.59), and other 0.54 (0.25, 1.14).80 Walsh 2010, in two year followup 

to the Ballard, 2006 trial, found no significant interaction between iNO treatment and race, white 

57 62 infants versus non-white infants, in NDI . Mercier 2010 reported no difference between those 

receiving iNO and controls in survival without BPD for black infants, RR 1.49 (0.61, 3.65), or 

non-black infants, RR 0.94 (0.69, 1.28). (Appendix E, Evidence Table 16). None of the studies 

reporting on race/ethnicity were powered to address these subgroups. 

Socioeconomic status. In the only study to consider socioeconomic indicators of outcome, 

Walsh, 2010 reported no statistically different risk of NDI at two year followup for infants 

treated with iNO and controls when mothers had less than a high school education, RR 0.77 

(0.46, 1.30), compared to those that had a high school education or greater, RR 0.92 (0.72, 

1.17)57; no data was provided in the original trial34 (Appendix E, Evidence Table 16). 

Other subgroups. There were no trials that specified outcomes by subgroups of exposure to 

antenatal steroids, chorioamnionitis, multiple births, and small for gestational age. 

64
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Description of trials based on severity of illness. 

Oxygenation index. Three RCTs used the oxygenation index (OI, OI = mean airway pressure 

in cm H2O x fraction of inspired O2 x 100)/postductal arterial partial pressure of O2 (PaO2) in 

mm Hg) as a surrogate measure of severity of illness. 

The study of Van Meurs, 200540 required an OI > 10 on two consecutive arterial blood 

gases (ABGs) for study entry. Following the first interim analysis, due to a higher than expected 

mortality rate in both treatment and control arms, the respiratory criteria for study entry were 

revised to an OI > five followed by an OI > 7.5. In infants with birth weight 401 to 1500 g, the 

mean OI (SD) at randomization was 23+17 for the iNO treated infants and 22 + 17 for the 

controls. Post hoc analysis indicated no interaction between iNO treatment and OI stratum. The 

risk of death, BPD, and death or BPD were similar between the iNO treatment and control 

groups for those with a median OI < 17 and for those with OI > 17 at the time of randomization. 

Severe IVH or PVL rates were similar between groups within the OI strata40 (Appendix E, 

Evidence Table 16). 

Field, 2005 reported on a total cohort of 108 subjects with a notably high severity of illness 

as assessed by OI. At study entry, the iNO treated group had a median (IQR) OI of 32.9 (22.2, 

49.8), and 55 percent had an OI > 30 as compared to the control group median OI 31.9 (17.4, 

51.8), and 53 percent with an OI > 30. When primary outcomes were stratified by OI < 30 or > 

30, there were no significant differences in death or severe disability (defined as no/minimal 

head control or inability to sit unsupported or no/minimal responses to visual stimuli) (RR 0.99 

(0.76, 1.28), p-value = 0.62); death or supplemental O2 at expected date of delivery (RR 0.83 

(0.68, 1.02), p-value = 0.87); or death or supplemental O2 at 36 weeks PMA (RR 0.98 (0.87, 

1.12), p-value = 0.81) in the iNO group compared to controls63 (Appendix E, Evidence Table 

16). 

In Schreiber, 2003,58 a post hoc analysis was performed, stratified by OI as a measure of 

severity of illness. For the group of iNO treated infants with OI < 6.94 (median), there was a 

significantly decreased risk of the composite outcome death or survival with CLD compared 

with the placebo group (36 percent versus 67.4 percent; RR 0.53 (0.35, 0.81)). There was no 

significant difference for the subgroup with OI > 6.94. Mestan, 200956 reported the 

neurodevelopmental outcomes at a corrected age of two years for the cohort of survivors (N = 

138). In a post hoc analysis, in comparison with the placebo group the iNO treated group with 

initial OI < 6.94 had no significant difference in abnormal neurodevelopmental outcome (defined 

as either disability (CP, bilateral blindness, or bilateral hearing loss) or delay (MDI < 70 or PDI 

<70), RR 0.52 (0.26, 1.01), but for the iNO treated infants with initial OI > 6.94 there was 62 

percent lower risk for abnormal neurodevelopmental outcome, RR 0.38 (0.16, 0.93) (Appendix 

E, Evidence Table 16). 

We opted not to undertake a meta-analysis since these three RCTs had such a wide disparity 

in the OI criteria used, rendering them much less clinically comparable. The relatively low 

median OI in the Schreiber trial58 reflects a population of infants presumably less critically ill 

than those in the Van Meurs trial40 with a median OI of 17, and markedly less critically ill then 

those infants in the Field trial63 with more than half having an OI > 30. The Mestan study is the 

only one to report neurodevelopmental outcomes by OI. 

Respiratory severity score. In Ballard, 2006,34 a simplified respiratory severity score was 

used, calculated as the mean airway pressure x FiO2, since actual PaO2 (needed to calculate the 

OI) was often not available. At study entry, the median severity score was 3.5 for both iNO 

treated and control groups, and was noted to be equivalent to an OI in the range of five to nine. 

65
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In post hoc analyses, there was no interaction between the severity score at study entry and 

34, 80 treatment for the outcome survival without CLD at 36 weeks PMA. Followup at two years 

corrected age showed no difference in NDI between iNO treated and control infants if the 

respiratory severity score was < 3.5, RR 0.93 (0.69, 1.26) or > 3.5, RR 0.93 (0.72, 1.19)57 

(Appendix E, Evidence Table 16). 

Other measures of severity of illness. We found no trials that studied the effect of iNO 

therapy by subgroups defined by oxygen requirement alone. 

Description of trials based on causes of respiratory failure. 

Respiratory distress syndrome. In Field, 2005, the primary outcome measures were stratified 

by principal diagnoses, defined as acute preterm lung disease (presenting immediately after birth 

and randomized at < 3 days of age), chronic preterm lung disease (presenting immediately after 

birth and randomized for continuing problems after 3 days of age), and other (developed lung 

disease after recovering from an initial respiratory problem). There were no differences between 

iNO treated infants and controls in death or supplemental O2 at 36 weeks PMA, RR 0.98 (0.87, 

1.11); death or supplemental O2 at the expected date of delivery, RR 0.83 (0.68, 1.01); or death 

or severe disability, RR 0.99 (0.76, 1.28) 63 (Appendix E, Evidence Table 16). 

Pulmonary hypoplasia. In very low birth weight preterm infants, pulmonary hypoplasia can 

occur following maternal preterm premature rupture of membranes (PPROM) > five days with 

subsequent oligohydramnios, and may further be complicated by persistent pulmonary 

hypertension. Two groups of investigators conducted retrospective analyses of infants with 

suspected pulmonary hypoplasia. In a subset analysis of infants with suspected pulmonary 

hypoplasia from the two Van Meurs trials, Chock, 200977 compared six infants exposed to iNO 

with six controls; the infants were similar at baseline. There was no statistically significant 

difference between iNO treated infants and controls in death (33 percent versus 67 percent, pvalue = 0.57), BPD at 36 weeks PMA in the seven survivors (2/5 (40 percent) versus 2/2 (100 

percent), p-value = 0.43)), or death or BPD (50 percent versus 100 percent, RR 0.50 (0.22, 

1.11)). At 18 to 22 months followup, none of the four surviving iNO treated infants assessed had 

NDI (defined as moderate to severe CP, blindness, or deafness); the two survivors from the 

placebo group were lost to followup, and thus no comparisons were made. Uga, 200469 

compared eight infants treated with iNO to 10 controls. All eight infants treated with iNO 

survived to 28 days compared to 5/10 control infants (p-value < 0.05). The groups had similar 

rates of BPD (undefined) (Appendix E, Evidence Table 16). 

A meta-analysis was not performed for these two retrospective cohort studies with very 

limited numbers of infants enrolled, and widely different time points for death, i.e., prior to 

77 69 discharge home or within 365 days in hospitalized infants versus seven and 28 days.

Pulmonary hypertension. In persistent pulmonary hypertension of the newborn (PPHN), the 

pulmonary vascular resistance remains elevated in the newborn period, and it is the primary U.S. 

FDA approved indication for iNO in the term and near term infant population. In a retrospective 

case control study of 31 singleton preterm infants at median 25 weeks gestational age (IQR 24 – 

28 weeks) with clinical pulmonary hypertension confirmed by echocardiography, Tanaka, 2007 

reported that at three years of age 2/9 (22.2 percent) infants with CP had been treated with iNO 

compared to 14/22 (63.6 percent) infants without CP38 (Appendix E, Evidence Table 16). 

iNO responders compared to nonresponders. Four studies reported primary outcomes by the 

presence or absence of response to iNO therapy. Yadav, 1999 reported results from a 

retrospective study of iNO given to 41 preterm infants with a mean OI of 40 on maximal medical 

therapies. Response to an initial 10 ppm iNO was defined as a decrease in OI by > 10 at one hour 

66
 
 

 

 

 

 

 

 

 

 

 

 

 

of treatment. The 26 responders and 15 nonresponders were similar with respect to birth weight, 

gestational age, and OI at the start of treatment. Death was reported as 11/26 (42 percent) for 

responders but 14/15 (93 percent) for nonresponders. In a multivariable model, early response to 

iNO was associated with survival to discharge (p-value = 0.01)73 (Appendix E, Evidence 

Table16). 

Banks, 1999 studied iNO usage in severe BPD in 16 ventilator dependent preterm infants 

more than a month old (range 1 to 7 months). In this open label non controlled trial, iNO was 

administered at 20 ppm for the first 72 hours, then titrated slowly (median duration 27 days) for 

responders or discontinued in 24 hrs for nonresponders. Non response was defined as a 10 

percent increase in oxygen requirement, a PaCO2 of 70 mm Hg on baseline ventilator settings, 

worsening chest x ray, or a methemoglobin of > five percent within 72 hours of starting iNO 

therapy. Mortality for the overall cohort was 44 percent (7/16). For iNO responders, 4/11 (36 

percent) died over the range of 11 days to five months, while in the nonresponder group 3/5 (60 

percent) died and the two survivors remained ventilator dependent70 (Appendix E, Evidence 

Table 16). 

Kumar, 2007 performed a retrospective chart review of preterm infants < 37 weeks 

gestational age at birth with pulmonary hypertension treated with iNO. Pulmonary hypertension 

was diagnosed by echocardiography within the first four weeks of life; iNO treatment at doses of 

5 to 15 ppm was at the discretion of the clinical team after an infant failed standard medical 

management. Within the gestational age range of interest in this evidence report, < 34 weeks 

gestation, response to iNO was least likely to occur in the most immature infants: only 1/6 (16 

percent) of infants < 29 weeks responded to iNO, defined as an increase in postductal PaO2 of 20 

mm Hg or greater within 30 minutes without any change in inspired oxygen, while 5/6 (83 

percent) of infants 29 to 31 weeks gestation, and 5/6 (83 percent) of infants 32 to 34 weeks 

gestation responded to iNO68 (Appendix E, Evidence Table 16). Mortality was significantly 

higher for the non responders (6/8, 75 percent) compared to iNO responders (4/15, 26 percent) (p 

< 0.04) (Appendix E, Evidence Table 16). 

In a pilot study of the European iNO Registry, Dewhurst 2010,74 reported the outcome for 44 

preterm infants <34 weeks gestational age at birth. Infants with congenital heart disease were 

excluded. Infants were treated with a median starting dose of iNO of 20 ppm (range 3.3 to 25 

ppm), and a median maintenance dose of 10 ppm (range 0.7 to 25 ppm). Response to iNO was 

defined as a 15 percent reduction in the baseline OI within 30 to 60 minutes of starting therapy; 

26 infants responded and eight did not. Infants that responded to iNO were younger than non 

responders (median (IQR) gestational age at birth, 26 (25 to 29) weeks versus 29 (27 to 30) 

weeks, p-value = 0.043) and had a significantly higher baseline oxygen requirement (median 

(IQR) Fi02 1.0 (0.9, 1.0) responders versus 0.8 (0.5, 1.0) non responders; p-value = 0.021). Birth 

weight, age at starting iNO, starting dose, and baseline OI were similar between responders and 

non responders. There was no difference in mortality: 12 of the 21 responders for whom 

complete data were available died; 5/8 non responders died (Appendix E, Evidence Table 16). 

No meta-analysis for the iNO responder versus non responder studies was undertaken due to 

the wide variations in iNO dosage and timing, as well as the variability and incomplete 

description of the diagnoses underlying the respiratory failure in these preterm cohorts. 

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Conclusions 

For the question of whether iNO therapy has an effect on the major outcomes of interest 

(death and/or BPD or neurodevelopmental impairment) across various subpopulations of 

34, 37, 40, 58, 63, 74 premature infants, we reviewed 17 studies which included six original RCTs, with 

30, 36, 56, 57, 77	 38, 68, 69, 73, 70, 74, 77 four followup studies, and seven other studies, As noted in the 

conclusion of Key Question 1, some of the studies that reported no significant differences in 

rates of death, BPD at 36 weeks PMA, or the composite outcome death or BPD at 36 weeks 

PMA for the overall cohort did find statistically significant subgroup differences. For example, 

37, 40 two studies report decreased rates of one or more of the major outcomes among infants with 

36, 56 birth weight > 1000 grams. The lack of consistency in defining or subdividing certain 

subgroups, (e.g., by birth weight, or oxygenation index) hampered the ability to answer this Key 

Question. In addition, many of the subgroup analyses performed were by post hoc analyses (e.g., 

birth weight, race), increasing the need for cautious interpretation of results. Some of the specific 

subpopulations of interest had little or no outcomes related data at all. Based on the current body 

of evidence, no definitive and generalizable conclusions may be made about iNO treatment in 

specific subpopulations. Future research is needed to examine the role of iNO treatment in these 

and alternative subgroups, so as to more clearly define populations of preterm infants which may 

benefit most from this therapy. 

Key Question 5. Does the effect of iNO therapy on BPD 

and/or death or neurodevelopmental impairment vary by 

timing of initiation, mode of delivery, dose and duration, or 

concurrent therapies? 

Major Findings 

●		 There is insufficient evidence to determine if initiating iNO therapy for acute respiratory 

distress at < three days reduces the risk of death or bronchopulmonary dysplasia (BPD) at 36 

weeks PMA, or death and neurodevelopmental disability at one year of age, corrected for 

gestational age at birth. 

●		 In infants with developing BPD, there is insufficient evidence to determine if treatment with 

iNO during the second week after birth improves survival without BPD compared with 

treatment during the third week after birth. 

●		 There is insufficient evidence to determine the effect of delivery of iNO by high frequency 

ventilation on either death or BPD, or neurodevelopmental outcome compared with 

conventional ventilation. 

●		 There is insufficient evidence to support an optimal dose of iNO or duration of exposure to 

improve outcome or prevent harm. 

●		 There is insufficient evidence to determine the effect of iNO with concurrent therapy. 

68
 
 

 

 

 

 

 

 

 

 

 

 

 

 

Detailed Analysis 

Fourteen RCTs reported in 21 papers addressed this key question. Two trials investigated the 

34, 63 timing of the initiation of iNO therapy, and two the mode of drug delivery, conventional or 

40, 58 high frequency ventilation. The dose of iNO varied considerably among the 14 studies. To 

examine the effect of dose on the primary outcomes, studies were categorized into those that 

37, 59, 62 39, 40, 58, administered iNO at only 5 ppm, those that delivered a maximum dose of 10 ppm,

61, 67 34, 60, 63-66 and those that gave 20 ppm or titrated the dose to the patients’ response. Duration 

of iNO exposure also varied considerably among the 14 studies, from three to four days64 to a 

minimum of 24 days.34 As the majority of the studies administered iNO therapy until extubation, 

the evidence for the effect of duration of exposure of iNO on the primary outcomes of BPD 

and/or death or neurodevelopmental impairment could not be evaluated. Only two studies 

explicitly considered concurrent therapies, specifically systemic steroids, on the effect of iNO 

64, 76 treatment.

All trials reported death or survival, although the time of ascertainment of the outcomes 

varied across studies. If death or survival was reported at multiple endpoints in either the original 

study or in a long term followup publication (e.g., before NICU discharge, and at one year of 

age, corrected for gestational age at birth), the data are included in this evidence report. Seven of 

30, 35, 36, 56, 57, 76, 78 the randomized trials have reported long term followup. The followup studies 

have varying definitions of neurodevelopmental impairment (NDI), and use different measures 

of developmental progress, making direct comparison difficult. For questions concerning some 

subgroups (timing of initiation of iNO therapy, and mode of iNO delivery) the analyses are post 

hoc, therefore the results must be considered exploratory, as infants were neither randomly 

assigned to the subgroup, nor was the study powered to consider the variable (Appendix E, 

Evidence Tables 3 and 4; Table 10). The differences in treatment protocols in studies reporting 

on subgroups of infants may make pooled estimates of the effect of iNO therapy spurious, so 

meta-analyses were performed only with RCTs using similar dosing regimens. 

Timing: Early versus late iNO administration. Two populations of preterm infants have 

been treated with iNO, those with early acute respiratory distress (immediately after birth), and 

those with evolving BPD. Early treatment generally begins within the first three days after birth 

in an effort to improve oxygenation in infants with acute hypoxemia, as in respiratory distress 

syndrome (RDS) or pneumonia. Late treatment may begin any time after three days, with 

evidence of progressive respiratory failure. Theoretically, late treatment avoids exposing an 

infant to iNO who would otherwise have resolving RDS during the first week. The goal of both 

strategies is to prevent the development of BPD and all its sequelae. Although the age at 

initiation of iNO therapy was available for all trials, aggregating studies into meaningful 

categories was problematic; RCTs started iNO therapy at < 48 hours, < 72 hours, < 96 hrs, four 

to 120 hours, < seven days, seven to 21 days, and < 28 days of age. Some trials also had varying 

additional entry criteria concerning severity of illness, further complicating the ability to 

combine studies into clinically meaningful groups. Because of this variability we did not conduct 

meta-analyses; instead we report the results of two RCTs that specifically considered the timing 

of the initiation of iNO therapy, both in post hoc analyses (Appendix E, Evidence Table 17). 

69
 
 

 

 

 

 

 

 

 

 

 

 

Table 10. Summary of outcomes for RCTs addressing KQ5 

Subanalysis Outcome Number of Studies Total sample 

size 

Timing: Early vs. late iNO 

administration 

Death 134 582 

Death or BPD 163 108 

Death or Severe 

Disability 

163 108 

Survival without BPD 134 582 

Mode of drug delivery Death 230, 40 838 

Death or BPD 158 207 

Death or CP 130 399 

Motor Developmental 

Impairment 

130 58 184 

NDI 240, 58 627 

Dose of iNO, 5 ppm Death 337, 59, 62 1666 

BPD at 36 weeks 337, 59, 62 1563 

Death or BPD 337, 59, 62 1661 

NDI 136 455 

Dose of iNO, 10 ppm Death 539, 40, 58, 61, 67 839 

BPD at 36 weeks 439, 40, 56, 58, 67 696 

Death or BPD 439, 40, 58, 67 694 

Dose of iNO 20 ppm Death 634, 60, 63-66 962 

BPD at 36 weeks 534, 60, 63-65 55 

Death or BPD 434, 60, 63, 64 774 

NDI 730, 35, 56, 57, 63 ,64, 76 977 

iNO with concurrent therapies Death 264, 76 84 

BPD at 36 weeks 264,76 84 

Death or BPD 264,76 84 

BPD = Bronchopulmonary dysplasia; iNO = Inhaled nitric oxide; NDI = Neurodevelopmental impairment; 

CP = Cerebral palsy 

In a small sample, Field, 200563 found a similar risk of death or BPD at 36 weeks PMA in 

infants treated with iNO within three days of birth (25/38, 66 percent) and those treated at four to 

28 days (12/17, 71 percent; RR 0.98 (0.87, 1.11)). There was an advantage to early iNO 

administration when death or BPD was measured at the expected date of delivery (61 percent 

versus 94 percent when iNO was initiated at 4 to 28 days), but the difference was attenuated after 

adjustment for diagnosis (acute lung disease beginning at birth and treated at < three days, 

chronic lung disease with respiratory distress at birth and continuing at four to 24 days; and other 

respiratory distress after recovery from an initial respiratory problem), and severity of illness (OI 

< 30 versus > 30), RR 0.83 (0.69, 1.01). The time of initiation of iNO had no effect on death or 

severe disability, defined as no/minimal head control or the inability to sit unsupported or 

no/minimal response to visual stimuli, at one year of age corrected for gestational age at birth 

(RR 0.99 (0.76, 1.28)). No data were provided on the median time that iNO therapy was initiated 

in the early or late group, but the median (IQR) age of initiation for all infants receiving iNO 

therapy in the study was 1 (0, 6) days, making it unlikely that the groups were very different 

(Appendix E, Evidence Table 17). 

In a large sample of nearly 600 infants with developing BPD, Ballard, 200634 reported a 

similar incidence of death at 36 weeks PMA between the iNO and placebo groups for those 

entering treatment at seven to 14 days (10.7 percent iNO versus 11.3 percent placebo), or those 

entering treatment at 15 to 21 days (6.6 percent iNO versus 5.8 percent placebo) 34 However, the 

likelihood of survival without BPD increased for infants beginning treatment at 7 to 14 days (RR 

1.91 (1.31, 2.78)), a result that was not observed in those beginning treatment later, at 15 to 21 

70
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

days (RR 0.99 (0.77, 1.28)).34 This result may have been observed because of damage already 

done to the developing lung before late enrollment (Appendix E, Evidence Table 17). 

In both of these studies analyses were conducted post hoc, so neither study was powered to 

find a statistically significant difference between the groups (Appendix E, Evidence Table 17). 

Mode of drug delivery. Two randomized controlled trials, Van Meurs, 200540 and 

Schreiber, 200358 reported outcomes for infants treated with iNO and conventional mechanical 

ventilation compared with those treated with iNO and high frequency ventilation. Patients were 

randomly assigned to ventilation strategy in one trial,58 but in the other, analyses were done post 

hoc. 40 Both studies reported neurodevelopmental followup to 18 to 24 months of age, corrected 

30, 56 for gestational age at birth. Patients in the two trials differed by birth weight inclusion 

40 58 criteria (401 to 1500 grams, < 2000 grams ) (Appendix E, Evidence Table 17). 

Schreiber, 200358 found no difference in the combined outcome of death or BPD at 36 weeks 

PMA between infants randomized to treatment with iNO and conventional ventilation (RR 0.61 

(0.41, 0.90)) compared with placebo and those randomized to iNO and high frequency 

ventilation (RR 0.92 (0.67, 1.26)) compared to placebo. Among survivors, the risk of abnormal 

neurodevelopmental outcome, defined as disability (CP, bilateral blindness, or bilateral hearing 

loss) or developmental delay (a score of <70 on the Bayley Scales of Infant Development II, but 

no disability) was not statistically different between high frequency ventilation and conventional 

ventilation, RR 0.92 (0.58, 1.46) 56 (Appendix E, Evidence Table 17). 

In post hoc analysis, Van Meurs, 200540 reported that iNO delivered by conventional 

mechanical ventilation was associated with a 46 percent increase in the risk of death before 

discharge to home or within 365 days of birth among infants still hospitalized compared with 

placebo (RR 1.46 (1.10, 1.92)). The risk remained elevated at 18 to 22 months of age (RR 1.37 

(1.05, 1.79)).30 There was no increase in death, at either time, among infants treated with iNO 

delivered by high frequency ventilation compared to placebo. The risk of developing BPD at 36 

weeks PMA was similar if iNO was delivered by conventional ventilation (RR 0.90 (0.65, 1.24)), 

or high frequency ventilation (RR 0.89 (0.72, 1.10)) (Appendix E, Evidence Table 17). Motor 

development was impaired at 18 to 22 months of age, in those treated with iNO and conventional 

ventilation (CP RR 1.29 (1.03, 1.60)), and there was an increased risk of death or moderate to 

severe CP (moderate CP was defined as the ability to sit independently or with support but 

cannot independently ambulate; severe CP was defined as unable to sit or walk even with 

support), RR 1.29 (1.03, 1.60)30 (Appendix E, Evidence Table 17). The risk of disability, defined 

as moderate/severe CP, bilateral blindness, deafness, or MDI or PDI < 70, was not affected by 

mode of iNO delivery, nor was the combined outcome of death or disability (high frequency 

ventilation RR 0.97 (0.70, 1.35); conventional ventilation RR 1.07 (0.64, 1.80)30 (Appendix E, 

Evidence Table 17). 

Although treatment with iNO and conventional ventilation was associated with some 

measures of adverse outcome, the estimates of harm are the result of post hoc analyses and so 

must be considered cautiously (Appendix E, Evidence Table 17). We did not perform a metaanalysis for mode of delivery as only one study prospectively randomized infants to conventional 

versus high frequency ventilation and the other generated comparisons by post hoc analyses. 

No data are available on other methods of iNO delivery, such as high or low flow nasal 

cannula, or continuous positive airway pressure. 

Dose of iNO. The initial dose of iNO varied from 5 ppm to 20 ppm among the 14 

randomized trials. Data in preterm animal models of RDS indicates improvement in oxygenation 

in this range.93 Fear of adverse side effects, specifically bleeding with resulting IVH, resulted in 

71
 
 

 

 

 

 

 

 

 

 

 

 

limitation of iNO exposure in some studies (Appendix E, Evidence Table 17). For this review, 

studies were grouped as follows: dose restricted to 5 ppm; dose restricted to 10 ppm; dose 

titrated to response with a maximum of dose 20 ppm to 40 ppm, or dose given as 20 ppm. The 

effect of iNO doses on the primary outcomes are reviewed below. Meta-analyses were conducted 

with trials that reported death in the NICU at 36 weeks PMA or later; trials that reported death at 

seven days or 28 days were excluded. Separate meta-analyses were done that excluded Ballard 

2006, because it was the only RCT that delivered iNO for a prolonged period of time (minimum 

24 days); the results did not differ from what is reported. 

Death. When the dose of iNO was restricted to 5 ppm there was no difference in death at 36 

weeks PMA in two trials with 800 infants enrolled in each, RR 0.79 (0.61, 1.03) 37 and RR 1.34 

(0.92, 1.95) 62, or in death prior to hospital discharge, RR 0.90 (0.58, 1.40), in one trial with 80 

infants59 (Appendix E, Evidence Table 17). The pooled estimate of the risk of death showed no 

significant differences in treatment with this dose of iNO, RR 0.97 (0.70, 1.35) (Figure 16). 

The risk of death was similar in infants that received iNO therapy at a maximum dose of 10 

39, 40, 58, 61, 67 ppm compared with those receiving placebo in five randomized controlled trials

(Appendix E, Evidence Table 17). In the two studies by Van Meurs the risk of death before 

discharge home or within 365 days for those still hospitalized was not improved with iNO 

therapy in infants weighing 401 to 1500 grams birth weight, RR 1.16 (0.96, 1.39),40 or those with 

birth weight greater than 1500 grams, RR 1.34 (0.45, 4.00) 39 (Appendix E, Evidence Table 17). 

Three other studies found no significant decrease in death in the NICU (RR 0.68 (0.38, 1.20))58; 

20 percent iNO versus 30 percent placebo, p-value = 0.494 67, or at 28 days (41 percent iNO 

versus 31 percent placebo, no significant difference)61 (Appendix E, Evidence Table 17). Metaanalysis of the four studies that reported death in the NICU at 36 weeks PMA or later confirmed 

no statistically significant difference in death for infants treated with 10 ppm iNO compared to 

controls, RR 1.00 (0.73, 1.38) (Figure 16). 

No study found a difference in death between infants that were treated with iNO at 20 ppm or 

iNO titrated to response and those given standard care, regardless of whether the outcome was 

66 60, 64, 65 34 measured at seven days, during NICU hospitalization, at 36 weeks PMA, 40 weeks 

34 34 63 PMA, 44 weeks PMA, at one year of age corrected for gestational age at birth , or four to 

five years of age 35 (Appendix E, Evidence Table 17). The pooled estimate of the relative risk of 

death at 36 weeks PMA or later during NICU hospitalization showed no statistically significant 

difference between infants given iNO therapy delivered at 20 ppm or titrated to response and 

controls, RR 0.91 (0.63, 1.30) (Figure 16). 

The RR is similar across each dose category, with little heterogeneity, suggesting that the 

effect of iNO on the outcome of death does not vary by dose. 

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Figure 16. Meta-analysis for dose-stratified death, including only studies that reported death in the NICU at 

36 weeks PMA or later 

BPD at 36 weeks PMA. Bronchopulmonary dysplasia developed as frequently in those 

treated with 5ppm iNO as those treated with standard therapy when measured at 36 weeks PMA 

37, 59, 62 59 and when measured prior to hospital discharge (Appendix E, Evidence Table 17) The 

pooled estimate of the risk of BPD for the three trials that reported the outcome at 36 weeks 

PMA was RR 0.94 (0.87, 1.02) (Figure 17). 

The risk of BPD at 36 weeks PMA was mixed when iNO was given at a maximum dose of 

10 ppm. The largest trial, conducted by Van Meurs 2005, with more than 420 infants, reported a 

24 percent decrease in the risk of BPD compared to controls, RR 0.76 (0.58, 0.98).40 Three other 

trials, with a combined enrollment of 276 infants, reported no significant difference between 

39, 40, 58, 67 infants treated with iNO and controls (Appendix E, Evidence Table 17). A metaanalysis with all four RCTs found a 25 percent reduction in the risk of BPD at 36 weeks for 

infants treated with iNO at 10 ppm compared to controls, RR 0.75 (0.61, 0.91) (Figure 17). 

BPD at 36 weeks PMA was common, affecting one third to one half of all infants; the rate 

was not different between infants treated with 20 ppm or iNO titrated to response and those 

34, 63, 64, 65 receiving standard care in the four RCT that used this dosing strategy. The rate of BPD 

was also similar between the groups when defined as an oxygen requirement measured at 40 

73
 
 

 

 

 

 

 

 

 

Figure 17: Meta-analysis for dose-stratified BPD at 36 weeks PMA 

weeks PMA (22 percent iNO versus 29 percent placebo)34, 44 weeks PMA (9 percent iNO versus 

12 percent placebo),34 and at one year, corrected for gestational age at birth (15 percent iNO 

versus 6 percent placebo)60 (Appendix E, Evidence Table 17). A meta-analysis confirmed no 

significant difference in the risk of BPD at 36 weeks with iNO therapy at this dose, RR 1.00 

(0.74, 1.34) (Figure 17). 

Death or BPD. There was no reduction in the composite outcome of death or BPD with 

37, 62 5ppm iNO compared with controls, when measured at 36 weeks PMA, or prior to hospital 

discharge 59 (Appendix E, Evidence Table 17). Meta-analysis with these three trials resulted in a 

RR 0.94 (0.88, 1.01) (Figure 18). 

Evidence concerning the risk of death or BPD was mixed among the trials that gave 10 ppm 

iNO (Appendix E, Evidence Table 17). In the largest trial,40 with more than 200 patients in each 

arm, the RR of death or BPD at 36 weeks PMA in the iNO group was 0.97 (0.88, 1.07). A 

similar lack of benefit was found in a small trial of infants with birth weight > 1500 g when 

death was measured before hospital discharge or at 365 days for infants still hospitalized (RR 

0.83 (0.43 1.62)).39 However, two other studies reported iNO was associated with a decreased 

risk of death or BPD at 36 weeks PMA. In Schreiber, 2003,58 with more than 100 infants in each 

arm, the risk of death or BPD was decreased 23 percent in the iNO treated group (RR 0.77 (0.60, 

0.98)),and in a small study with 20 infants in each group, Dani, 200667 reported an 89 percent 

decrease in risk (OR 0.11 (0.02, 0.61)) among the iNO treated group (Figure 18). 

74
 
 

 

 

 

 

 

 

 

 

The opposite direction of the effect of iNO therapy at 10 ppm in the two largest trials may be 

accounted for by the degree of illness of infants at study entry. Infants in the study of Schreiber, 

200358 had a substantially lower oxygenation index at study entry (OI median (IQR) 7.3 (4.1, 

12.3 ) iNO group versus 6.8 (4.4, 12.7) control group) than infants in the study of Van Meurs, 

200540 ( OI mean (SD), 23 (17) iNO group versus 22 (17) placebo group) (see discussion of OI 

under Key Question 4) (Appendix E, Evidence Table 17). A meta-analysis revealed no 

significant difference in the risk of the combined outcome of death or BPD at 36 weeks PMA for 

infants treated with iNO at 10 ppm compared to controls, RR 0.81 (0.64, 1.03) (Figure 18). 

34, 60, 63, 64 In the four studies that dosed iNO at 20 ppm or titrated to response, 50 percent to 

100 percent of infants in each arm died or had BPD at 36 weeks PMA (Appendix E, Evidence 

Table 17). The pooled relative risk, RR 0.94 (0.84, 1.06), confirmed no difference to iNO 

treatment under these treatment protocols (Figure 18). 

Neurodevelopmental impairment. In a followup study of Kinsella, 2006, Watson 200936 

reported the rate of neurodevelopmental impairment (CP, severe hearing loss, blindness, or MDI 

or PDI < 70) at one year of age, corrected for gestational age at birth, was similar in the infants 

that received iNO at 5 ppm (35.4 percent) and those that received standard therapy (33.5 percent) 

groups (Appendix E, Evidence Table 17). 

Figure 18: Meta-analysis for dose-stratified death or BPD. 

75
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Only two of the studies giving iNO at 10 ppm evaluated long term neurodevelopmental 

40, 58 outcome and they found opposite effects. Reporting the followup of Van Meurs, 2005, 

Hintz, 2007,30 found no improvement in the combined outcome of death or neurodevelopmental 

impairment, defined as moderate to severe CP, blindness, deafness or an MDI or PDI < 70, at 18 

to 22 months of age for infants treated with iNO compared to placebo, RR 1.07 (0.95, 1.19), or in 

death or moderate to severe CP, RR 1.17 (0.99, 1.38). Moderate to severe CP was increased in 

the iNO group (20 percent versus 11 percent), a difference that was not significant in univariate 

analysis, but reached significance in multivariable models after adjustment for infant 

characteristics at study entry in one model, RR 2.01 (1.01, 3.98), and infant characteristics and 

NICU morbidities in another model, RR 2.41 (1.01, 5.75). In both models the confidence 

intervals are wide (Appendix E, Evidence Table 17). 

However, Mestan, 2005,56 reporting on the outcome of survivors at two years of age of the 

Schreiber, 2003 study, described a 47 percent decrease in the risk of cognitive impairment, 

defined as an a MDI < 70 (RR 0.53 (0.29, 0.94)), but no effect on motor impairment, defined as a 

PDI < 70 (RR 0.73 (0.33, 1.61)). Fewer infants treated with iNO had neurodevelopmental 

impairment, a composite variable including CP, blindness, hearing loss, and developmental 

delay, than infants treated with placebo (24 percent versus 46 percent respectively, p-value = 

0.01). This difference in the composite outcome was the result of fewer infants with cognitive 

impairment in the iNO group as there was no difference between the groups in the rate of CP, 

vision or hearing loss (Appendix E, Evidence Table 17). 

Three of the RCTs that gave iNO at 20 ppm or titrated the dose based on response reported 

35, 57, 76 57 long term developmental followup. Walsh, 2010 found no improvement in function at 

two years of age among infants treated with iNO in the study of Ballard, 2006.34 Rates of CP, 

cognitive delay, vision impairment, and hearing impairment were similar between the groups. In 

64 76 30 month followup of infants enrolled in the Subhedar, 1997, and Bennett, 2001 studies 

similar rates of neurodevelopmental delay (MDI or PDI < 85), severe disability (defined as MDI 

or PDI < 70, or hearing loss or blindness), or death and severe disability were found between 

iNO treated infants and those receiving standard care. Huddy, 200835 found no difference at four 

to five years of age between the groups enrolled in the study of Field, 200563 in the rates of CP, 

cognitive delay, vision, and hearing impairment, combined moderate to severe disability, or in 

those free of impairment (23 percent iNO versus 19 percent placebo) (Appendix E, Evidence 

Table 17). 

No meta-analyses were conducted for dose of iNO and neurodevelopmental impairment as 

the definition of impairment varied significantly between studies. 

In summary, a meta-analysis of studies of 10 ppm dose of iNO found a statistically 

significantly reduction in BPD at 36 weeks PMA but meta-analyses found no statistically 

significant effect on death, or the combined outcome of death or BPD compared to control. The 

finding of a statistically significant effect at 10 ppm may be spurious as there is no clinical 

34, 63-66 rationale for why that dose would be different from the others. Results for 

neurodevelopmental impairment at this dose were inconsistent. There was no statistically 

significant different between iNO and control at doses of 5 ppm, 20 ppm or titrating the dose to 

the patients’ response. 37 

iNO with concurrent therapies. Two studies directly addressed the effect of iNO with 

concurrent therapies. In a factorial design, Subhedar, 199764 randomized 20 infants to treatment 

with iNO and dexamethasone and compared their outcome to 22 infants randomized to 

dexamethasone alone. Dexamethasone was given intravenously every 12 hours for six days at 

76
 
 

 

 

 

 

 

 

0.5 mg/kg/dose for six doses, and 0.25 mg/kg/dose for the remaining six doses. All infants were 

less than 32 weeks gestational age at birth (Appendix E, Evidence Table 17). There was no 

difference between groups in the risk of death (RR 1.57 (0.76, 3.38)); BPD at 36 weeks PMA, 

defined as an oxygen requirement beyond 36 weeks PMA and an abnormal chest radiograph (RR 

0.79 (0.44, 1.33)); the combined outcome of death or BPD at 36 weeks PMA (RR 1.05 (0.84, 

1.25)); or BPD in survivors (RR 1.07 (0.71, 1.37)) (Appendix E, Evidence Table 17). 

In a post hoc analysis, Ballard, 2006 34 reported that there were no significant differences in 

response to iNO by exposure to postnatal corticosteroids, though data were not shown. In two 

year followup, Walsh 201057 found that there was no interaction between iNO treatment and 

postnatal dexamethasone therapy given > three days after study enrollment compared with 

dexamethasone given < three days from enrollment in a multivariable model of NDI. 

Conclusion 

Only two of the 14 randomized controlled trials that reported death, BPD, death or BPD, or 

58, 64 neurodevelopmental impairment planned a priori to evaluate infants by subgroups, so the 

evidence to answer this Key Question is not optimal. There is insufficient evidence to support 

treatment with iNO for acute lung disease within the first three days after birth. The one trial that 

compared infants treated at < three days with those treated at four to 28 days found no difference 

between the groups. Given that none of the 14 RCTs reviewed in Key Question 1 found a 

significant difference in mortality or survival between those treated with iNO controls, many of 

which initiated therapy at less than three days, it is likely that early treatment is not beneficial. 

However, the duration of exposure to iNO varied in the trials and has yet to be systematically 

studied. For infants with developing BPD, earlier treatment (7 to 14 days) may prove to be more 

beneficial than later treatment (15 to 21 days) as shown by improved survival without BPD in the 

Ballard 2006 trial; an RCT with this primary hypothesis needs to be done. It is not surprising that 

delivery of iNO by high frequency ventilation conferred no convincing benefit, as high 

frequency ventilation alone has not been shown to reduce mortality, BPD, or improve 

neurodevelopmental impairment in preterm infants compared to conventional ventilation in 

systematic review.94 The optimal dose of iNO has yet to be determined. Our meta-analysis found 

a statistically significant effect for 10 ppm for BPD at 36 weeks PMA, but this may be a spurious 

finding. A similar effect was not seen for death or the composite outcome of death or BPD. Dose 

34, 37, 63-66 may be less important than the duration of iNO exposure, but data are insufficient to 

make that determination. The effect of concurrent therapies other than postnatal dexamethasone 

and iNO administration has not been studied in preterm infants. 

77
 
78
 
 

 

 

 

 

 

Chapter 4. Discussion 

The most prevalent finding of this report is the lack of effectiveness of iNO in improving 

survival or decreasing pulmonary morbidity or neurodevelopmental impairment for preterm 

infants who receive respiratory support. A systematic review of the evidence and meta-analyses 

revealed no significant difference between preterm infants < 34 weeks gestational age treated 

with iNO and control infants in the risk for mortality, BPD at 36 weeks PMA, short term risks 

(PDA, sepsis, NEC, treated ROP, pulmonary hemorrhage, or air leak), brain injury, motor or 

cognitive impairment, sensory impairments, growth or many other health outcomes. 

The most important positive finding of this review is a meta-analysis of pooled data from 11 

RCTs that reported the composite outcome of death or BPD at 36 weeks PMA which found a 

small (7 percent) but statistically significant reduction in the risk with iNO therapy. Power 

calculations for sample size determination were performed a priori for death or BPD or its 

complement, survival without BPD, in eight of the 11 (73%) trials in the meta-analysis. It has 

been suggested that the study by Ballard, 200634 should not be included in meta-analyses as it 

had a very different study design as well as the lowest mortality rates when compared to the 

other RCTs. In a sensitivity analysis, removing Ballard, 2006 from this meta-analysis did 

not change the effect estimate (RR 0.93) but did result in wider confidence interval that included 

1. We feel that the meta-analysis with all 11 trials provides a more complete picture of the 

available evidence, considering the effect of iNO as a continuum of exposure 

By analyzing reported outcomes from the 14 RCTs and, where appropriate, other cohort 

studies, we tried to glean as much evidence as possible of how exposure to iNO influences 

preterm outcomes. Some statistically significant differences were reported for a few individual 

37, 58 RCTs included in this review. Two large trials reported a statistically significant reduction of 

brain injury in favor of iNO, and raised hopes that iNO may be neuroprotective. One followup 

study of a RCT found a statistically significant reduction in cognitive and neurodevelopmental 

impairment.56 One large multicenter trial was stopped early for concern that the iNO group had a 

higher rate of brain injury,40 and on followup at two years, found a statistically significant 

increase in the rate of CP with iNO compared to the control group. In contrast, a smaller trial in 

preterm infants with pulmonary hypertension found a reduction in CP rate with iNO38 None of 

our meta-analyses of these variables found statistically significant effects of iNO exposure, but 

variability in definitions of outcome variables hindered our ability to aggregate all of the 

available data and perform meaningful meta-analyses. 

Once iNO was found to be an effective treatment for full term and late preterm infants with 

hypoxemic respiratory failure,4 attention turned to using it in more immature preterm infants. 

Some of the earlier and smaller studies of iNO in preterm infants focused on immediate 

physiological response to iNO (i.e., improvement in oxygenation index, arterial-alveolar 

oxygenation ratio, changes in echocardiographic estimates of pulmonary artery pressure) and 

59-61, 64-67 toxicities, including methemoglobinemia, and pulmonary and intracranial hemorrhages.

72 64, 66, Some early studies started with the iNO dose recommended for full term infants, 20 ppm,

72 whereas other early studies started at 5 to 10 ppm, and some increased to 20-40 ppm if there 

60, 63, 65 was no response. The majority of the earlier RCTs began weaning iNO within two to six 

60, 61, 64-67 hours. An alternative approach views iNO as a potential growth promoter of the lung 

and its underlying vascular bed, requiring a longer duration of treatment. Since 2003, four well 

conducted multicenter RCTs and one single center RCT have published their outcomes for 200 

34, 37, 40, 58, 62 or more infants randomized to receive iNO or placebo gas for one or more weeks.

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Barrington and Finer conducted a systematic review of the evidence for efficacy and 

toxicities of iNO in preterm infants born before 35 weeks gestation, updated in 2007.31 They 

grouped 11 RCTs into categories based on inclusion criteria: 1) the early routine use of iNO (i.e., 

RCTs that treated preterm infants on mechanical ventilation in the first three days after birth) 

found a marginally significant reduction in death or BPD, RR 0.91 (95 percent CI 0.84, 0.99), 

and, in severe IVH, IPH or PVL, RR 0.70 (CI 0.53, 0.91); 2) early rescue treatment based on 

oxygenation inclusion criteria found no significant differences in death or BPD but a trend 

toward increased risk of severe IVH; and 3) enrollment based on increased risk of BPD at four or 

more days after birth, and there were no statistically significant effects of iNO on mortality or 

BPD or increase progression of IVH. They were able to report on neurodevelopmental outcomes 

56, 76 from only two RCTs.

The strength of the evidence was graded for all outcomes included in each key question and 

the results are presented below (Tables 11 to 15). A summary of the meta-analyses completed, 

by key question and outcome, is provided in Table 16. 

Our review differs from the Barrington and Finer Cochrane review31 in that there have been 

three more RCTs published: 1) a small Asian RCT of 65 infants with severe respiratory distress 

syndrome (Su, 200865), 2) a report of the 29 infants born below 34 weeks gestation but with 

birth weight above 1500 g from the NICHD Neonatal Research Network (Van Meurs, 2007),39 

and 3) a large multicenter trial of 800 infants with gestational ages of 24 to 28 weeks.62 In 

addition, we were charged with a broader mission: to review the data regarding a number of 

short term risks, long term pulmonary and neurodevelopmental outcomes, outcomes among 

subpopulations, and the effects of iNO dose, timing, duration, and concurrent therapies on 

outcomes. By using a broader definition to include outcome at one year corrected for degree of 

prematurity, and finding more recent outcome studies, including one with outcomes at four to 

30, 35, 36, 39, 44, 56, 57, 76 five years, we were able to review long term outcomes for eight RCTs. The 

Barrington and Finer Cochrane systematic review31 makes a valid point that the studies of iNO in 

preterm infants vary substantially in their eligibility criteria. The RCTs also vary widely in dose, 

method, and duration of administration of iNO. But the focus of studying effects of iNO on 

preterm infants has evolved from immediate pulmonary or cardiovascular effects, to how it may 

influence the growth and maturation of the developing lung and its cardiovascular support. To 

provide another perspective, we chose to view the variation in respiratory disease severity, iNO 

dose, method, and duration of iNO administration as varying degrees of iNO exposure on a 

continuum of degree of organ maturation, as measured by postmenstrual age. Postmenstrual age 

is the sum of gestational age at birth and chronological age, and is currently the best measure of 

preterm maturation that we have. We view brain injury and neurodevelopmental outcomes also 

in terms of degree of maturation (i.e., PMA) when exposed to iNO. The heterogeneity of our 

meta-analyses for the composite brain injury variable and for cognitive impairment could be 

explained by the effect of iNO in the two trials that included preterm infants with birth weights 

39, 58 over 1500 g (Schreiber, 2003 and Van Meurs, 2007). The bigger infants are more likely to be 

the more mature infants, and may benefit more from iNO effects on pulmonary blood flow 

because they are better able to autoregulate their cerebral blood flow. 

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Table 11. Strength of evidence for articles addressing Key Question 1 

Outcome Number of 

Studies; 

Subjects 

Risk of Bias 

Design/ 

Quality 

Consistency Directness Precision Strength of 

Evidence 

Death/Survival 14; 4754 RCT/ fair Consistent Direct Imprecise Moderate 

Death or BPD 12; 3301 RCT/ fair Inconsistent Direct Imprecise Low 

BPD at 36 Weeks 12; 2665 RCT/ fair Consistent Direct Imprecise Moderate 

BPD, other 

measures 

11; 3315 RCT/ fair Inconsistent Indirect Imprecise Low 

BPD = bronchopulmonary dysplasia 

Table 12. Strength of evidence for articles addressing Key Question 2 

Outcome Number of 

Studies; 

Subjects 

Risk of Bias 

Design; 

Quality 

Consistency Directness Precision Strength 

of 

Evidence 

Pulmonary 

Hemorrhage 

7; 2085 RCT/ fair Consistent Direct Imprecise Moderate 

Air leak or 

Pneumothorax 

10; 2361 RCT/ fair Consistent Direct Imprecise Moderate 

Methemoglobine 

mia 

12; 3190 RCT/ fair Consistent Direct Imprecise Moderate 

Brain Injury 13; 2936 RCT/ good Unknown Direct Imprecise Low 

PDA 11; 2870 RCT/ fair Consistent Direct Imprecise Moderate 

Sepsis 8; 2958 RCT/poor Consistent Indirect Imprecise Low 

NEC 8; 2683 RCT/ fair Consistent Direct Imprecise Moderate 

ROP 8; 2025 RCT/fair Consistent Direct Imprecise Moderate 

PDA = patent ductus arteriosus; NEC = necrotizing enterocolitis; ROP = severe retinopathy of prematurity 

81
 
Table 13.Strength of evidence for articles addressing Key Question 3 

Outcome Number of 

Studies; 

Subjects 

Risk of 

Bias 

Design; 

Quality 

Consistency Directness Precision Strength 

of 

Evidence 

Death and 

Survival 

9; 2635 RCT/ fair Consistent Direct Imprecise Moderate 

Cerebral palsy 6; 914 RCT/ fair Inconsistent Direct Imprecise Low 

1; 9 Cohort/fair 

Sensory 

Impairment 

7; 951 RCT/ poor Consistent Direct Imprecise Moderate 

Cognitive 

Outcomes 

5; 896 RCT/ poor Inconsistent Direct Imprecise Low 

Neurodevelopme 

ntal Impairment 

7; 1315 RCT/ good Inconsistent Direct Imprecise Low 

Death or 

Neurodevelopme 

ntal Impairment 

4; 1236 RCT/ good Consistent Direct Imprecise Moderate 

Growth 5; 968 RCT/ fair Consistent Direct Imprecise Low 

1; 10 Cohort/poor Unknown Direct Unknown Insufficient 

Pulmonary and 

other health 

outcomes 

4; 1329 RCT/poor Inconsistent Direct Imprecise Low 

2; 35 Cohort/poor 

Oral feeding 1; 108 RCT/ poor Unknown Direct Unknown Insufficient 

Table 14. Strength of Evidence for articles being addressed by Key Question 4 

Outcome Number of 

Studies; 

Subjects 

Risk of Bias 

Design/ 

Quality 

Consistency Directness Precision Strength of 

Evidence 

Death 6; 1444 RCT/ fair Consistent Direct Imprecise Moderate 

2; 57 Cohort/ poor 

Death or BPD 6; 1529 RCT/ fair Inconsistent Direct Imprecise Low 

Death or NDI 3; 851 RCT/ fair Consistent Direct Imprecise Low 

BPD at 36 weeks 4; 1321 RCT/ good Consistent Direct Imprecise Moderate 

BPD not defined 1; 18 Cohort/fair Unknown Indirect Imprecise Low 

Severe BPD, 

Mechanical vent 

(survivors) 

1; 16 Cohort/fair Unknown Direct Imprecise Low 

On O2 at 1 year 1: 502 RCT/Good Inconsistent Direct Imprecise Low 

Survival without 

BPD 

2; 790 RCT/ fair Consistent Direct Imprecise Moderate 

Survival to 

discharge 

1; 41 Cohort/ poor Unknown Direct Imprecise Low 

Survival > 28 days 1; 18 Cohort/fair Unknown Direct Imprecise Low 

Survival with BPD 1; 208 RCT/good Unknown Direct Imprecise Low 

Cerebral palsy 1; 31 Cohort/ fair Unknown Direct Imprecise Low 

Neurodevelopmental 

Index-related 

outcomes 

5; 1442 RCT/ good Inconsistent Direct Imprecise Low 

Severe IVH (3-4) or 

PVL 

1; 420 RCT/ good Unknown Direct Imprecise Low 

82
 
 

Table 14. Strength of Evidence for articles being addressed by Key Question 4 (continued) 

BPD = bronchopulmonary dyplasia; NDI = neurodevelopmental impairment; IVH = intraventricular hemorrhage; PVL = 

periventricular leukomalacia 

Table 15. Strength of Evidence for articles being addressed by Key Question 5 

Outcomes Number of 

Studies; 

Subjects 

Risk of Bias 

Design/ 

Quality 

Consistenc 

y 

Directness Precision Strength 

of 

Evidence 

Death 14; 2693 RCT/ fair Consistent Direct Imprecise Low 

Death or BPD 11; 2365 RCT/ fair Inconsistent Direct Imprecise Low 

Death or cerebral 

palsy 

1; 420 RCT/good Inconsistent Direct Imprecise Low 

Survival without 

BPD 

2; 734 RCT/ good Consistent Direct Imprecise Moderate 

BPD at 36 weeks 11; 1690 RCT/ fair Consistent Direct Imprecise Moderate 

Cerebral palsy 1; 420 RCT/good Inconsistent Direct Imprecise Low 

NDI 5; 1034 RCT/ fair Consistent Direct Imprecise Low 

Severe Disability 1; 420 RCT/good Inconsistent Direct Imprecise Low 

Table 16. Summary of meta-analyses 

Key 

Question Outcome 

Studies, 

N 

Studies 

included 

in the 

metaanalysis GRADE RR (95% CI) 

1 Survival/Death 14 11 Moderate 0.97 (0.82, 1.15) 

Survival/Death 2* 14 10 Moderate 0.98 (0.81, 1.17) 

BPD at 36 weeks PMA 12 8 Moderate 0.93 (0.86, 1.003) 

Death or BPD at 36 

weeks PMA 

12 11 Low 0.93 (0.87, 0.99) 

Death or BPD at 36 

weeks PMA* 

12 10 Low 0.93 (0.87, 1.00) 

2 Brain injury 13 5 Low 0.86 (0.56, 1.29) 

PDA 11 9 Moderate 1.01 (0.86, 1.19) 

Sepsis 8 8 Low 1.05 (0.95, 1.18) 

NEC 8 7 Moderate 1.23 (0.94, 1.26) 

ROP 8 8 Moderate 1.01 (0.82. 1.24) 

Pulmonary hemorrhage 7 4 Moderate 0.89 (0.60, 1.33) 

Air leak 10 7 Moderate 0.95 (0.71, 1.28) 

3 Survival/Death 9 7 Moderate 1.02 (0.86, 1.20) 

Cerebral palsy 7 7 Low 1.07 (0.67, 1.71) 

PDI < 70 4 4 Low 0.95 (0.66, 1.36) 

MDI < 70 3 3 Low 0.78 (0.39, 1.60) 

Sensory impairment 

(visual) 

7 6 Moderate 1.09 (0.52, 2.034 

Sensory impairment 

(hearing) 

7 6 Moderate 1.50 (0.69, 3.27) 

NDI 7 6 Low 0.91 (0.74, 1.12) 

4 NO META-ANALYSES 

83
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 16. Summary of meta-analyses (continued) 

Key 

Question Outcome 

Studies, 

N 

Studies 

included 

in the 

metaanalysis GRADE RR (95% CI) 

5 Dose stratified death 14 11 Low 0.97 (0.82, 1.15) 

5 ppm iNO 3 3 0.97 (0.70, 1.35) 

10 ppm iNO 5 4 1.00 (0.73, 1.38) 

20 ppm iNO 6 4 0.91 (0.63, 1.30) 

BPD at 36 weeks PMA 13 11 Moderate 0.90 (0.82, 0.98) 

5 ppm iNO 3 3 0.94 (0.87, 1.02) 

10 ppm iNO 5 4 0.75 (0.61, 0.91) 

20 ppm iNO 5 4 0.99 (0.74, 1.34) 

Death or BPD at 36 

weeks PMA 

11 11 Low 0.93 (0.87, 0.99) 

5 ppm iNO 3 3 0.94 (0.88, 1.01) 

10 ppm iNO 4 4 0.08 (0.64, 1.03) 

20 ppm iNO 4 4 0.94 (0.84, 1.06) 

*Analysis does not include the Ballard, 200634 data 

RR = Risk ratio; CI = confidence interval; BPD = bronchopulmonary dysplasia; PMA = post menstrual age; PDA = patent ductus 

arteriosis; NEC = Necrotizing enterocolitis, ROP = retinopathy of prematurity, treated; PDI = physical development index; MDI 

= mental development index; ppm = parts per million 

A recent individual patient data meta-analysis has been presented,95 but has not yet been 

published. A synthesis of data on short term outcomes on 3298 preterm infants (< 37 weeks) 

from 11 trials found no statistically significant differences in death or CLD, RR 0.96 (0.92, 1.01) 

or in severe neurological abnormalities on neuroimaging, RR 1.12 (0.98, 1.28).95 They concluded 

that there was a lack of evidence to support the “indiscriminate” use of iNO in treating preterm 

infants with respiratory failure. 

The driving force behind the studies of iNO in preterm infants who receive respiratory 

support is the search for an effective treatment that improves survival and pulmonary health 

without increasing the risk of adverse short and long term outcomes. As many as one third to one 

half of the preterm infants enrolled in the studies discussed in this report died in the NICU. Most 

of the survivors had residual chronic lung disease (BPD) that significantly prolonged their 

hospitalization and influenced their quality of life after discharge home from the NICU. In the 

two studies that reported it, only 20 to 40 percent of survivors in both the iNO and control groups 

30, 35, 36 had normal neurodevelopmental outcomes at one to two years. As cohort studies and 

RCTs of iNO in preterm infants born at or before 34 weeks gestation were being conducted, off 

label use of iNO in this population dramatically increased. One publication reported a six fold 

increase in its use between 2000 and 2008 in a large multisite pediatric group.47 

Whether the small statistically significant reduction of death or BPD we found on metaanalysis is clinically meaningful depends on one’s point of view. When compared to the 

evidence amassed for the efficacy iNO in treating full term infants and preterm infants born after 

34 weeks gestation with respiratory failure, a reduction of death or BPD by less than 10% is very 

weak. But many parents would grasp at even that small a difference in their sick preterm infant’s 

chances in surviving without BPD or NDI. We agree with Barrington and Finer in their 2007 

31 96 Cochrane review and Askie, 2010 (abstract) that current evidence does not support the 

routine use of iNO to treat preterm infants. We do not conclude, however, that we should 

abandon the possibility that iNO may someday become a component of a treatment strategy for 

some preterm infants receiving respiratory support. Several factors contribute to our 

84
 
 

recommendation to continue the study of iNO: 1) our finding a small but statistically significant 

difference in death or BPD at 36 weeks PMA, the common primary outcome variable of 73 

percent of RCT conducted to date; 2) the statistically significant finding of a diminished need for 

chronic pulmonary medication at one year corrected age, suggesting less severe lung disease in 

those treated with iNO, and 3) no studies have been powered to detect meaningful differences in 

infant functional outcome or quality of life with iNO treatment compared to standard therapy. 

Treatment of preterm infants born at or below 34 weeks gestation with iNO should occur 

only in the context of rigorously conducted RCTs that have the power to detect meaningful long 

term outcomes. Strategies for treatment need to consider how different preterm infants are from 

full term infants. Their immature organs are not prepared to support extrauterine life, persistent 

pulmonary hypertension is not as much of a problem early in the disease process, they lack 

important natural defenses (e.g., surfactant, cortisol, immune responses), and their response to 

organ injury seems to vary depending on degree of maturation. Studies of iNO therapy to date 

have enrolled and treated infants based on gestational age and chronological age, both imperfect 

measures of maturity. Degree of lung and brain maturation seems to be a very important 

variable, and treatment should be viewed in terms of postmenstrual age, a construct that better 

reflects organ maturation. Consideration of postmenstrual age at the time of initiation and 

duration of iNO therapy may help select subgroups of infants most like to benefit from the 

therapy. Funded, ongoing basic research into the mechanisms by which iNO may influence the 

developing lung can provide insight into how to design future clinical trials. Evaluating the effect 

of iNO on brain injury requires neuroimaging before treatment, as well as on serial studies. BPD 

at 36 weeks PMA and evidence of brain injury are important mediators. Prolonged 

hospitalizations, use of supplemental oxygen and pulmonary medications after NICU discharge, 

prevalence of reactive airway disease and recurrent hospitalizations (as reported by Ballard, 

34 44 44 2006 and Hibbs, 2007 ) are more important indicators of pulmonary function and health. 

Neurodevelopmental outcomes and functional abilities in childhood are far more important 

outcomes than evidence of brain injury on neuroimaging studies. Careful assessment of the few 

statistically significant but inconsistent differences with iNO exposure, combined with ongoing 

basic science and clinical research on the developing lung and brain, their response to and 

recovery from injury can provide insights that lead to testable hypotheses for future randomized 

controlled trials. 

85
 
86
 
 

 

 

 

 

Chapter 5. Future Research 

Future studies on the efficacy of iNO therapy for preterm infants that require respiratory 

support should have strong conceptual frameworks that test hypotheses on the mechanism by 

which iNO therapy improves pulmonary or neurodevelopmental outcomes. Such research should 

measure biomarkers of this mechanism of action, beyond improvement in oxygenation and 

neuroimaging. Inhaled NO has been given to infants as prophylaxis to prevent the development 

of BPD, as rescue therapy for respiratory failure, and as treatment in those with evolving BPD. 

Future studies should postulate and test hypotheses concerning the role of iNO in improving 

outcomes for any of these conditions or groups of preterm infants. 

Bronchopulmonary dysplasia at 36 weeks PMA and intraventricular hemorrhage, 

intraparenchymal hemorrhage, and periventricular leaukomalacia are useful intermediate 

variables and should be thought of in that context. Although neuroimaging of brain injury can 

monitor for safety, the more important outcomes for future RCTs are neurodevelopmental 

outcomes and function in childhood. Standardized tools that measure childhood quality of life 

and functional outcomes would assess the long term impact of iNO on health and development. 

Considerations of the frequency of pulmonary rehospitalization, chronic and episodic pulmonary 

medication, and missed school days would provide a broader context in which to view the 

efficacy of iNO. Studies should be powered to assess pulmonary, neurodevelopmental, and 

health outcomes at two to five years or more. Measuring such outcomes will require substantial 

investment by funders. What follows are considerations for future research. 

Other Future Research Needs 

Patients 

RCTs must be adequately powered to assess the effect of iNO on subgroups of preterm 

infants, such as those of varying birth weight. 

Special care must be taken if infants born at the limit of viability are included in 

randomized controlled trials. These infants do not yet have alveoli (gas exchange occurs 

through their terminal bronchioles) and their brains do not yet have gyri or sulci. They are 

most vulnerable to organ injury, which may be most evident on long term followup. 

Every effort must be taken to obtain pulmonary, neurodevelopmental and health followup 

for all infants in this category. 

There may be a value to viewing the use of iNO in terms of postmenstrual age, which is a 

better measure of degree of maturation and takes into account both gestational age and 

chronologic age in developing preterm infants. 

Intervention 

Since the goal is to support pulmonary and brain development in the NICU, courses of 

iNO given for weeks, not days, should be studied. 

87
 
 

 

 

 

Mode of ventilation should be considered in randomization schemes for trials restricted to 

infants < 1500 grams, those at highest risk for death, BPD, and neurodevelopmental 

impairment, to adequately address the question concerning mode of delivery. 

As many of the smallest preterm infants are managed with CPAP or high flow nasal 

cannula alone, without intubation, information concerning iNO delivery with these 

devices is needed. 

Outcomes 

Future RCTs should require neuroimaging by standardized protocols before trial 

enrollment, to detect the occurrence and progression of brain injury during iNO 

treatment. 

Studies should be powered to assess long term neurodevelopmental, pulmonary, and 

other health outcomes. 

Outcomes should focus on functional status and quality of life, as well as 

neurodevelopmental disabilities. 

Studies are needed to provide information on resource utilization such as 

rehospitalizations, medications, physicians’ visits. Future focus should be on the real 

pulmonary problems of prolonged hospitalizations, use of supplemental oxygen, and 

pulmonary medications after NICU discharge, prevalence of reactive airway disease, and 

recurrent hospitalizations. 

Consideration should be given to assess longer term childhood outcomes (e.g., pulmonary 

function tests, school performances). 

Cost benefit analyses should be conducted with multicenter RCTs of iNO. 

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nitric oxide for prevention of bronchopulmonary 

dysplasia in premature babies (EUNO): a randomised 

controlled trial. Lancet 2010;376(9738):346-54 

63.	 Field D, Elbourne D, Truesdale A et al. Neonatal 

Ventilation With Inhaled Nitric Oxide Versus 

Ventilatory Support Without Inhaled Nitric Oxide for 

Preterm Infants With Severe Respiratory Failure: the 

INNOVO multicentre randomised controlled trial 

(ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

64.	 Subhedar NV, Ryan SW, Shaw NJ. Open randomised 

controlled trial of inhaled nitric oxide and early 

dexamethasone in high risk preterm infants. Arch Dis 

Child Fetal Neonatal Ed 1997; 77(3):F185-90. 

65.	 Su PH, Chen JY. Inhaled nitric oxide in the 

management of preterm infants with severe respiratory 

failure. J Perinatol 2008; 28(2):112-6. 

66.	 Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled 

nitric oxide therapy in premature infants with mild to 

moderate respiratory distress syndrome. J Med Assoc 

Thai 2002; 85 Suppl 2:S469-78. 

67.	 Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, 

Rubaltelli FF. Inhaled nitric oxide in very preterm 

infants with severe respiratory distress syndrome. Acta 

Paediatr 2006; 95(9):1116-23. 

68.	 Kumar VH, Hutchison AA, Lakshminrusimha S, 

Morin FC 3rd, Wynn RJ, Ryan RM. Characteristics of 

pulmonary hypertension in preterm neonates. J 

Perinatol 2007; 27(4):214-9. 

69.	 Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric 

oxide inhalation therapy in very low-birthweight 

infants with hypoplastic lung due to oligohydramnios. 

Pediatr. Int. 2004; 46(1):10-4. 

70.	 Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, 

Ballard RA. Changes in oxygenation with inhaled 

nitric oxide in severe bronchopulmonary dysplasia. 

Pediatrics 1999; 103(3):610-8. 

71.	 Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog 

WE. Safety and efficacy of nitric oxide in chronic lung 

disease. Arch Dis Child Fetal Neonatal Ed 2002; 

86(1):F41-5. 

72.	 Cheung P-Y, Peliowski A, Robertson CMT. The 

outcome of very low birth weight neonates ((less-than 

or equal to)1500 g) rescued by inhaled nitric oxide: 

Neurodevelopment in early childhood. J. Pediatr. 

1998; 133(6):735-9. 

73.	 Yadav M, Emmerson AJ. Inhaled nitric oxide in 

premature neonates. Lancet 1999; 354(9196):2162-3. 

74.	 Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, 

Subhedar N. Use of inhaled nitric oxide in the new 

born period: Results from the European inhaled nitric 

oxide registry. Acta Paediatr. 2010; 99(6):854-60. 

75.	 Ballard RA. Inhaled nitric oxide in preterm infants-­

correction. N Engl J Med 2007; 357(14):1444-5. 

76. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. 

Neurodevelopmental outcome in high-risk preterm 

infants treated with inhaled nitric oxide. Acta Paediatr 

2001; 90(5):573-6. 

77. Chock VY, Van Meurs KP, Hintz SR et al. Inhaled 

nitric oxide for preterm premature rupture of 

membranes, oligohydramnios, and pulmonary 

hypoplasia. Am J Perinatol 2009; 26(4):317-22. 

78. Hamon I, Fresson J, Nicolas MB, Buchweiller MC, 

Franck P, Hascoet JM. Early inhaled nitric oxide 

improves oxidative balance in very preterm infants. 

Pediatr Res 2005; 57(5 Pt 1):637-43. 

79.	 McAdams RM, Garza-Cox S, Yoder BA. Early-onset 

neonatal pneumococcal sepsis syndrome. Pediatr Crit 

Care Med 2005; 6(5):595-7. 

80.	 Ballard RA. Inhaled nitric oxide in preterm infants-­

correction. N Engl J Med 2007; 357(14):1444-5. 

81.	 Ryan SW, Nycyk J, Shaw BN. Prediction of chronic 

neonatal lung disease on day 4 of life. Eur J Pediatr 

1996; 155(8):668-71. 

82.	 Northway WH Jr, Rosan RC, Porter DY. Pulmonary 

disease following respirator therapy of hyalinemembrane disease: bronchopulmonary dysplasia. N 

Engl J Med 1967; 276:357-68. 

83.	 Van Marter LJ. Epidemiology of bronchopulmonary 

dysplasia. Semin Fetal Neonatal Med 2009; 

14(6):358-66. 

84.	 Walsh MC, Wilson-Costello D, Zadell A, Newman N, 

Fanaroff A. Safety, reliability, and validity of a 

physiologic definition of bronchopulmonary dysplasia. 

J Perinatol 2003; 23:451-6. 

85.	 Tennakoon J, Koh TH, Alcock G. Pyloric stenosis in a 

newborn baby with polycystic kidneys. J Perinatol 

2007; 27(2):125-6. 

86.	 Institute of Medicine, Committee on Understanding 

Premature Birth and Assuring Healthy Outcomes, 

Board on Health Sciences Policy. Preterm Birth: 

Causes, Consequences and Prevention. Behrman RE, 

Stith Butler A (Eds)Washington, DC: National 

Academies Press; 2007. 

87.	 Papile LA, Burnstein J, Burnstein R, Koffler H. 

Incidence and evolution of subependymal and 

intraventricular hemorrhage: a study of infants less 

than 1500 gm. J Pediatr 1978; 92:529-34. 

88.	 Palisano R, Rosenbaum P, Walter S, Russell D, Wood 

E, Galuppi B. Development and reliability of a system 

to classify gross motor function in children with 

cerebral palsy. Dev Med Child Neurol 1997; 

39(4):214-23. 

89.	 Elliot CD, Smith P, McCulloch K. British ability 

scales second edition (BAS II). Windsor: NFERNelson, 1996. 

90.	 Kuczmarski RJ, Ogden CL, Grummer-Strawn LM et 

al. CDC growth charts: United States. Advance data 

from vital and health statistics; no. 314. Hyattsville, 

MD: National Center for Health Statistics 2000. 

91.	 Da Costa DE, Nair AK, Pai MG, Al Khusaiby SM. 

Steroids in full term infants with respiratory failure 

and pulmonary hypertension due to meconium 

aspiration syndrome. Eur. J. Pediatr. 2001; 

160(3):150-3. 

92.	 Groenendaal F, Lammers H, Smit D, Nikkels PG. 

Nitrotyrosine in brain tissue of neonates after perinatal 

asphyxia. Arch Dis Child Fetal Neonatal Ed 2006; 

91(6):F429-33. 

93.	 Skimming JW, DeMarco VG, Cassin S. The effects of 

nitric oxide inhalation on the pulmonary circulation of 

preterm lambs. Pediatr Res 1995; 37(1):35-40. 

91
 
 

 

 

 

 

 

 

 

 

 

 

94.	 Cools F, Henderson-Smart DJ, Offringa M, Askie LM. 

Elective high frequency oscillatory ventilation versus 

conventional ventilation for acute pulmonary 

dysfunction in preterm infants. Cochrane Database 

Syst Rev. 2009 Jul 8;(3):CD000104. 

95.	 Askie L, Ballard R, Cutter G, et al. Inhaled Nitric 

Oxide in Preterm Infants: An Individual Patient Data 

Meta-Analysis. PASA Abstract, E-PAS2010: 

1172.7,2010. 

96.	 Askie LM, Ballard RA, Cutter G et al. Inhaled Nitric 

Oxide in preterm infants: a systematic review and 

individual patient data meta-analysis. BMC Pediatr 

2010; 10:15. 

92 
 

Appendix A: List of Acronyms 

Acronym Definition 

AHRQ Agency for Healthcare Research and Quality 

ArtrCath Arterial catheter 

BPD Bronchopulmonary dysplasia 

BSID Bayley scale of infant development 

BW Birth weight 

CMV Conventional mechanical ventilation 

Congen Congenital anomaly/malformation 

CP Cerebral palsy 

CPAP Continuous Positive Airway Pressure 

DQ Developmental quotient 

Dshunting Ductal Shunting 

ECMO Extracorporeal membrane oxygenation 

EDC Estimated date of confinement 

F/U Follow- up 

FDA Food and Drug Administration 

FiO2 Fraction of Inspired Oxygen 

g grams 

GA Gestational age 

GCAS General conceptual ability 

HFFI High-frequency flow interruption 

HFOV High-frequency oscillatory ventilation 

HFV High-frequency ventilation 

HRF Hypoxemic respiratory failure 

iNO inhaled Nitric Oxide 

intrprncyml Intraparenchymal lesion 

IPH intraparenchymal hemorrhage 

IQR Inter-quartile range 

IVH Intraventricular Hemorrhage 

JHU Johns Hopkins University 

KG Kilograms 

MAP Mean airway pressure 

MDI Mental developmental index 

mmHg millimeters of mercury 

NDI Neurodevelopmental impairment 

NEC Necrotizing enterocolitis 

NICU Neonatal intensive care unit 

NIH National Institutes of Health 

NO Nitric oxide 

NO2 Nitrogen dioxide 

OI Oxygenation Index 

Oligho Oligohydramnios 

OMAR Office of Medical Applications of Research 

PDA Patent Ductus Arteriosis 

PDI Physical developmental index 

PMA post menstrual age 

PPHN Persistent Pulmonary Hypertension of the Newborn 

ppm parts per million 

Pulmhyp Pulmonary hypoplasia 

PVL Periventricular leukomalacia 

RCT Randomized controlled trial 

RDS Respiratory distress syndrome 

Respfail Respiratory failure 

ROP Retinopathy of Prematurity 

RX treatment 

SD Standard deviation 

Vent Support Ventilation Support 

A‐1
 
APPENDIX B: Detailed Electronic Database Search Strategies
 

MEDLINE Strategy 

Terms Returns 

(("nitric oxide"[tiab] OR "nitric oxide"[mh] OR iNO[tiab]) AND ("infant, 

newborn"[mh] OR premature[tiab] OR preterm[tiab] OR prematurity[tiab])) NOT 

(Animal[mh] NOT Human[mh]) 

1747 

EMBASE Strategy 

(('nitric oxide':ab,ti OR 'nitric oxide'/exp OR 'ino':ab,ti) AND ('newborn'/exp OR 

'newborn':ab,ti OR 'prematurity'/exp OR 'premature':ab,ti OR 'prematurity':ab,ti 

OR 'preterm':ab,ti)) NOT ([animals]/lim NOT [humans]/lim) 

2464 

The Cochrane Central Register of Controlled Trials (CENTRAL) 

((((nitric oxide):ti,ab,kw OR (iNO):ti,ab,kw) AND ((infant):ti,ab,kw OR 

(newborn):ti,ab,kw OR (premature):ti,ab,kw OR (preterm):ti,ab,kw)) NOT 

((animals) NOT (humans))) 

260 

Psycinfo Strategy 

( TX "nitric oxide" or TX "iNO" ) and ( TX "infant, newborn" or TX "premature" or TX 

"preterm" or TX prematurity ) 

13 

B‐1
 
C‐1
C‐2
C‐3
C‐4
C‐5
C‐6
C‐7
C‐8
C‐9
C‐10
C‐11
C‐12
C‐13
C‐14
C‐15
C‐16
C‐17
C‐18
C‐19
C‐20
C‐21
C‐22
C‐23
C‐24
C‐25
C‐26
C‐27
C‐28
C‐29
C‐30
C‐31
C‐32
C‐33
C‐34
C‐35
C‐36
C‐37
C‐38
C‐39
C‐40
C‐41
C‐42
C‐43
C‐44
C‐45
C‐46
 

Appendix D: List of Excluded Articles
 

 Caution over nitric oxide. Pharm. J. 2003; 271(7279):818. 

No original data 

Nitric oxide to prevent bronchopulmonary dysplasia. Arch. 

Dis. Child. 2006; 91(12):1022. 

No original data 

Abman, S. H. and Kinsella, J. P.. Inhaled nitric oxide for 

persistent pulmonary hypertension of the newborn: the 

physiology matters!. Pediatrics 95; 96(6):1153-5. 

No original data 

Abman, S. H. and Kinsella, J. P.. Inhaled nitric oxide 

therapy of pulmonary hypertension and respiratory failure 

in premature and term neonates.. Adv. Pharmacol. 95; 

34:457-474. 

No original data 

Abman, S. H.. Inhaled nitric oxide therapy of severe 

neonatal pulmonary hypertension. ACTA Anaesthesiol. 

Scand. Suppl. 95; 39 (105):65-68. 

No original data 

Abman, S. H.. Neonatal pulmonary hypertension: A 

physiologic approach to treatment. Pediatr. Pulmonol. 

2004; 37(Suppl. 26):127-128. 

No original data 

Abman, S. H.. New developments in the pathogenesis and 

treatment of neonatal pulmonary hypertension.. Pediatr 

Pulmonol Suppl 99; 18:201-204. 

No original data 

Abman, S. H.. Role of inhaled nitric oxide in treatment of 

neonatal pulmonary hypertension. Zhongguo Yao Li Xue 

Bao 1997; 18(6):542-5. 

No original data 

Adisesh, A. and Snashall, D.. Inhaled nitric oxide. Lancet 

1996; 348(9039):1447-8. 

No original data 

Ahluwadia, J. S., Kelsall, A. W. R., Raine, J., Rennie, J. 

M., Mahmood, M., Oduro, A., Latimer, R., Pickett, J., and 

Higenbottam, T. W.. Safety of inhaled nitric oxide in 

premature neonates [6]. ACTA Paediatr. Int. J. Paediatr. 

1994; 83(3):347-348. 

No abstractable data 

No original data 

Ahluwalia, J., Tooley, J., Cheema, I., Sweet, D. G., Curley, 

A. E., Halliday, H. L., Field, D., Al'malik, H., Annamalai, 

S., Midgley, P., Hardy, P., Tomlin, K., and Elbourne, D.. A 

dose response study of inhaled nitric oxide in hypoxic 

respiratory failure in preterm infants. Early Hum. Dev. 

2006; 82(7):477-483. 

Article does not address any of the Key Questions 

Aikio, O., Saarela, T., Pokela, M. L., and Hallman, M.. 

Nitric oxide treatment and acute pulmonary inflammatory 

response in very premature infants with intractable 

respiratory failure shortly after birth. Acta Paediatr. Int. J. 

Paediatr. 2003; 92(1):65-69. 

Article does not address any of the Key Questions 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Aikio, O. and Hallman, M. Nitric oxide in the acute care of 

newborns and premature infants: Typpioksidi 

Vastasyntyneitten ja Keskosten Akuuttihoidossa. 

Duodecim. 2004; 120(15):1853-1858. 

Unobtainable 

Alano, M. A., Ngougmna, E., Ostrea, E. M. Jr, and 

Konduri, G. G.. Analysis of nonsteroidal antiinflammatory 

drugs in meconium and its relation to persistent pulmonary 

hypertension of the newborn. Pediatrics 2001; 107(3):519­

23. 

Article does not include infants born at less than 34 

weeks gestation 

Albert Bretons, D., Girona Comas, J., Casaldaliga Ferrer, 

J., Roqueta Mas, J., Perapoch Lopez, J., and Murtra Ferre, 

M.. Transposition of the great arteries and pulmonary 

hypertension: Inhaled nitric oxide as a therapy and surgical 

correction: Transposicion de grandes arterias e hipertension 

pulmonar: Tratamiento con oxido nitrico inhalado y 

correccion anatomica Precoz. An. Esp. Pediatr. 1997; 

47(6):633-635. 

Not written in English and cannot determine eligibility 

Aly, H., Sahni, R., and Wung, J. T.. Weaning strategy with 

inhaled nitric oxide treatment in persistent pulmonary 

hypertension of the newborn. Arch Dis Child Fetal 

Neonatal Ed 1997; 76(2):F118-22. 

Article does not address any of the Key Questions 

Ambalavanan, N., Van Meurs, K. P., Perritt, R., Carlo, W. 

A., Ehrenkranz, R. A., Stevenson, D. K., Lemons, J. A., 

Poole, W. K., and Higgins, R. D.. Predictors of death or 

bronchopulmonary dysplasia in preterm infants with 

respiratory failure. J Perinatol 2008; 28(6):420-6. 

No abstractable data 

Andelfinger, G., Shirali, G. S., Raunikar, R. A., and Atz, A. 

M.. Functional pulmonary atresia in neonatal Marfan's 

Syndrome: Successful treatment with inhaled nitric oxide. 

Pediatr. Cardiol. 2001; 22(6):525-526. 

Article does not include infants born at less than 34 

weeks gestation 

Arioni, C., Bellini, C., Mazzella, M., Zullino, E., Serra, G., 

and Toma, P.. Congenital right diaphragmatic hernia. 

Pediatr. Radiol. 2003; 33(11):807-808. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Ashida, Y., Miyahara, H., Sawada, H., Mitani, Y., and 

Maruyama, K.. Anesthetic management of a neonate with 

vein of galen aneurysmal malformations and severe 

D‐1
 

 

 

Appendix D: List of Excluded Articles
 

pulmonary hypertension. Paediatr. Anaesth. 2005; 

15(6):525-528. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Athavale, K., Claure, N., D'Ugard, C., Everett, R., 

Swaminathan, S., and Bancalari, E.. Acute effects of 

inhaled nitric oxide on pulmonary and cardiac function in 

preterm infants with evolving bronchopulmonary dysplasia. 

J Perinatol 2004; 24(12):769-74. 

Article addresses Key Question 1 or 2 ONLY and is not 

a randomized controlled trial 

Other reason 

Athena IP-H. The effect of inhaled nitric oxide on medical 

andf functional Outcomes of premature infants at early 

school-age. American Pediatric Society/SocieTY for 

Pediatric Research Abstract. 2008. CODEN: RCT; ISSN: 

CN-00709184. 

Unobtainable 

Atz, A. M. and Wessel, D. L.. Inhaled nitric oxide in the 

neonate with cardiac disease. Semin Perinatol 1997; 

21(5):441-55. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Atz, A. M. and Wessel, D. L.. Sildenafil ameliorates effects 

of inhaled nitric oxide withdrawal. Anesthesiology 1999; 

91(1):307-10. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Atz, A. M., Munoz, R. A., Adatia, I., and Wessel, D. L.. 

Diagnostic and therapeutic uses of inhaled nitric oxide in 

neonatal Ebstein's Snomaly. Am J Cardiol 2003; 91(7):906­

8. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Bagolan, P., Casaccia, G., Crescenzi, F., Nahom, A., 

Trucchi, A., and Giorlandino, C.. Impact of a current 

treatment protocol on outcome of high-risk congenital 

diaphragmatic hernia. J Pediatr Surg 2004; 39(3):313-8; 

discussion 313-8. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Ballard R; Avital Cnaan; William E.Truog; Richard 

J.Martin; Anna Maria Hibbs; Philip L.Ballard; Jeffrey 

D.Merrill; Xiangun Luan; Sandra R.Wadlinger, and The 

NO CLD Study Group. decreased health services utilization 

in preterm infants treated with inhaled nitric oxide. 

Conference Abstracts Online. 2007. CODEN: RCT; ISSN: 

CN-00709217. 

Unobtainable 

Ballard, P. L., Merrill, J. D., Truog, W. E., Godinez, R. I., 

Godinez, M. H., McDevitt, T. M., Ning, Y., Golombek, S. 

G., Parton, L. A., Luan, X., Cnaan, A., and Ballard, R. A.. 

Surfactant function and composition in premature infants 

treated with ihaled nitric oxide. Pediatrics 2007; 

120(2):346-53. 

No abstractable data 

Ballard, P. L., Truog, W. E., Merrill, J. D., Gow, A., 

Posencheg, M., Golombek, S. G., Parton, L. A., Luan, X., 

Cnaan, A., and Ballard, R. A.. Plasma biomarkers of 

oxidative stress: relationship to lung disease and inhaled 

nitric oxide therapy in premature infants. Pediatrics 2008; 

121(3):555-61. 

Article does not address any of the Key Questions 

Ballard, R. A.. Inhaled nitric oxide in preterm infants-­

correction. N Engl J Med 2007; 357(14):1444-5. 

No abstractable data 

Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, 

Cannon BC, Kaine SF, Ivy DD, Webber SA, Rothman A, 

Ross RD, Aggarwal S, Takahashi M, and Waldman JD. 

Inhaled Nitric Oxide as a Preoperative Test (INOP Test I): 

the INOP Test Study Group.. Circulation 2002; 106(12 

Suppl 1):I76-81. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Banks BA, Pallotto E, and Ballard RA. A randomized, 

double blind, placebo controlled crossover pilot trial of 

inhaled nitric oxide (iNO) in preterm infants with evolving 

chronic lung disease (CLD). Pediatric Research 2001; 

49(4):284A. 

No abstractable data 

Baraldi, E., Bonetto, G., Zacchello, F., and Filippone, M.. 

Low exhaled nitric oxide in school-age children with 

bronchopulmonary dysplasia and airflow limitation. Am. J. 

Respir. Crit. Care Med. 2005; 171(1):68-72. 

Article does not address any of the Key Questions 

Barrington, K. J. and Finer, N. N.. Inhaled nitric oxide for 

preterm infants: a systematic review. Pediatrics 2007; 

120(5):1088-99. 

No original data 

Barton, L. L., Grant, K. L., and Lemen, R. J.. Changes in 

arterial oxygen tension when weaning neonates from 

inhaled nitric oxide. Pediatr. Pulmonol. 2001; 32(1):14-19. 

Article does not include infants born at less than 34 

weeks gestation 

Bassler, D., Choong, K., McNamara, P., and Kirpalani, H.. 

Neonatal persistent pulmonary hypertension treated with 

milrinone: Four case reports. Biol. Neonate 2006; 89(1):1­

5. 

Article does not address any of the Key Questions 

D‐2
 
 

Appendix D: List of Excluded Articles
 

Beligere, N. and Rao, R.. Neurodevelopmental outcome of 

infants with meconium aspiration syndrome: report of a 

study and literature review. J Perinatol 2008; 28 Suppl 

3:S93-101. 

Article does not include infants born at less than 34 

weeks gestation 

Bell, S. G.. The story of nitric oxide: from rascally radical 

to miracle molecule. Neonatal Netw 2004; 23(4):47-51. 

No original data 

Other reason 

Benitz, W. E., Rhine, W. D., Van Meurs, K. P., and 

Stevenson, D. K.. Nitrovasodilator therapy for severe 

respiratory distress syndrome.. J Perinatol 1996; 16(6):443­

448. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Benjamin, J. T., Hamm, C. R., Zayek, M., Eyal, F. G., 

Carlson, S., and Manci, E.. Acquired Left-Sided Pulmonary 

Vein Stenosis in an Extremely Premature Infant: A New 

Entity?. J. Pediatr. 2009; 154(3):459-459.e1. 

Article does not address any of the Key Questions 

Other reason 

Benjamin, J. T.. Practice and guidelines.. Pediatrics 1996; 

97(4):604-605. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Betremieux, P., Gaillot, T., De La Pintiere, A., Beuchee, 

A., Pasquier, L., Habonimana, E., Le Bouar, G., Branger, 

B., Milon, J., Fremond, B., Wodey, E., Odent, S., Poulain, 

P., and Pladys, P.. Congenital diaphragmatic hernia: 

Prenatal diagnosis permits immediate intensive care with 

high survival rate in isolated cases. A population-based 

study. Prenat. Diagn. 2004; 24(7):487-493. 

Article does not include infants born at less than 34 

weeks gestation 

Bhutani, V. K., Chima, R., and Sivieri, E. M.. Innovative 

neonatal ventilation and meconium aspiration syndrome. 

Indian J Pediatr 2003; 70(5):421-7. 

Article does not include infants born at less than 34 

weeks gestation 

Biban, P., Trevisanuto, D., Pettenazzo, A., Ferrarese, P., 

Baraldi, E., and Zacchello, F.. Inhaled nitric oxide in 

hypoxaemic newborns who are candidates for 

extracorporeal life support. Eur. Respir. J. 1998; 11(2):371­

376. 

Article does not include infants born at less than 34 

weeks gestation 

Bland, R. D.. Inhaled nitric oxide: A premature remedy for 

chronic lung disease?. Pediatrics 1999; 103(3):667-670. 

No original data 

Bohnhorst, B., Poets, C., and Freihorst, J.. Inhaled nitric 

oxide in severe bronchopulmonary dysplasia: Inhalatives 

stickstoffmonoxid in der therapie der schweren 

bronchopulmonalen dysplasie. Monatsschr. Kinderheilkd. 

2001; 149(7):686-690 

Not written in English and cannot determine eligibility 

Boloker, J., Bateman, D. A., Wung, J.-T., and Stolar, C. J. 

H.. Congenital diaphragmatic hernia in 120 infants treated 

consecutively with permissive hypercapnea/spontaneous 

respiration/elective repair. J. Pediatr. Surg. 2002; 

37(3):357-366. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Booth, G. R., Thornton, K., Jureidini, S., and Fleming, R. 

E.. Subendocardial infarction associated with ventricular 

hypertrophy in preterm infants with chronic lung disease. J. 

Perinatol. 2008; 28(8):580-583. 

Article does not address any of the Key Questions 

Bouchet, M., Renaudin, M.-H., Raveau, C., Mercier, J.-C., 

Dehan, M., and Zupan, V.. Safety requirement for use of 

inhaled nitric oxide in neonates [25]. LANCET 1993; 

341(8850):968-969. 

No human data included 

Other reason 

Braschi, A., Iannuzzi, M., Belliato, M., and Iotti, G. A.. 

Therapeutic use of nitric oxide in critical settings. Monaldi 

Arch Chest Dis 2001; 56(2):177-9. 

No original data 

Bruckheimer, E., Bulbul, Z., Pinter, E., Gailani, M., 

Kleinman, C. S., and Fahey, J. T.. Inhaled nitric oxide 

therapy in a critically ill neonate with Ebstein's anomaly. 

Pediatr. Cardiol. 1998; 19(6):477-479. 

Article does not include infants born at less than 34 

weeks gestation 

Burchfield, D. J., Blackmon, L. R., and Barrington, K. J.. 

Postnatal steroids to treat or prevent chronic lung disease in 

preterm infants [4] (multiple letters). Pediatrics 2003; 

111(1):221-222. 

No original data 

Cavallaro, G., Agazzani, E., Andaloro, L., Bottura, C., 

Cristofori, G., Mussini, P., Sacco, F., and Compagnoni, G.. 

[Sildenafil and nitric oxide inhalation in neonatal 

pulmonary hypertension. Three case reports]. Pediatr Med 

Chir 2008; 30(3):149-55. 

Not written in English and cannot determine eligibility 

Channick, R. N. and Rubin, L. J.. Combination therapy for 

pulmonary hypertension: a glimpse into the future?. Crit 

Care Med 2000; 28(3):896-7. 

No original data 

D‐3
 
 

 

 

Appendix D: List of Excluded Articles
 

Chaudhari, M., Vogel, M., Wright, C., Smith, J., and 

Haworth, S. G.. Sildenafil in neonatal pulmonary 

hypertension due to impaired alveolarisation and plexiform 

pulmonary arteriopathy. Arch Dis Child Fetal Neonatal Ed 

2005; 90(6):F527-8. 

Article does not include infants born at less than 34 

weeks gestation 

Cheifetz, I. M.. Inhaled nitric oxide: plenty of data, no 

consensus. Crit Care Med 2000; 28(3):902-3. 

No original data 

Cheung, P. Y., Etches, P. C., and Radomski, M. W.. NO 

effect on hemostasis. J Pediatr 1999; 134(3):383-4. 

No original data 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Cheung, P.-Y., Salas, E., Etches, P. C., Phillipos, E., 

Schulz, R., and Radomski, M. W.. Inhaled nitric oxide and 

inhibition of platelet aggregation in critically ill neonates. 

Lancet 1998; 351(9110):1181-1182. 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Other reason 

Christopher Rhee, Sudhir Sriram Michael Schreiber 

William Meadow. Pediatrics University of Chicago 

Chicago IL.. Effects of Inhaled Nitric Oxide on Cardiac 

Output Using Point-Of-Care Bedside Echocardiography in 

Preterm Infants. PASAbstracts 2009; 

#volume#:#startpage#. 

Article does not address any of the Key Questions 

No abstractable data 

Christou, H., Adatia, I., Van Marter, L. J., Kane, J. W., 

Thompson, J. E., Stark, A. R., Wessel, D. L., and 

Kourembanas, S.. Effect of inhaled nitric oxide on 

endothelin-1 and cyclic guanosine 5'- monophosphate 

plasma concentrations in newborn infants with persistent 

pulmonary hypertension. J. PEDIATR. 1997; 130(4):603­

611. 

Article does not include infants born at less than 34 

weeks gestation 

Christou, H., Magnani, B., Morse, D. S., Allred, E. N., Van 

Marter, L. J., Wessel, D. L., and Kourembanas, S.. Inhaled 

nitric oxide does not affect adenosine 5'-diphosphatedependent platelet activation in infants with persistent 

pulmonary hypertension of the newborn. Pediatrics 98; 

102(6):1390-1393. 

Article does not include infants born at less than 34 

weeks gestation 

Claire-Marie Loys, Delphine Maucort-Boulch Guy Putet 

Stephane Hays. Neonatologie Hopital de la Croix Rousse 

Hospices Civils de Lyon Université Claude Bernard Lyon 

France and Biostatistique, Hopital Lyon Sud Hospices 

Civils de Lyon Université Claude Bernard Lyon France.. 

Early Risk Factors for Death or Severe Brain Lesions in 

Extremely Low Birth Weight Preterm Infants. 

PASAbstracts 2009; #volume#:#startpage#. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

No abstractable data 

Clark, R. H., Bloom, B. T., Spitzer, A. R., and Gerstmann, 

D. R.. Reported medication use in the neonatal intensive 

care unit: data from a large national data set.. Pediatrics 

2006; 117(6):1979-1987. 

Article does not address any of the Key Questions 

Other reason 

Concheiro Guisan, A., Sousa Rouco, C., Suarez Traba, B., 

Paradela Carreira, A., Ocampo Cardalda, S., and Antelo 

Cortizas, J.. Inhaled iloprost: A therapeutic alternative for 

persistent pulmonary hypertension of the newborn [1]: 

Iloprost inhalado: Una alternativa terapeutica para la 

hipertension pulmonar persistente del recien nacido. An. 

Pediatr. 2005; 63(2):175-176. 

Not written in English and cannot determine eligibility 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Cornfield, D. N. and Abman, S. H.. Inhalational nitric 

oxide in pulmonary parenchymal and vascular disease. J 

Lab Clin Med 1996; 127(6):530-9. 

No original data 

Other reason 

Cui, X., Quezado, Z. M. N., and Eichacker, P. Q.. Inhaled 

nitric oxide: Is systemic host defense at risk?. Crit. Care 

Med. 2002; 30(4):945-946. 

No original data 

Article does not address any of the Key Questions 

Dahlheim, M., Witsch, M., Demirakca, S., Lorenz, C., and 

Schaible, T.. Congenital diaphragmatic hernia - Results of 

an ECMO-centre: Angeborene zwerchfellhernie - 

Ergebnisse eines ECMO-zentrums. Klin. Padiatr. 2003; 

215(4):213-222. 

Not written in English and cannot determine eligibility 

Dani, C., Bertini, G., and Rubaltelli, F. F.. Inhaled nitric 

oxide. N Engl J Med 2005; 353(15):1626-8; author reply 

1626-8. 

No abstractable data 

Datin-Dorriere, V., Rouzies, S., Taupin, P., Walter-Nicolet, 

E., Benachi, A., Sonigo, P., and Mitanchez, D.. Prenatal 

prognosis in isolated congenital diaphragmatic hernia. Am 

J Obstet Gynecol 2008; 198(1):80.e1-5. 

Article does not address any of the Key Questions 

Datin-Dorriere, V., Walter-Nicolet, E., Rousseau, V., 

Taupin, P., Benachi, A., Parat, S., Hubert, P., Revillon, Y., 

and Mitanchez, D.. Experience in the management of 

eighty-two newborns with congenital diaphragmatic hernia 

treated with high-frequency oscillatory ventilation and 

delayed surgery without the use of extracorporeal 

D‐4
 
 

 

 

 

 

Appendix D: List of Excluded Articles
 

membrane oxygenation. J. Intensive Care Med. 2008; 

23(2):128-135. 

Other reason 

Davis, C. F. and Sabharwal, A. J.. Management of 

congenital diaphragmatic hernia. Arch Dis Child Fetal 

Neonatal Ed 1998; 79(1):F1-3. 

No original data 

Day, R. W., Lynch, J. M., White, K. S., and Ward, R. M.. 

Acute response to inhaled nitric oxide in newborns with 

respiratory failure and pulmonary hypertension. Pediatrics 

1996; 98(4 Pt 1):698-705. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Day, R. W.. Cerebral blood flow velocity acutely decreases 

in newborns who respond to inhaled nitric oxide. Am. J. 

Perinatol. 2001; 18(4):185-194. 

Article does not address any of the Key Questions 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Day, R. W.. Inhaled nitric oxide prevents severe hypoxemia 

in newborns with acute lung disease and pulmonary 

hypertension. Pediatrics 1998; 101(6):1093-4. 

Article does not include infants born at less than 34 

weeks gestation 

Day, R. W.. Right ventricular size is acutely decreased by 

inhaled nitric oxide in newborns with pulmonary 

hypertension. Am J Perinatol 1998; 15(7):445-51. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

De Groote, K. and Van Overmeire, B.. Inhaled nitric oxide 

as treatment of persistent pulmonary hypertension in 

newborns: A review: INHALATIE VAN 

STIKSTOFMONOXIDE ALS BEHANDELING VAN 

PERSISTERENDE PULMONALE HYPERTENSIE BIJ 

DE PASGBORENE. EEN OVERZICHT. Tijdschr. 

Geneeskd. 1998; 54(12):817-823. 

Not written in English and cannot determine eligibility 

De Luca, D., Zecca, E., Vento, G., De Carolis, M. P., and 

Romagnoli, C.. Transient effect of epoprostenol and 

sildenafil combined with iNO for pulmonary hypertension 

in congenital diaphragmatic hernia [2]. Paediatr. Anaesth. 

2006; 16(5):597-598. 

Article does not include infants born at less than 34 

weeks gestation 

Di Fiore, J. M., Hibbs, A. M., Zadell, A. E., Merrill, J. D., 

Eichenwald, E. C., Puri, A. R., Mayock, D. E., Courtney, S. 

E., Ballard, R. A., and Martin, R. J.. The effect of inhaled 

nitric oxide on pulmonary function in preterm infants. J 

Perinatol 2007; 27(12):766-71. 

No abstractable data 

Dimitriou, G., Greenough, A., Kavvadia, V., Devane, S. P., 

and Rennie, J. M.. Outcome predictors in nitric oxide 

treated preterm infants. Eur. J. Pediatr. 1999; 158(7):589­

591. 

No abstractable data 

Dobyns, E. L., Anas, N. G., Fortenberry, J. D., Deshpande, 

J., Cornfield, D. N., Tasker, R. C., Liu, P., Eells, P. L., 

Griebel, J., Kinsella, J. P., and Abman, S. H.. Interactive 

effects of high-frequency oscillatory ventilation and inhaled 

nitric oxide in acute hypoxemic respiratory failure in 

pediatrics. Crit. Care Med. 2002; 30(11):2425-2429. 

Article does not address any of the Key Questions 

Dobyns, E. L., Griebel, J., Kinsella, J. P., Abman, S. H., 

and Accurso, F. J.. Infant lung function after inhaled nitric 

oxide therapy for persistent pulmonary hypertension of the 

newborn. Pediatr Pulmonol 1999; 28(1):24-30. 

Article does not include infants born at less than 34 

weeks gestation 

Dominguez, E. D., Vasallo, J. C., Berrueta, M., Acosta, L., 

Gaivironsky, R., and Polack, N.. High frequency 

ventilation and inhaled nitric oxide in pediatrics and 

neonatology: Avances en terapia intensiva neonatal y 

pediatrica. Ventilacion de alta frecuencia administracion de 

oxido nitrico inhalatorio. Prensa Med. Argent. 1998; 

85(7):823-827. 

Not written in English and cannot determine eligibility 

Drinkwater Jr., D. C., Aharon, A. S., Quisling, S. V., Dodd, 

D., Reddy, V. S., Kavanaugh-McHugh, A., Doyle, T., 

Patel, N. R., Barr, F. E., Kambam, J. K., Graham, T. P., and 

Chang, P. A.. Modified norwood operation for hypoplastic 

left heart syndrome. Ann. Thorac. Surg. 2001; 72(6):2081­

2087. 

Article does not address any of the Key Questions 

Drury, J. A., Nycyk, J. A., Subhedar, N. V., Shaw, N. J., 

and Cooke, R. W.. Inhaled nitric oxide does not increase 

lipid peroxidation in preterm infants. Eur J Pediatr 1998; 

157(12):1033. 

No abstractable data 

Du, L.-Z., Shi, L.-P., Sun, M.-Y., Zhou, B.-H., Chen, C., 

Shao, X.-M., Zhang, X.-D., Lu, Y., and Sun, B.. Inhaled 

nitric oxide in preterm and term neonates with hypoxemic 

respiratory failure and persistent pulmonary hypertension. 

Acta Pharmacol. Sin. 2002; 23(SUPPL.):69-73. 

No abstractable data 

Dubois, A., Storme, L., Jaillard, S., Truffert, P., Riou, Y., 

Rakza, T., Pierrat, V., Gottrand, F., Pruvot, F. R., Leclerc, 

F., and Lequien, P.. Congenital diaphragmatic hernia: 

Retrospective study of 123 cases: Les hernies congenitales 

des coupoles diaphragmatiques. Etude retrospective de 123 

observations recueillies dans le service de medecine 

neonatale du CHRU de Lille entre 1985 et 1996. Arch. 

Pediatr. 2000; 7(2):132-142. 

Not written in English and cannot determine eligibility 

D‐5
 
 

Appendix D: List of Excluded Articles
 

Dursun, S. M. and Robertson, H.. Nitric oxide in neonates. 

Lancet 2000; 356(9237):1274-5. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Duval, E. L. I. M., Leroy, P. L. J. M., Gemke, R. J. B. J., 

and Van Vught, A. J.. High-frequency oscillatory 

ventilation in RSV bronchiolitis patients. Respir. Med. 

1999; 93(6):435-440. 

Article does not address any of the Key Questions 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Dweik, R. A.. The promise and reality of nitric oxide in the 

diagnosis and treatment of lung disease. Cleve Clin J Med 

2001; 68(6):486, 488, 490, 493. 

No original data 

Easa, D., Murai, D. T., Oka, B., Dressel, M., Vanderford, 

P., Pelke, S., and Balaraman, V.. Early experience with 

inhaled nitric oxide for the treatment of infants and children 

with pulmonary hypertension. Hawaii Med J 1996; 

55(4):67-9. 

Article does not include infants born at less than 34 

weeks gestation 

Ehlen, M. and Wiebe, B.. Iloprost in persistent pulmonary 

hypertension of the newborn.. Cardiol Young 2003; 

13(4):361-363. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Ehrenkranz, R. A.. Inhaled nitric oxide and treatment of 

hypoxic respiratory failure. Zhongguo Yao Li Xue Bao 

1997; 18(6):546-7. 

Article does not include infants born at less than 34 

weeks gestation 

Ellington Jr., M., O'Reilly, D., Allred, E. N., McCormick, 

M. C., Wessel, D. L., and Kourembanas, S.. Child health 

status, neurodevelopmental outcome, and parental 

satisfaction in a randomized, controlled trial of nitric oxide 

for persistent pulmonary hypertension of the newborn. 

Pediatrics 2001; 107(6):1351-1356. 

Article does not include infants born at less than 34 

weeks gestation 

Ergenekon, E.. Inhaled nitric oxide in premature infants. J 

Pediatr 1998; 132(2):375. 

No original data 

Etches, P. C., Finer, N. N., Ehrenkranz, R. A., and Wright, 

L. L.. Clinical monitoring of inhaled nitric oxide. Pediatrics 

1995; 95(4):620-1. 

No original data 

Article does not address any of the Key Questions 

Favilli, S., De Simone, L., Pollini, I., Bettuzzi, M. G., 

Cianfrini, D., Crepaz, R., Santillo, V., Trevisanuto, D., 

Vignati, G., and Manetti, A.. Persistent pulmonary 

hypertension in newborns: Prevalence and clinical and 

echocardiographic features. A multicentric study: 

Prevalenza e caratteristiche della ipertensione polmonare 

persistente del neonato. Studio multicentrico. G. Ital. 

Cardiol. 1998; 28(11):1247-1252. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Field, D. and Elbourne, D.. Use of inhaled nitric oxide to 

improve oxygenation in the neonate [4]. Arch. Dis. Child. 

Fetal Neonatal Ed. 2000; 82(3):F258-F259. 

No original data
 

Field, D., Normand, C., and Elbourne, D.. Costeffectiveness of inhaled nitric oxide in the treatment of
 

neonatal respiratory failure in the US. Pediatrics 2003; 

112(6 Pt 1):1422-3. 

No original data 

Article does not address any of the Key Questions 

Field, D.. Trials of nitric oxide.. Biol. Neonate 2003; 

84(1):103-104. 

No original data 

Figueras Aloy, J., Sorni Hubrecht, A., Botet Moussons, F., 

Rodriguez Miguelez, J. M., and Jimenez Gonzalez, R.. 

[The immediate response to the administration of inhaled 

nitric oxide in a newborn infant with congenital 

diaphragmatic hernia and pulmonary hypertension]. An Esp 

Pediatr 1996; 44(1):70-2. 

Not written in English and cannot determine eligibility 

Figueras-Aloy, J., Gomez, L., Rodriguez-Miguelez, J. M., 

Jordan, Y., Salvia, M. D., Jimenez, W., and CarbonellEstrany, X.. Plasma nitrite/nitrate and endothelin-1 

concentrations in neonatal sepsis. Acta Paediatr. Int. J. 

Paediatr. 2003; 92(5):582-587. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Finer, N. N.. Inhaled nitric oxide for preterm infants: a 

therapy in search of an indication? The search continues. J 

Pediatr 2005; 146(3):301-3. 

No original data 

Firth, A. L. and Yuan, J. X.. Bringing down the ROS: a 

new therapeutic approach for PPHN. Am J Physiol Lung 

Cell Mol Physiol 2008; 295(6):L976-8. 

No original data 

Fletcher, G. and Daniel, M.. Problems in assessing the 

effect of nebulized prostacyclin in patients whose lungs are 

ventilated. Anesthesiology 1996; 84(1):242-3 

No original data 

Flieger, K.. The benefit of nitric oxide inhalation in 

premature infants is disputed: Nutzen der NO-inhalation 

D‐6
 
 

 

 

 

 

 

 

 

Appendix D: List of Excluded Articles
 

bei fruhgeborenen umstritten. Geburtshilfe Frauenheilkd. 

2006; 66(3):216. 

Not written in English and cannot determine eligibility 

Fraisse, A., Geva, T., Gaudart, J., and Wessel, D. L.. 

Predictive factors of Doppler echocardiography in 

persistent pulmonary artery hypertension of the neonate: 

Facteurs predictifs de l'echocardiographie-Doppler dans 

l'hypertension arterielle pulmonaire persistante du nouveaune. Arch. Mal. Coeur Vaiss. 2004; 97(5):501-506. 

Not written in English and cannot determine eligibility 

Article does not include infants born at less than 34 

weeks gestation 

Fredly, S., Aksnes, G., Viddal, K. O., Lindemann, R., and 

Fugelseth, D.. The outcome in newborns with congenital 

diaphragmatic hernia in a Norwegian region. Acta Paediatr 

2009; 98(1):107-11. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Frenckner, B.. Congenital diaphragmatic hernia. INT. J. 

ARTIF. ORGANS 1995; 18(10):579-583. 

No original data 

Article does not address any of the Key Questions 

Frostell, C. G., Lonnqvist, P. A., Sonesson, S. E., 

Gustafsson, L. E., Lohr, G., and Noack, G.. Near fatal 

pulmonary hypertension after surgical repair of congenital 

diaphragmatic hernia. Successful use of inhaled nitric 

oxide. Anaesthesia 1993; 48(8):679-83. 

Article does not include infants born at less than 34 

weeks gestation 

Frostell, C. G.. Clinical aspects of nitric oxide and 

surfactant replacement. Biol Neonate 1997; 71 Suppl 1:39­

43. 

No original data 

Frostell, C. G.. Nitric oxide and acute respiratory failure. 

Monaldi Arch Chest Dis 1996; 51(6):538-42. 

No original data 

Fujikawa, S., Yang, L., Waffarn, F., and Lerner, M.. 

Persistent pulmonary hypertension of the newborn (PPHN) 

treated with inhaled nitric oxide: preliminary hearing 

outcomes. J Am Acad Audiol 1997; 8(4):263-8; quiz 297. 

Article does not include infants born at less than 34 

weeks gestation 

Gaio, G., Santoro, G., Esposito, R., Bianco, G., Giliberti, 

P., Russo, M. G., and Calabro, R.. Patent ductus arteriosus 

'stenting' as a life-saving approach in severe neonatal 

Ebstein's anomaly. J Cardiovasc Med (Hagerstown) 2007; 

8(11):937-9. 

Article does not include infants born at less than 34 

weeks gestation 

Gao, X. R., Wu, Y. Q., and Li, L.. [Clinical analysis of 

chronic lung disease in preterm infants]. Zhongguo Dang 

Dai Er Ke Za Zhi 2008; 10(4):539-40. 

Not written in English and cannot determine eligibility 

Gao, X. R., Wu, Y. Q., Peng, X. M., Huang, M., and Liu, 

X. H.. Inhaled nitric oxide for newborn infants with severe 

respiratory failure. Zhongguo Dang Dai Er Ke Za Zhi 2006; 

8(2):155-157. 

Not written in English and cannot determine eligibility 

Gaston, B. and Keith, J. F. 3rd. Nitric oxide and bleeding 

time. Pediatrics 94; 94(1):134-5 No original data 

Gaston, B., Keith III, J. F., Kinsella, J. P., and Abman, S. 

H.. Nitric oxide and bleeding time [4]. PEDIATRICS 1994; 

94(1):134-135. 

No original data 

Article does not address any of the Key Questions 

Geary, C. and Whitsett, J.. Inhaled nitric oxide for 

oligohydramnios-induced pulmonary hypoplasia: A report 

of two cases and review of the literature. J. Perinatol. 2002; 

22(1):82-85. 

Article does not address any of the Key Questions 

Geggel, R. L.. Inhalational nitric oxide: a selective 

pulmonary vasodilator for treatment of persistent 

pulmonary hypertension of the newborn. J Pediatr 1993; 

123(1):76-9. 

No original data 

George, T. N., Johnson, K. J., Bates, J. N., and Segar, J. L.. 

The effect of inhaled nitric oxide therapy on bleeding time 

and platelet aggregation in neonates. J. Pediatr. 1998; 

132(4):731-734. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Gessler, P., Nebe, T., Birle, A., Mueller, W., and Kachel, 

W.. A new side effect of inhaled nitric oxide in neonates 

and infants with pulmonary hypertension: Functional 

impairment of the neutrophil respiratory burst. 

INTENSIVE CARE MED. 1996; 22(3):252-258. 

Article does not include infants born at less than 34 

weeks gestation 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Gewillig, M., Brown, S. C., De Catte, L., Debeer, A., 

Eyskens, B., Cossey, V., Van Schoubroeck, D., Van Hole, 

C., and Devlieger, R.. Premature foetal closure of the 

arterial duct: Clinical presentations and outcome. Eur. 

Heart J. 2009; 30(12):1530-1536. 

Article does not address any of the Key Questions 

Gin-Mestan KK, Srisuparp P, Carlson AD, Thomas G, Lee 

G, Marks JD, and Schreiber MD. Inhaled nitric oxide 

improves oxygenation in premature infants with respiratory 

distress syndrome: preliminary results of a prospective, 

randomized trial. Pediatric research 2002; 51(4):348A. 

D‐7
 
 

 

 

 

Appendix D: List of Excluded Articles
 

No abstractable data 

Gin-Mestan KK, Troyke S, Lee G, Hecox KE, and 

Schreiber MD. Improved neurodevelopmental outcome at 

one year in premature infants treated with inhaled nitric 

oxide: preliminary results of a prospective, randomized 

trial. Pediatric research 2002; 51(4):405A. 

No abstractable data 

Goldman, A. P., Tasker, R. C., Cook, P., and Macrae, D. J.. 

Transfer of critically ill patients with inhaled nitric oxide. 

Arch Dis Child 1995; 73(5):480. 

Article does not include infants born at less than 34 

weeks gestation 

Golzand, E., Bar-Oz, B., and Arad, I.. Intravenous 

prostacyclin in the treatment of persistent pulmonary 

hypertension of the newborn refractory to inhaled nitric 

oxide. Isr Med Assoc J 2005; 7(6):408-9. 

Article does not include infants born at less than 34 

weeks gestation 

Gonzalez, A., Fabres, J., D'Apremont, I., Urcelay, G., 

Avaca, M., Gandolfi, C., and Kattan, J.. Randomized 

controlled trial of early compared with delayed use of 

inhaled nitric oxide in newborns with a moderate 

respiratory failure and pulmonary hypertension. J. 

Perinatol. 2009; :#startpage#. 

Article does not include infants born at less than 34 

weeks gestation 

Gorrotxategi Gorrotxategi, P., Eizaguirre Sexmilo, I., 

Iturrioz Mata, A., Miranda Abejon, G., Collado Espina, V., 

and Birritxinaga Gaztelurrutia, B.. [Use of nitric oxide in a 

newborn child with pulmonary cystic adenomatoid 

malformation]. Cir Pediatr 2000; 13(1):35-8. 

Not written in English and cannot determine eligibility 

No abstractable data 

Gortner, L.. Neonatal intensive care medicine: 

Neonatologische intensivmedizin. Arzneim.-Forsch. Drug 

Res. 2004; 54(11):781-782. 

Not written in English and cannot determine eligibility 

Gothberg, S., Edberg, K. E., Tang, S. F., Michelsen, S., 

Winberg, P., Holmgren, D., Miller, O., Thaulow, E., and 

Lonnqvist, P. A.. Residual pulmonary hypertension in 

children after treatment with inhaled nitric oxide: a followup study regarding cardiopulmonary and neurological 

symptoms. Acta Paediatr 2000; 89(12):1414-9. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Graham, E. M., Bradley, S. M., and Atz, A. M.. 

Preoperative management of hypoplastic left heart 

syndrome. Expert Opin. Pharmacother. 2005; 6(5):687-693. 

No original data 

Greenough, A.. Respiratory support techniques for 

prematurely born infants: new advances and perspectives. 

Acta Paediatr Taiwan 2001; 42(4):201-6. 

No original data 

Gressens, P., Rogido, M., Paindaveine, B., and Sola, A.. 

The impact of neonatal intensive care practices on the 

developing brain. J Pediatr 2002; 140(6):646-53. 

No original data 

Gupta, A., Rastogi, S., Sahni, R., Bhutada, A., Bateman, 

D., Rastogi, D., Smerling, A., and Wung, J. T.. Inhaled 

nitric oxide and gentle ventilation in the treatment of 

pulmonary hypertension of the newborn--a single-center, 5­

year experience. J Perinatol 2002; 22(6):435-41. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Guthrie, S. O., Walsh, W. F., Auten, K., and Clark, R. H.. 

Initial dosing of inhaled nitric oxide in infants with hypoxic 

respiratory failure. J Perinatol 2004; 24(5):290-4. 

Article does not include infants born at less than 34 

weeks gestation 

Hallman, M. and Aikio, O.. Nitric oxide in critical 

respiratory failure of very low birth weight infants. 

Paediatr. Respir. Rev. 2004; 5(SUPPL. A):S249-S252. 

No original data 

Hamon I, Schroeder H, Buchweiller MC, Franck P, Nicolas 

MB, Fresson J, Dousset B, Nabet P, and Hascoet JM. Early 

effect of inhaled nitric oxide (iNO) on the oxidative 

balance in 23-32 weeks gestation infants: preliminary data 

from a randomized controlled trial. Pediatric Research 

2001; 49(4):266A. 

No abstractable data 

Hanna MG; Shaltout FF; El-Fikky MA, and Gamal H. 

Assessment of the role of inhaled nitric oxide and high 

frequency oscillatory ventilation in persistent pulmonary 

hypertension of the newborn. Egyptian Journal of 

Anaesthesia. 2004; 20(1):47-52. CODEN: CCT; ISSN: CN00515709. 

Unobtainable 

Hancock Friesen, C. L., Zurakowski, D., Thiagarajan, R. 

R., Forbess, J. M., del Nido, P. J., Mayer, J. E., and Jonas, 

R. A.. Total anomalous pulmonary venous connection: an 

analysis of current management strategies in a single 

institution. Ann Thorac Surg 2005; 79(2):596-606; 

discussion 596-606. 

Other reason 

Hansen, T. W. R.. Nitric oxide in the treatment of 

oxygenation difficulties in neonates: Nitrogenoksid I 

Behandlingen Av Oksygeneringssvikthos Nyfodte. Tidsskr. 

Nor. Laegeforen. 1995; 115(28):3493-3495. 

Not written in English and cannot determine eligibility 

D‐8
 
 

 

 

 

Appendix D: List of Excluded Articles
 

Haruda, F. D. and Volpe, J. J.. The structure of blood 

vessels in the germinal matrix and the autoregulation of 

cerebral blood flow in premature infants [6]. Pediatrics 

2001; 108(4):1050. 

No original data 

No human data included 

Heal, C. A. and Spencer, S. A.. Methaemoglobinaemia with 

high-dose nitric oxide administration. Acta Paeddtr. Int. J. 

Paediatr. 1995; 84(11):1318-1319. 

Article does not include infants born at less than 34 

weeks gestation 

Henneberg, S. W., Jepsen, S., Andersen, P. K., and 

Pedersen, S. A.. Inhalation of nitric oxide as a treatment of 

pulmonary hypertension in congenital diaphragmatic 

hernia. J. Pediatr. Surg. 1995; 30(6):853-855. 

Article does not include infants born at less than 34 

weeks gestation 

Henrichsen, T., Goldman, A. P., and Macrae, D. J.. Inhaled 

nitric oxide can cause severe systemic hypotension. J 

Pediatr 1996; 129(1):18.3 

Article does not include infants born at less than 34 

weeks gestation 

Hering, F.. Congress report on the 29th Neonatal and Infant 

Respiratory Symposium in Vail, February 13th to 16th, 

2002: Kongressbericht uber das 29. Neonatal und Infant 

Respiratory Symposium in Vail, 13. bis 16. Februar 2002. 

Anasthesiol. Intensivmed. Notf.med. Schmerzther. 2002; 

37(8):496-500. 

Not written in English and cannot determine eligibility 

Herkenhoff, M., Schaible, T., Reiss, I., Kandzora, J., 

Moller, J., and Gortner, L.. Persistent pulmonary 

hypertension of the newborn and preterm infant: Selective 

pulmonary vasodilatation with inhalational nitric oxide 

(iNO): Persistierende pulmonale hypertension (PPHN) im 

fruh- und neugeborenenalter: Selektive pulmonale 

vasodilatation mit inhalativem stickstoffmonoxid (iNO). Z. 

Geburtshilfe Neonatol. 1998; 202(1):25-29. 

Not written in English and cannot determine eligibility 

Hintz, S. R., Benitz, W. E., Halamek, L. P., Van Meurs, K. 

P., and Rhine, W. D.. Secondary infection presenting as 

recurrent pulmonary hypertension. J Perinatol 2000; 

20(4):262-4. 

Article does not include infants born at less than 34 

weeks gestation 

Hoehn, T., Gratopp, A., Raehse, K., and Koehne, P.. 

Effects of hyperoxia and nitric oxide on endogenous nitric 

oxide production in polymorphonuclear leukocytes. 

Neonatology 2008; 94(2):132-137. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Hoehn, T., Krause, M., Wildberg, A., Pringsheim, W., and 

Leititis, J. U.. [Reversal of a right-left shunt and permanent 

improvement of oxygenation by inhalation of nitrogen 

monoxide in a premature infant with lung hypoplasia and 

asphyxia]. Z Geburtshilfe Neonatol 1997; 201(3):105-7. 

Not written in English and cannot determine eligibility 

Hoffman, G. M. and Nelin, L. D.. Mean airway pressure 

and response to inhaled nitric oxide in neonatal and 

pediatric patients. Lung 2005; 183(6):441-53. 

Article does not include infants born at less than 34 

weeks gestation 

Hohn, T. and Schiffer, B.. Treatment of persistent 

pulmonary hypertension of the newborn by nitrogen 

monoxide inhalation: Die Behandlung der persistierenden 

pulmonalen Hypertonie des Neugeborenen mit inhalativem 

Stickstoffmonoxid (iNO).. Kinderkrankenschwester 1997; 

16(10):422-424. 

Not written in English and cannot determine eligibility 

Holmer Fiori, H. and Machado Fiori, R.. Nitric oxide in 

persistent pulmonary hypertension of the newborn: Oxido 

nitrico na hipertensao pulmonar persistente do recemnascido. J. PEDIATR. 96; 72(3):121-122. 

Not written in English and cannot determine eligibility 

Hoo, A.-F., Beardsmore, C. S., Castle, R. A., Ranganathan, 

S. C., Tomlin, K., Field, D., Elbourne, D., and Stocks, J.. 

Respiratory function during infancy in survivors of the 

INNOVO trial. Pediatr. Pulmonol. 2009; 44(2):155-16.1 

No abstractable data 

Hoshi, M., Suzumura, H., Nitta, A., Tsuboi, Y., Tsuboi, T., 

Inoue, H., Tanaka, G., and Arisaka, O.. Treatment of 

persistent pulmonary hypertension of the newborn. Dokkyo 

J. Med. Sci. 2002; 29(1):119-124. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Hosono, S., Ohno, T., Kimoto, H., Shimizu, M., Takahashi, 

S., and Harada, K.. Developmental outcomes in persistent 

pulmonary hypertension treated with nitric oxide therapy. 

Pediatr Int 2009; 51(1):79-83. 

Article does not include infants born at less than 34 

weeks gestation 

Hosono, S., Ohno, T., Kimoto, H., Shimizu, M., Takahashi, 

S., and Harada, K.. Inhaled nitric oxide therapy might 

reduce the need for hyperventilation therapy in infants with 

persistent pulmonary hypertension of the newborn. J. 

Perinat. Med. 2006; 34(4):333-337. 

Article does not include infants born at less than 34 

weeks gestation 

Hsieh, W. S.. Role of nitric oxide in neonatal diseases. Acta 

Paediatr Taiwan 2002; 43(3):122-3. 

No original data 

Hsieh, W.-S.. Meconium-stained amniotic fluid, meconium 

aspiration syndrome, and persistent pulmonary 

hypertension of the newborn. Acta Paediatr. Taiwan. 2004; 

45(4):197-199. 

D‐9
 
 

 

 

Appendix D: List of Excluded Articles
 

No original data 

Hsu, H. T., Lin, J. Y., Tseng, H. I., Chang, Y. L., Yu, K. L., 

Cheng, K. I., and Tang, C. S.. Total intravenous anesthesia 

for repair of congenitral diaphragmatic hernia: a case 

report. Kaohsiung J Med Sci 2004; 20(9):465-9. 

Article does not include infants born at less than 34 

weeks gestation 

Hsu, H.-Y., Huang, C.-B., Chen, C.-C., Huang, H.-C., Liu, 

C.-A., and Chung, M.-Y.. The therapeutic effect of inhaled 

nitric oxide in neonatal persistent pulmonary hypertension 

with and without Congenital Heart Disease. Clin. Neonatol. 

2006; 13(1):1-5. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Hui, T. T., Danielson, P. D., Anderson, K. D., and Stein, J. 

E.. The impact of changing neonatal respiratory 

management on extracorporeal membrane oxygenation 

utilization. J. Pediatr. Surg. 2002; 37(5):703-705. 

Article does not include infants born at less than 34 

weeks gestation 

Hutchin, M. E., Gilmer, C., and Yarbrough, W. G.. 

Delayed-onset sensorineural hearing loss in a 3-year-old 

survivor of persistent pulmonary hypertension of the 

newborn. Arch. Otolaryngol. Head Neck Surg. 2000; 

126(8):1014-1017. 

Article does not include infants born at less than 34 

weeks gestation 

Hwang, S. J., Lee, K. H., Hwang, J. H., Choi, C. W., Shim, 

J. W., Chang, Y. S., and Park, W. S.. Factors affecting the 

response to inhaled nitric oxide therapy in persistent 

pulmonary hypertension of the newborn infants. Yonsei 

Med J 2004; 45(1):49-55. 

Article does not include infants born at less than 34 

weeks gestation 

Ibrahim TS and El-Mohamady HS. Inhaled nitric oxide and 

prone position: How far they can improve oxygenation in 

pediatric patients with acute respiratory distress syndrome?. 

Journal of Medical Sciences 2007; 7(3):390-5. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Ichiba, H., Fujioka, H., Saitoh, M., and Shintaku, H.. 

Neonatal listeriosis with severe respiratory failure 

responding to nitric oxide inhalation. Pediatr Int 2000; 

42(6):696-8. 

Article does not include infants born at less than 34 

weeks gestation 

IJsselstijn, H. and Tibboel, D.. The lungs in congenital 

diaphragmatic hernia: Do we understand?. Pediatr. 

Pulmonol. 1998; 26(3):204-218. 

No original data 

Article does not address any of the Key Questions 

Inamura, N., Kubota, A., Nakajima, T., Kayatani, F., 

Okuyama, H., Oue, T., and Kawahara, H.. A proposal of 

new therapeutic strategy for antenatally diagnosed 

congenital diaphragmatic hernia. J. Pediatr. Surg. 2005; 

40(8):1315-1319. 

No abstractable data 

Iocono, J. A., Cilley, R. E., Mauger, D. T., Krummel, T. 

M., and Dillon, P. W.. Postnatal pulmonary hypertension 

after repair of congenital diaphragmatic hernia: Predicting 

risk and outcome. J. Pediatr. Surg. 1999; 34(2):349-353. 

Article does not address any of the Key Questions 

Islam, S., Masiakos, P., Schnitzer, J. J., Doody, D. P., and 

Ryan, D. P.. Diltiazem reduces pulmonary arterial 

pressures in recurrent pulmonary hypertension associated 

with pulmonary hypoplasia. J. Pediatr. Surg. 1999; 

34(5):712-714. 

Article does not include infants born at less than 34 

weeks gestation 

Izhar FM, Rumilla K, Kim Y-J, Hershenson MB, and 

Schreiber MD. Inhaled nitric oxide prevents the increase in 

tracheal aspirate IL-8 concentrations in premature newborn 

infants with respiratory distress syndrome. Pediatric 

Research 2001; 49(4):402A. 

No abstractable data 

Izhar FM, Rumilla KM, Borg MJ, Kim Y-J, Hershenson 

MB, and Schreiber MD. Pulmonary safety of inhaled nitric 

oxide in premature newborn infants with respiratory 

distress syndrome. Pediatric Research 2000; 47(4):362A. 

No abstractable data 

Janzen, P. R. and Darowski, M.. Nitric oxide in a premature 

infant in the operating room. Anesthesiology 1995; 

83(6):1388. 

Article does not address any of the Key Questions 

Jerwood, D. C. and Stokes, M. A.. Nitric oxide in the 

management of persistent pulmonary hypertension of the 

newborn--an unusual cause of failure.. Paediatr Anaesth 

1995; 5(3):193-195. 

Article does not include infants born at less than 34 

weeks gestation 

Journois, D.; Lefebvre, D.; Deny, N.; Sidhom, N.; 

Djamouri, R.; Vaccaroni, L., and Safran, D. Treatment of 

the pulmonary hypertension with inhaled nitric oxide 

following surgey for congenital heart defects: Traitement 

De L’hypertension Arterielle Pulmonaire Par LE Monoxide 

D’azote Inhale Lors de la Correction Chirurgicale de 

Cardiopathies Congenitales. RBM Rev. Eur. Technol. 

Biomed. 1993; 15(3):167-174. 

Unobtainable 

Journois, D., Pouard, P., Mauriat, P., Malhere, T., Vouhe, 

P., and Safran, D.. Inhaled nitric oxide as a therapy for 

pulmonary hypertension after operations for congenital 

D‐10
 
 

 

 

 

 

 

 

 

 

Appendix D: List of Excluded Articles
 

heart defects. J Thorac Cardiovasc Surg 1994; 107(4):1129­

35. 

Other reason 

Kachel, W., Varnholt, V., Lasch, P., Muller, W., Lorenz, 

C., and Wirth, H.. High-frequency oscillatory ventilation 

and nitric oxide: Alternative or complementary to ECMO. 

INT. J. ARTIF. ORGANS 1995; 18(10):589-597. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Other reason 

Kakuya, F., Takase, M., Ishii, N., Kajino, M., Hayashi, T., 

Miyamoto, K., Muraki, S., Iwamoto, J., and Okuno, A.. 

Inhaled nitric oxide therapy via nasopharyngeal tube in an 

infant with end-stage pulmonary hypertension. Acta 

Paediatr Jpn 1998; 40(2):155-8. 

Article does not include infants born at less than 34 

weeks gestation 

Kamiyama, M., Kawahara, H., Okuyama, H., Oue, T., 

Kuroda, S., Kubota, A., and Okada, A.. Gastroesophageal 

reflux after repair of congenital diaphragmatic hernia. J. 

Pediatr. Surg. 2002; 37(12):1681-1684. 

Article does not address any of the Key Questions 

Karamanoukian, H. L., Glick, P. L., Zayek, M., Steinhorn, 

R. H., Zwass, M. S., Fineman, J. R., and Morin, F. C. 3rd. 

Inhaled nitric oxide in congenital hypoplasia of the lungs 

due to diaphragmatic hernia or oligohydramnios. Pediatrics 

1994; 94(5):715-8. 

Article does not include infants born at less than 34 

weeks gestation 

Kauffmann, F. and Nadif, R.. Candidate interactions. Eur 

Respir J 2007; 30(1):3-4. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Kavvadia, V., Greenough, A., Lilley, J., Laubscher, B., 

Dimitriou, G., Boa, F., and Poyser, K.. Plasma arginine 

levels and the response to inhaled nitric oxide in neonates. 

Biol. Neonate 1999; 76(6):340-347. 

Article does not address any of the Key Questions 

Kawakami, H. and Ichinose, F.. Inhaled nitric oxide in 

pediatric cardiac surgery. Int Anesthesiol Clin 2004; 

42(4):93-100 

No original data 

Keller RL, Hawgood S, Neuhaus JM, Farmer DL, Lee H, 

Albanese CT, Harrison MR, and Kitterman JA. Infant 

pulmonary function in a randomized trial of fetal tracheal 

occlusion for severe congenital diaphragmatic hernia.. 

Pediatric research 2004; 56(5):818-25. 

Article does not address any of the Key Questions 

Kelly, L. K., Porta, N. F., Goodman, D. M., Carroll, C. L., 

and Steinhorn, R. H.. Inhaled prostacyclin for term infants 

with persistent pulmonary hypertension refractory to 

inhaled nitric oxide. J Pediatr 2002; 141(6):830-2. 

Article does not include infants born at less than 34 

weeks gestation 

Khawahur, H., Kattan, A., Al-Alaiyan, S., and Saidy, K.. 

Congenital diaphragmatic hernia: A local experience. Ann. 

Saudi Med. 1999; 19(6):501-504. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Khemani, E., McElhinney, D. B., Rhein, L., Andrade, O., 

Lacro, R. V., Thomas, K. C., and Mullen, M. P.. Pulmonary 

artery hypertension in formerly premature infants with 

bronchopulmonary dysplasia: clinical features and 

outcomes in the surfactant era. Pediatrics 2007; 

120(6):1260-9. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Kieffer, F.; Kassis, M.; Coatantiec, Y.; Magny, J. F., and 

Voyer, M. Persistent pulmonary hypertension of the 

newborn and nitric oxide: From the physiology to the 

therapy: Hypertension arterielle pulmonaire persistante du 

nouvea-ne et monoxyde d'azote: De la physiologie a la 

therapeutique. J. Pediatr. Pueric. 1997; 10(4):195-199. 

Unobtainable 

Kiefer, A. S., Wickremasinghe, A. C., Johnson, J. N., 

Hartman, T. K., Hintz, S. R., Carey, W. A., and Colby, C. 

E.. Medical management of extremely low-birth-weight 

infants in the first week of life: a survey of practices in the 

United States. Am J Perinatol 2009; 26(6):407-18. 

Article does not address any of the Key Questions 

Kilbride, H. W. and Thibeault, D. W.. Strategies of 

cardiovascular and ventilatory management in preterm 

infants with prolonged rupture of fetal membranes and 

oligohydramnios. J Perinatol 2002; 22(6):510. 

No original data 

Kim do, H., Park, J. D., Kim, H. S., Shim, S. Y., Kim, E. 

K., Kim, B. I., Choi, J. H., and Park, G. W.. Survival rate 

changes in neonates with congenital diaphragmatic hernia 

and its contributing factors. J Korean Med Sci 2007; 

22(4):687-92. 

Article does not address any of the Key Questions 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Kinsella JP and Abman SH. High-frequency oscillatory 

ventilation augments the response to inhaled nitric oxide in 

persistent pulmonary hypertension of the newborn: Nitric 

Oxide Study Group.. Chest 1998; 114(1 Suppl):100S. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

D‐11
 
 

 

 

 

 

Appendix D: List of Excluded Articles
 

Kinsella, J. P. and Abman, S. H.. Clinical approach to 

inhaled nitric oxide therapy in the newborn with 

hypoxemia. J. Pediatr. 2000; 136(6):717-726. 

No original data 

Kinsella, J. P. and Abman, S. H.. Efficacy of inhalational 

nitric oxide therapy in the clinical management of 

persistent pulmonary hypertension of the newborn. Chest 

1994; 105(3 Suppl):92S-94S. 

Article does not include infants born at less than 34 

weeks gestation 

Kinsella, J. P. and Abman, S. H.. Methaemoglobin during 

nitric oxide therapy with high-frequency ventilation [4]. 

Lancet 93; 342(8871):615. 

Article does not address any of the Key Questions 

Other reason 

Kinsella, J. P., Griebel, J., Schmidt, J. M., and Abman, S. 

H.. Use of inhaled nitric oxide during interhospital 

transport of newborns with hypoxemic respiratory failure. 

Pediatrics 2002; 109(1):158-161. 

Article does not address any of the Key Questions 

Kinsella, J. P., Neish, S. R., Shaffer, E., and Abman, S. H.. 

Low-dose inhalation nitric oxide in persistent pulmonary 

hypertension of the newborn. Lancet 1992; 340(8823):819­

20. 

Article does not include infants born at less than 34 

weeks gestation 

Kinsella, J. P., Parker, T. A., Ivy, D. D., and Abman, S. H.. 

Noninvasive delivery of inhaled nitric oxide therapy for 

late pulmonary hypertension in newborn infants with 

congenital diaphragmatic hernia. J. Pediatr. 2003; 

142(4):397-401. 

Article does not include infants born at less than 34 

weeks gestation 

Kinsella, J. P., Schmidt, J. M., Griebel, J., and Abman, S. 

H.. Inhaled nitric oxide treatment for stabilization and 

emergency medical transport of critically ill newborns and 

infants. Pediatrics 1995; 95(5):773-6. 

Article does not include infants born at less than 34 

weeks gestation 

Kinsella, J. P., Torielli, F., Ziegler, J. W., Dunbar Ivy, D., 

and Abman, S. H.. Dipyridamole augmentation of response 

to nitric oxide [28]. LANCET 1995; 346(8975):647-648. 

No original data 

Article does not address any of the Key Questions 

Kinsella, J. P., Truog, W. E., Walsh, W. F., Goldberg, R. 

N., Bancalari, E., Mayock, D. E., Redding, G. J., deLemos, 

R. A., Sardesai, S., McCurnin, D. C., Moreland, S. G., 

Cutter, G. R., and Abman, S. H.. Randomized, multicenter 

trial of inhaled nitric oxide and high-frequency oscillatory 

ventilation in severe, persistent pulmonary hypertension of 

the newborn. J Pediatr 1997; 131(1 Pt 1):55-62. 

Article does not include infants born at less than 34 

weeks gestation 

Kinsella, J. P.. Clinical trials of inhaled nitric oxide therapy 

in the newborn. Pediatr Rev 1999; 20(11):e110-3. 

No original data 

Kissoon, N.. Nitric oxide: to inhale or not to inhale.. Pediatr 

Crit Care Med 2004; 5(2):196-198. 

No original data 

Knopf, D.. Neonatology: Help for preterm infants: 

Neonatologie: Hilfe fur fruhgeborene. Pharm. Ztg. 2005; 

150(33):29. 

Not written in English and cannot determine eligibility 

Koh, T. H., Gandini, D., and Vijayakumar, P.. The neonatal 

inhaled nitric oxide study. J Pediatr 2001; 138(2):300. 

No human data included 

Other reason 

Kohelet, D.. Nitric oxide inhalation and high frequency 

oscillatory ventilation for hypoxemic respiratory failure in 

infants. Isr. Med. Assoc. J. 2003; 5(1):19-23. 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Konig, K. and Henschke, P.. Successful weaning of nitric 

oxide facilitated by a single dose of sildenafil in a baby 

with persistent pulmonary hypertension of the newborn. 

Pediatr Pulmonol 2009; 44(8):837. 

Article does not include infants born at less than 34 

weeks gestation 

Kruse-Ruijter, M. F. and Zimmermann, L. J. I.. Persistent 

pulmonary hypertension in a neonate caused by blood 

aspiration following vaginal blood loss: Persisterende 

pulmonale hypertensie bij een neonaat door bloedaspiratie 

ten gevolge van vaginaal bloedverlies. Ned. Tijdschr. 

Geneeskd. 2007; 151(28):1585-1588. 

Not written in English and cannot determine eligibility 

Kulkarni, A.. Changing trends in neonatal 

pharmacotherapy. Perinatology 2004; 6(5):231-236. 

No original data 

Lago, P., Meneghini, L., Chiandetti, L., Tormena, F., 

Metrangolo, S., and Gamba, P.. Congenital diaphragmatic 

hernia: Intensive care unit or operating room?. Am. J. 

Perinatol. 2005; 22(4):189-197. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Lakatos, L. and Oroszlan, G.. Possible effect of Dpenicillamine on the physiologic action of inhaled nitric 

oxide in neonates. J Pediatr 1994; 124(4):656-7. 

No original data 

No human data included 

Lakatos, L.. [Effect of penicillamine D, nitric oxide, or 

both?]. Orv Hetil 1993; 134(41):2283. 

Not written in English and cannot determine eligibility 

D‐12
 
 

 

Appendix D: List of Excluded Articles
 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Laubscher, B., Greenough, A., Kavvadia, V., and Devane, 

S. P.. Response to nitric oxide in term and proterm infants. 

EUR. J. PEDIATR. 1997; 156(8):639-642. 

Article does not address any of the Key Questions 

No abstractable data 

Lal, M. K. and Field, D. J. Clinical management of 

persistent pulmonary hypertension of the newborn. 

Perinatology. 2001; 3(5):249-261. 

Unobtainable 

Lee, S. K., McMillan, D. D., Ohlsson, A., Pendray, M., 

Synnes, A., Whyte, R., Chien, L. Y., and Sale, J.. 

Variations in practice and outcomes in the Canadian NICU 

network: 1996-1997. Pediatrics 2000; 106(5):1070-9. 

Article does not address any of the Key Questions 

Leipala, J. A., Williams, O., Sreekumar, S., Cheeseman, P., 

Rafferty, G. F., Hannam, S., Milner, A., and Greenough, 

A.. Exhaled nitric oxide levels in infants with chronic lung 

disease. Eur. J. Pediatr. 2004; 163(9):555-558 

Article does not address any of the Key Questions 

Lemke, R. P., Belik, J., Giddins, N. G., Fajardo, C. A., and 

Manitoba. Clinical experience in the use of inhaled nitric 

oxide in infants with pulmonary hypertension: Experience 

clinique relative a l'utilisation d'oxyde nitrique en 

inhalation chez les nourrissons atteints d'hypertension 

pulmonaire. Can. Respir. J. 1996; 3(5):295-300. 

No abstractable data 

Li, J. H.. [Treatment of periventricular leukomalacia in 

preterm infants]. Zhongguo Dang Dai Er Ke Za Zhi 2007; 

9(4):327-9. 

Not written in English and cannot determine eligibility 

Lindner, W., Pohlandt, F., Grab, D., and Flock, F.. Acute 

respiratory failure and short-term outcome after premature 

rupture of the membranes and oligohydramnios before 20 

weeks of gestation. J. Pediatr. 2002; 140(2):177-182. 

Article does not address any of the Key Questions 

Lindroth, M.. [Are there any cost-benefit limits in 

connection with neonatal care?]. Lakartidningen 2002; 

99(3):208. 

Not written in English and cannot determine eligibility 

Lonnqvist, P. A. and Jonsson, B.. [Premature infants 

benefit from inhaled nitric oxide, too. Not only full-term 

infants with severe hypoxic respiratory failure]. 

Lakartidningen 2005; 102(50):3880-2. 

Not written in English and cannot determine eligibility 

Article does not include infants born at less than 34 

weeks gestation 

Lonnqvist, P. A., Jonsson, B., Winberg, P., and Frostell, C. 

G.. Inhaled nitric oxide in infants with developing or 

established chronic lung disease. Acta Paediatr 1995; 

84(10):1188-92. 

No abstractable data 

Lonnqvist, P. A.. Efficacy and economy of inhaled nitric 

oxide in neonates accepted for extra-corporeal membrane 

oxygenation. Acta Physiol Scand 1999; 167(2):175-9. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Lonnqvist, P. A.. Inhaled nitric oxide in newborn and 

paediatric patients with pulmonary hypertension and 

moderate to severe impaired oxygenation: Effects of doses 

of 3-100 parts per million. Intensive Care Med. 1997; 

23(7):773-779. 

Article does not include infants born at less than 34 

weeks gestation 

Lopez Herrera, M. C., Roman, L., Lopez De Heredia, J., 

and Valls Soler, I. A.. Nitric oxide administration [1]: 

Administracion de Oxido Nitrico [1]. An. Esp. Pediatr. 

1995; 43(4):293-294. 

Not written in English and cannot determine eligibility 

Other reason 

Lopez-Herce Cid, J., Garcia Sanchez, E., Garcia Sanz, C., 

Ruperez Lucas, M., Alcaraz Romero, A., and Carrillo 

Alvarez, A.. [Effects of prone position, inhaled nitric oxide 

and surfactant in children with hypoxemic pulmonary 

disease]. An Pediatr (Barc) 2003; 58(2):106-14. 

Not written in English and cannot determine eligibility 

Lopez-Herce Cid, J., Sanchez Galindo, A., Carrillo 

Alvarez, A., Sancho Perez, L., Serina Ramirez, C., and 

Cuesta Alvaro, P.. [Nitric oxide treatment in children: 

clinical course, toxicity and factors influencing its effects]. 

An Esp Pediatr 1997; 46(6):542-8. 

Not written in English and cannot determine eligibility 

Lopez-Herce Cid, J., Sanchez Galindo, A., Carrillo 

Alvarez, A., Sancho Perez, L., Serina Ramirez, C., and 

Cuesta Alvaro, P.. Nitric oxide treatment in children: 

Clinical evolution, toxicity and factors influencing its 

effects: Tratamiento con oxido nitrico en ninos: Evolucion 

clinica, toxicidad y factores que influyen en la respuesta. 

An. Esp. Pediatr. 1997; 46(6):542-548. 

Not written in English and cannot determine eligibility 

Lopez-Herce Cid, J.; Cueto Calvo, E.; Carrillo Alvarez, A.; 

Vazquez Garcia, P.; Bustinza Arriortua, A., and Moral 

Torrero, R. Acute effects of inhaled nitric oxide in children: 

Respuesta aguda a la administracion de oxido nitrico en 

ninos. An. Esp. Pediatr. 1997; 46(6):581-586. 

Unobtainable 

Lorch S A, Cnaan A, and Barnhart K. Cost-effectiveness of 

inhaled nitric oxide for the management of persistent 

pulmonary hypertension of the newborn (Structured 

abstract). Pediatrics 2004; 114(2):417-426. 

D‐13
 
 

 

 

 

 

Appendix D: List of Excluded Articles
 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Lorch, S. A., Banks, B. A., Christie, J., Merrill, J. D., 

Althaus, J., Schmidt, K., Ballard, P. L., Ischiropoulos, H., 

and Ballard, R. A.. Plasma 3-nitrotyrosine and outcome in 

neonates with severe bronchopulmonary dysplasia after 

inhaled nitric oxide. Free Radic Biol Med 2003; 

34(9):1146-52. 

No abstractable data 

Lu, Y. and Sun, B.. [Effect of inhaled nitric oxide on 

methemoglobin levels in children]. Zhongguo Dang Dai Er 

Ke Za Zhi 2008; 10(2):257-8. 

Not written in English and cannot determine eligibility 

Luis, A. L., Avila, L. F., Encinas, J. L., Andres, A. M., 

Suarez, O., Elorza, D., Rodriguez, I., Martinez, L., Murcia, 

J., Lassaletta, L., and Tovar, J. A.. Results of the treatment 

of congenital diaphagmatic hernia with conventional 

terapeutics modalities: Resultados en el tratamiento de la 

hernia diafragmaitica con terapias convencionales.. Cir 

Pediatr 2006; 19(3):167-172. 

Not written in English and cannot determine eligibility 

Maderuelo Rodriguez, E., Sanz Lopez, E., Franco 

Fernandez, M. L., Bernardo Atienza, B., and Sanchez Luna, 

M.. Rescue treatment with inhaled nitric oxide in preterm 

newborns with respiratory failure: Oxido nitrico inhalado 

como rescate en insuficiencia respiratoria del recien nacido 

inmaduro. An. Pediatr. 2005; 62(1):68-71. 

Not written in English and cannot determine eligibility 

Martin, R. J.. Nitric oxide for preemies--not so fast. N Engl 

J Med 2003; 349(22):2157-9. 

No original data 

Meadow, W., Lee, G., Lin, K., and Lantos, J.. Changes in 

mortality for extremely low birth weight infants in the 

1990s: implications for treatment decisions and resource 

use. Pediatrics 2004; 113(5):1223-9. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Mercier, J. C., Zupan, V., Renaudin, M. H., Raveau, C., 

and Dehan, M.. Inhaled nitric oxide in newborns: 

Inhalation de Monoxide d'Azote: Espoirs et Precautions en 

Neonatologie. RBM Rev. Eur. Technol. Biomed. 1993; 

15(3):150-155. 

Not written in English and cannot determine eligibility 

Mercier, J. C.. Uncertainties about the use of inhaled nitric 

oxide in preterm infants. Acta Paediatr Suppl 2001; 

90(436):15-8. 

No original data 

Mercier, J.-C., Lacaze, T., Storme, L., Roze, J.-C., DinhXuan, A. T., Dehan, M., Zupan, V., Gouyon, J. B., 

Francoise, M., Durand, P., Galperine, I., Oriot, D., Menget, 

A., Daoud, P., Jouvet, P., Morville, P., Devaux, A. M., 

Desfreres, L., Magny, J. F., and Simeoni, U.. Diseaserelated response to inhaled nitric oxide in newborns with 

severe hypoxaemic respiratory failure. Eur. J. Pediatr. 

1998; 157(9):747-752. 

No abstractable data 

Mercier, J.-C., Zupan, V., Dehan, M., Renaudin, M.-H., 

Bouchet, M., and Raveau, C.. Device to monitor 

concentration of inhaled nitric oxide [5]. Lancet 1993; 

342(8868):431-432. 

No original data 

Article does not address any of the Key Questions 

Mersal, A., Attili, I., and Alkhotani, A.. Severe neonatal 

pulmonary hypertension secondary to antenatal maternal 

diclofenac ingestion reversed by inhaled nitric oxide and 

oral sildenafil. Ann Saudi Med 2007; 27(6):448-9. 

Article does not include infants born at less than 34 

weeks gestation 

Migliazza, L., Bellan, C., Alberti, D., Auriemma, A., 

Burgio, G., and Colombo, G. L. e. A.. Retrospective study 

of 111 cases of congenital diaphragmatic hernia treated 

with early high-frequency oscillatory ventilation and 

presurgical stabilization. J. Pediatr. Surg. 2007; 42(9):1526­

1532. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Miller, A. A.. Diseases of progress in neonatal care [1]. J. 

Perinatol. 2005; 25(8):557. 

No original data 

Milner, A. D. and Aiton, N.. Nitric oxide inhalation.. 

Pediatr Pulmonol Suppl 1995; 11:100-101. 

No original data 

Moore, F. A. and Haenel, J. B.. Ventilatory strategies for 

acute respiratory failure. Am J Surg 1997; 173(1):53-6; 

discussion 57-8. 

No original data 

Article does not address any of the Key Questions 

Morin, F. C. 3rd and Stenmark, K. R.. Persistent pulmonary 

hypertension of the newborn. Am J Respir Crit Care Med 

1995; 151(6):2010-32. 

No original data 

Mosca, F., Bray, M., Stucchi, I., and Fumagalli, M.. 

Pulmonary hypertension after ibuprofen prophylaxis in 

very preterm infants [5]. Lancet 2002; 360(9338):1023­

1024. 

Article does not address any of the Key Questions 

Motti, A., Tissot, C., Rimensberger, P. C., Prina-Rousso, 

A., Aggoun, Y., Berner, M., Beghetti, M., and Da Cruz, E.. 

Intravenous adenosine for refractory pulmonary 

hypertension in a low-weight premature newborn: A 

D‐14
 
 

 

 

Appendix D: List of Excluded Articles
 

potential new drug for rescue therapy. Pediatr. Crit. Care 

Med. 2006; 7(4):380-382. 

Article does not address any of the Key Questions 

Mourani, P. M., Ivy, D. D., Gao, D., and Abman, S. H.. 

Pulmonary vascular effects of inhaled nitric oxide and 

oxygen tension in bronchopulmonary dysplasia. Am J 

Respir Crit Care Med 2004; 170(9):1006-13. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Movahhedian, H. R., Kashani, I. A., Sine, D., Bull, D., 

Lyons Jones, K., and Rothman, A.. Pulmonary 

hypertension and trisomy 16. Pediatr. Cardiol. 1998; 

19(2):187-189. 

Article does not include infants born at less than 34 

weeks gestation 

Muller, W., Kachel, W., Kuntz, S., Lasch, P., and Varnholt, 

V.. Treatment of severe persistent pulmonary hypertension 

of the newborn (PPHN) with nitric oxide (NO): DIE 

BEHANDLUNG DER PERSISTIERENDEN 

PULMONALEN HYPERTONIE DES NEUGEBORENEN 

(PPHN) DURCH STICKOXIDINHALATION (NO). 

MONATSSCHR. KINDERHEILKD. 1995; 143(5):466­

474. 

Not written in English and cannot determine eligibility 

Munshi, U. K. and Clark, D. A.. Meconium aspiration 

syndrome. Contemp. Clin. Gynecol. Obstet. 2002; 

2(3):247-254. 

No original data 

Mupanemunda, R. H. and Edwards, A. D.. Treatment of 

newborn infants with inhaled nitric oxide. Arch Dis Child 

Fetal Neonatal Ed 1995; 72(2):F131-4. 

No original data 

Nakajima, W., Ishida, A., Arai, H., and Takada, G.. 

Methaemoglobinaemia after inhalation of nitric oxide in 

infant with pulmonary hypertension. Lancet 9197; 

350(9083):1002-3. 

Article does not include infants born at less than 34 

weeks gestation 

Namachivayam P, Theilen U, Butt WW, Cooper SM, 

Penny DJ, and Shekerdemian LS. Sildenafil prevents 

rebound pulmonary hypertension after withdrawal of nitric 

oxide in children.. American journal of respiratory and 

critical care medicine 2006; 174(9):1042-7. 

Article does not address any of the Key Questions 

Other reason 

Nawaz, A., Shawis, R., Matta, H., Jacobsz, A., and AlSalem, A.. Congenital diaphragmatic hernia: The impact of 

preoperative stabilization on outcome. Ann. Saudi Med. 

1999; 19(6):541-543. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Ng, G. Y., Derry, C., Marston, L., Choudhury, M., Holmes, 

K., and Calvert, S. A.. Reduction in ventilator-induced lung 

injury improves outcome in congenital diaphragmatic 

hernia?. Pediatr Surg Int 2008; 24(2):145-50. 

Article does not address any of the Key Questions 

Ng, P. C., Fok, T. F., Lee, C. H., Cheung, K. L., So, K. W., 

To, K. F., and Wong, W.. Congenital cytomegalovirus 

infection presenting as severe persistent pulmonary 

hypertension of the newborn.. J Perinatol 1998; 18(3):234­

237. 

Article does not include infants born at less than 34 

weeks gestation 

Ngougmna, E., Ostrea Jr., E. M., and Konduri, G. G.. 

Analysis of nonsteroidal antiinflammatory drugs in 

meconium and its relation to persistent pulmonary 

hypertension of the newborn. Pediatrics 2001; 107(3):519­

523. 

Article does not include infants born at less than 34 

weeks gestation 

Nicholl, R.. Nitric oxide in preterm babies. Arch Dis Child 

2002; 86(1):59-60. 

No original data 

Noori, S., Friedlich, P., Wong, P., Garingo, A., and Seri, I.. 

Cardiovascular effects of sildenafil in neonates and infants 

with congenital diaphragmatic hernia and pulmonary 

hypertension. Neonatology 2007; 91(2):92-100. 

No abstractable data 

Norden, M. A., Butt, W., and McDougall, P.. Predictors of 

survival for infants with congenital diaphragmatic hernia. J 

Pediatr Surg 1994; 29(11):1442-6. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Normand, C. E., Field, D., Elbourne, D., and Truesdale, A.. 

Nitric oxide is not licensed for preterm neonates. BMJ 

2002; 325(7374):1244. 

No original data 

Obara, H., MIkawa, K., Nishina, K., Maekawa, N., Kawai, 

S., Hisano, K., Shiga, M., Suzuki, K., Iga, K., and Ri, Y.. 

Inhalational nitric oxide therapy for pulmonary 

hypertension. Masui 1994; 43 Suppl:S207-215. 

Not written in English and cannot determine eligibility 

Ochikubo, C. G., Waffarn, F., Turbow, R., and Kanakriyeh, 

M.. Echocardiographic evidence of improved 

hemodynamics during inhaled nitric oxide therapy for 

persistent pulmonary hypertension of the newborn. Pediatr 

Cardiol 1997; 18(4):282-7. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

D‐15
 
 

Appendix D: List of Excluded Articles
 

Okawada, M., Okazaki, T., Yamataka, A., Yanai, T., Kato, 

Y., Kobayashi, H., Lane, G. J., and Miyano, T.. Efficacy of 

protocolized management for congenital diaphragmatic 

hernia. a review of 100 cases. Pediatr Surg Int 2006; 

22(11):925-30. 

Article does not include infants born at less than 34 

weeks gestation 

Okazaki, T., Okawada, M., Shiyanagi, S., Shoji, H., 

Shimizu, T., Tanaka, T., Takeda, S., Kawashima, K., Lane, 

G. J., and Yamataka, A.. Significance of pulmonary artery 

size and blood flow as a predictor of outcome in congenital 

diaphragmatic hernia. Pediatr Surg Int 2008; 24(12):1369­

73. 

Article does not include infants born at less than 34 

weeks gestation 

Okuyama, H., Kubota, A., Kawahara, H., Oue, T., 

Kitayama, Y., and Yagi, M.. Correlation between lung 

scintigraphy and long-term outcome in survivors of 

congenital diaphragmatic hernia. Pediatr. Pulmonol. 2006; 

41(9):882-886. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Okuyama, H., Kubota, A., Oue, T., Kuroda, S., Ikegami, 

R., Kamiyama, M., Kitayama, Y., and Yagi, M.. Inhaled 

nitric oxide with early surgery improves the outcome of 

antenatally diagnosed congenital diaphragmatic hernia. J 

Pediatr Surg 2002; 37(8):1188-90. 

Article does not include infants born at less than 34 

weeks gestation 

Oriot, D., Boussemart, T., Berthier, M., Bonneau, D., and 

Coisne, D.. Paradoxical effect of inhaled nitric oxide in a 

newborn with pulmonary hypertension. Lancet 1993; 

342(8867):364-5. 

Article does not include infants born at less than 34 

weeks gestation 

Osiovich, H. C.. Improving survival of neonates with 

isolated congenital diaphragmatic hernia. Indian Pediatr 

2004; 41(11):1138-42. 

Article does not include infants born at less than 34 

weeks gestation 

Parker, T. A., Ivy, D. D., Kinsella, J. P., Torielli, F., Ruyle, 

S. Z., Thilo, E. H., and Abman, S. H.. Combined therapy 

with inhaled nitric oxide and intravenous prostacyclin in an 

infant with alveolar-capillary dysplasia. Am. J. Respir. Crit. 

Care Med. 1997; 155(2):743-746. 

Article does not include infants born at less than 34 

weeks gestation 

Parker, T. A., Kinsella, J. P., and Abman, S. H.. Response 

to inhaled nitric oxide in persistent pulmonary hypertension 

of the newborn: relationship to baseline oxygenation. J 

Perinatol 1998; 18(3):221-5. 

Article does not include infants born at less than 34 

weeks gestation 

Patole, S., Lee, J., and Whitehall, J.. Adenosine infusion in 

the management of a micropremi neonate with pulmonary 

hypertension. Indian Pediatr. 1999; 36(3):307-310. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Pawlik, T. D., Porta, N. F., Steinhorn, R. H., Ogata, E., and 

deRegnier, R. A.. Medical and financial impact of a 

neonatal extracorporeal membrane oxygenation referral 

center in the nitric oxide era. Pediatrics 2009; 123(1):e17­

24. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Peliowski, A., Finer, N. N., Etches, P. C., Tierney, A. J., 

and Ryan, C. A.. Inhaled nitric oxide for premature infants 

after prolonged rupture of the membranes. J Pediatr 1995; 

126(3):450-3. 

Article does not address any of the Key Questions 

Perreault, T. ECMO or no ECMO: Do no harm: ECMO o 

no ECMO: No hacer dano. An. Esp. Pediatr. 2002; 57(1):1­

4. 

Unobtainable 

Peterson, A. L., Deatsman, S., Frommelt, M. A., Mussatto, 

K., and Frommelt, P. C.. Correlation of echocardiographic 

markers and therapy in persistent pulmonary hypertension 

of the newborn. Pediatr Cardiol 2009; 30(2):160-5. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Petros, A. J., Cox, P. B., and Bohn, D.. Simple method for 

monitoring concentration of inhaled nitric oxide [21]. 

Lancet 1992; 340(8828):1167. 

Article does not address any of the Key Questions 

Other reason 

Pierce, C. M., Petros, A. J., and Fielder, A. R.. No evidence 

for severe retinopathy of prematurity following sildenafil 

[14]. Br. J. Ophthalmol. 2005; 89(2):250. 

No original data 

Posencheg, M. A., Gow, A. J., Truog, W. E., Ballard, R. 

A., Cnaan, A., Golombek, S. G., and Ballard, P. L.. Inhaled 

nitric oxide in premature infants: effect on tracheal aspirate 

and plasma nitric oxide metabolites. J Perinatol 2009. 

No abstractable data 

Puckett, B.. Congenital diaphragmatic hernia: two case 

studies with atypical presentations. Neonatal Netw 2006; 

25(4):239-49. 

Article does not include infants born at less than 34 

weeks gestation 

D‐16
 
Appendix D: List of Excluded Articles
 

Raimondi, F., Migliaro, F., Capasso, L., Ausanio, G., 

Bisceglia, M., Giliberti, P., Messina, F., Salvia, G., and 

Paludetto, R.. Intravenous magnesium sulphate vs. inhaled 

nitric oxide for moderate, persistent pulmonary 

hypertension of the newborn. A Multicentre, retrospective 

study. J Trop Pediatr 2008; 54(3):196-9. 

Article does not include infants born at less than 34 

weeks gestation 

Reliability and Accuracy of Cranial Ultrasound in the 

NICHD Randomized Controlled Trial of Inhaled Nitric 

Oxide for Premature Infants with Severe Respiratory 

Failure. American Pediatric Society/SocieTY for Pediatric 

Research Abstract. 2006. CODEN: RCT; ISSN: CN00711876. 

Unobtainable 

Rennie, J. M. and Bokhari, S. A.. Recent advances in 

neonatology. Arch Dis Child Fetal Neonatal Ed 1999; 

81(1):F1-4. 

No original data 

Reyes, C., Chang, L. K., Waffarn, F., Mir, H., Warden, M. 

J., and Sills, J.. Delayed repair of congenital diaphragmatic 

hernia with early high-frequency oscillatory ventilation 

during preoperative stabilization. J Pediatr Surg 1998; 

33(7):1010-4; discussion 1014-6. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Riddle, E. M., Feltes, T. F., Rosen, K., Fraley, J. K., Mott, 

A. R., and Kovalchin, J. P.. Association of nitric oxide dose 

and methemoglobin levels in patients with congenital heart 

disease and pulmonary hypertension. Am J Cardiol 2002; 

90(4):442-4. 

Article does not include infants born at less than 34 

weeks gestation 

Other reason 

Rieger-Fackeldey, E., Genzel-Boroviczeny, O., and 

Schulze, A.. Severe systemic cytomegalovirus infection of 

premature infants acquired through breastmilk: Schwere 

systemische zytomegalie-virusinfektion fruhgeborener uber 

die muttermilch. Monatsschr. Kinderheilkd. 2001; 

149(10):1059-1062. 

Not written in English and cannot determine eligibility 

Rite Gracia, S., Ruiz Moreno, J. A., Sanchez Gimeno, J., 

Molina Chica, M. I., Marco Tello, A., and Rite Montanes, 

S.. [Inhaled nitric oxide in the treatment of persistent 

pulmonary hypertension in a newborn]. An Esp Pediatr 

1999; 51(2):181-5. 

Not written in English and cannot determine eligibility 

Roberts, J. D. Jr. Inhaled nitric oxide for treatment of 

pulmonary artery hypertension in the newborn and infant. 

Crit Care Med 1993; 21(9 Suppl):S374-6. 

No original data 

Roberts, J. D., Polaner, D. M., Lang, P., and Zapol, W. M.. 

Inhaled nitric oxide in persistent pulmonary hypertension 

of the newborn. Lancet 1992; 340(8823):818-819. 

Article does not include infants born at less than 34 

weeks gestation 

Roberta AB. Improved Outcome with Inhaled Nitric Oxide 

in Preterm Infants Mechanically Ventilated at 7–21 

Days of Age. American Pediatric Society/SocieTY for 

Pediatric Research Abstract. 2006. Coden: RCT; ISSN: 

CN-00711486. 

Unobtainable 

Robinson, T., Stewart, D. L., and Hilbert, T.. Use of 

inhaled nitric oxide for the treatment of persistent 

pulmonary hypertension of the newborn (PPHN). J Ky Med 

Assoc 1999; 97(3):100-4. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Rocha, G. M., Bianchi, R. F., Severo, M., Rodrigues, M. 

M., Baptista, M. J., Correia-Pinto, J., and Guimaraes, H. A.. 

Congenital diaphragmatic hernia - The neonatal period 

(Part I). Eur. J. Pediatr. Surg. 2008; 18(4):219-223. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Roofthooft, M. T. R., Bergman, K. A., Waterbolk, T. W., 

Ebels, T., Bartelds, B., and Berger, R. M. F.. Persistent 

Pulmonary Hypertension of the Newborn With 

Transposition of the Great Arteries. Ann. Thorac. Surg. 

2007; 83(4):1446-1450. 

No abstractable data 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Rosati, E., Butera, G., Bossone, E., De Felice, C., and 

Latini, G.. Inhaled nitric oxide and oral nifedipine in a 

preterm infant with bronchopulmonary dysplasia and 

pulmonary hypertension. Eur. J. Pediatr. 2007; 166(7):737­

738. 

No abstractable data 

Rosenberg, A. A.. Inhaled nitric oxide in the premature 

infant with severe hypoxemic respiratory failure: A time for 

caution. J. Pediatr. 1998; 133(6):720-722. 

No original data 

Roze, J.-C., Storme, L., Zupan, V., Morville, P., DinhXuan, A. T., and Mercier, J.-C.. Echocardiographic 

investigation of inhaled nitric oxide in newborn babies with 

severe hypoxaemia. Lancet 1994; 344(8918):303-305. 

No abstractable data 

Rutter, N.. Persistent pulmonary hypertension of the 

newborn. Care Crit. Ill 1993; 9(5):206-208. 

No original data 

D‐17
 
 

 

 

 

 

 

 

Appendix D: List of Excluded Articles
 

Ryan, A. and Tobias, J. D.. A 5-year survey of nitric oxide 

use in a pediatric intensive care unit. Am J Ther 2007; 

14(3):253-8. 

Article does not address any of the Key Questions 

Sarici, S. U., Kul, M., Candemir, G., Gursel, O., Alpay, F., 

and Gokcay, E.. Inhaled nitric oxide in a preterm newborn 

with severe hypoxemic respiratory failure. Gulhane Med. J. 

2004; 46(3):255-257. 

Article does not address any of the Key Questions 

Saugstad, O. D.. Inhaled nitric oxide for preterm infants - 

Still an experimental therapy. Lancet 1999; 

354(9184):1047-1048. 

No original data 

Saura, L., Castanon, M., Prat, J., Albert, A., Caceres, F., 

Moreno, J., and Gratacos, E.. Impact of fetal intervention 

on postnatal management of congenital diaphragmatic 

hernia. Eur J Pediatr Surg 2007; 17(6):404-7. 

Article does not address any of the Key Questions 

Other reason 

Saw, H.-P., Ho, M.-L., and Chen, J.-Y.. Hearing 

impairment in very low birth weight infants incidence, risks 

factors analysis and follow up. Clin. Neonatol. 2005; 

12(1):30-35. 

Article does not address any of the Key Questions 

Other reason 

Saxena, A. K., Haxihja, E., Kleinlein, B., and Hollwarth, 

M. E.. Lymphoceles in premature infants after congenital 

diaphragmatic hernia repair: Thoracoscopic management. J. 

Thorac. Cardiovasc. Surg. 2007; 133(2):584-585. 

Article does not address any of the Key Questions 

Saygili, A., Ledieu, C., Casterman, P., Leke, A., 

Maingourd, Y., and Krim, G.. [Value of nitric oxide (NO) 

in neonatal right ventricular dysfunction]. Arch Pediatr 

1998; 5(1):93-4. 

Not written in English and cannot determine eligibility 

Schmolzer, G., Urlesberger, B., Reiterer, F., Haim, M., 

Kutschera, J., Resch, B., and Muller, W.. Inhaled Nitric 

Oxide by Pulmonary Hypertension: Comparison Preterm 

Infants versus Newborn Infants: Inhalative Therapie mit 

Stickstoffmonoxid bei pulmonaler Hypertension: Vergleich 

des Effektes bei Fruh- und Neugeborenen. Klin. Padiatr. 

2003; 215(5):257-261. 

Not written in English and cannot determine eligibility 

Schnapf, B. M., Barness, E. G., Ackerman, J., and 

Pomerance, H. H.. A newborn infant with tachypnea, 

intercostal retractions, and poor oxygen saturation. Pediatr. 

Pathol. Mol. Med. 2000; 19(1):73-84. 

Article does not include infants born at less than 34 

weeks gestation 

Schreiber, M. D. and Marks, J. D.. No definitive 

recommendation for iNO in preterm infants. J Pediatr 2006; 

149(1):146-7; author reply 147. 

No abstractable data 

Schreiber, M. D., Gin-Mestan, K., Marks, J. D., Huo, D., 

Lee, G., Srisuparp, P., and Meau-Petit, V.. Inhaled nitric 

oxide in premature infants with the respiratory distress 

syndrome: Commentary. Arch. Pediatr. 2004; 11(11):1367­

1368. 

No original data 

Schreiber, M. D.. Methylene blue: NO panacea. J Pediatr 

1996; 129(6):790-3. 

No original data 

Sebald, M., Friedlich, P., Burns, C., Stein, J., Noori, S., 

Ramanathan, R., and Seri, I.. Risk of need for 

extracorporeal membrane oxygenation support in neonates 

with congenital diaphragmatic hernia treated with inhaled 

nitric oxide. J. Perinatol. 2004; 24(3):143-146. 

Article does not address any of the Key Questions 

Seeniraj, K.. Respiratory distress in new born: Surgical 

causes and management. Ind. J. Pract. Pediatr. 2004; 

6(1):27-31. 

No original data 

Sehgal, A., Callander, I., Stack, J., Momsen, T., and 

Sterling-Levis, K.. Experience with inhaled nitric oxide 

therapy in hypoxic respiratory failure of the newborn. 

Indian J Chest Dis Allied Sci 2005; 47(4):245-9. 

Article does not address any of the Key Questions 

Sehgal, A.. Continuous positive airway pressure - A gentler 

approach to ventilation [3]. Indian Pediatr. 2005; 

42(4):393-394. 

No original data 

No human data included 

Shah, N., Jacob, T., Exler, R., Morrow, S., Ford, H., 

Albanese, C., Wiener, E., Rowe, M., Billiar, T., Simmons, 

R., and et, a. l.. Inhaled nitric oxide in congenital 

diaphragmatic hernia. J Pediatr Surg 1994; 29(8):1010-4; 

discussion 1014-5. 

Article does not include infants born at less than 34 

weeks gestation 

Shiyanagi, S., Okazaki, T., Shoji, H., Shimizu, T., Tanaka, 

T., Takeda, S., Kawashima, K., Lane, G. J., and Yamataka, 

A.. Management of pulmonary hypertension in congenital 

diaphragmatic hernia: nitric oxide with prostaglandin-E1 

versus nitric oxide alone. Pediatr Surg Int 2008; 

24(10):1101-4. 

Article does not include infants born at less than 34 

weeks gestation 

Singh, M. and Kumar, L.. Management of respiratory 

failure.. Indian J Pediatr 1996; 63(1):53-60. 

No original data 

Siobal, M. S.. Combining heliox and inhaled nitric oxide as 

rescue treatment for pulmonary interstitial emphysema. 

Respir. Care 2009; 54(7):976-977. 

D‐18
 
 

 

 

Appendix D: List of Excluded Articles
 

Article does not address any of the Key Questions 

Skimming JW, Bender KA, Hutchison AA, and Drummond 

WH. Nitric oxide inhalation in infants with respiratory 

distress syndrome.. The Journal of pediatrics 1997; 

130(2):225-30. 

No abstractable data 

Skimming JW, Burchfield DJ, Wood CE, and Banner MJ. 

Nitric oxide inhalation facilitates carbon dioxide 

elimination in preterm infants with respiratory distress 

syndrome. Pediatric Research 2001; 49(4):283A. 

Article does not address any of the Key Questions 

Skott, O.. Renin. Am. J. Physiol. Regul. Integr. Comp. 

Physiol. 2002; 282(4 51-4):R937-R939. 

No original data 

Smyth, R. L.. Inhaled nitric oxide treatment for preterm 

infants with hypoxic respiratory failure. Thorax 2000; 55 

Suppl 1:S51-5. 

No original data 

Soares, S., Rocha, G., Pissarra, S., Carrico, A., Azevedo, I., 

Simoes, J. S., and Guimaraes, H.. Pertussis with severe 

pulmonary hypertension in a newborn with good outcome - 

Case report: Infeccao por Bordetella pertussis com 

hipertensao pulmonar grave num recem-nascido com boa 

evolucao clinica - Caso clinico. Rev. Port. Pneumol. 2008; 

14(5):687-692. 

Article does not include infants born at less than 34 

weeks gestation 

Sokol, G. M., Fineberg, N. S., Wright, L. L., and 

Ehrenkranz, R. A.. Changes in arterial oxygen tension 

when weaning neonates from inhaled nitric oxide. Pediatr 

Pulmonol 2001; 32(1):14-9. 

Article does not include infants born at less than 34 

weeks gestation 

Sood, B. G.. Re: Neonatal nitric oxide use: predictors of 

response and financial implications. J Perinatol 2004; 

24(2):132; author reply 133. 

No original data 

Article does not address any of the Key Questions 

Sreenan, C., Etches, P., and Osiovich, H.. The western 

Canadian experience with congenital diaphragmatic hernia: 

Perinatal factors predictive of extracorporeal membrane 

oxygenation and death. Pediatr. Surg. Int. 2001; 17(2­

3):196-200. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Steinhorn, R. H., Cox, P. N., Fineman, J. R., Finer, N. N., 

Rosenberg, E. M., Silver, M. M., Tyebkhan, J., Zwass, M. 

S., and Morin, F. C. 3rd. Inhaled nitric oxide enhances 

oxygenation but not survival in infants with alveolar 

capillary dysplasia. J Pediatr 1997; 130(3):417-22. 

Article does not include infants born at less than 34 

weeks gestation 

Steinhorn, R. H.. Persistent pulmonary hypertension of the 

newborn.. Acta Anaesthesiol Scand Suppl 1997; 111:135­

140. 

No original data 

Stoll, B. J. and Hansen, N.. Infections in VLBW infants: 

Studies from the NICHD Neonatal Research Network. 

Semin. Perinatol. 2003; 27(4):293-301. 

No original data 

Stranak, Z., Janota, J., Pycha, K., Snajdauf, J., and Simak, 

J.. [Delayed surgery in congenital diaphragmatic hernia 

without drainage of the ipsilateral hemithorax]. Rozhl Chir 

1999; 78(12):622-6.. 

Not written in English and cannot determine eligibility 

Stranak, Z., Zabrodsky, V., and Simak, J.. Changes in 

alveolar-arterial oxygen difference and oxygenation index 

during low-dose nitric oxide inhalation in 15 newborns 

with severe respiratory insufficiency. Eur J Pediatr 1996; 

155(10):907-10 

Article does not address any of the Key Questions 

Other reason 

Stranak, Z., Zabrodsky, V., and Simak, J.. Inhalation of 

nitric oxide in critically ill newborns. First clinical 

experience at the Inst. for the Care of Mother and Child, 

Prague: Inhalace Oxidu Dusnateho U Kriticky Nemocnych 

Novorozenco. Prvniklinicke Zkusenostiv Upmd Praha. 

Cesko-Slov. Pediatr. 1995; 50(5):275-279. 

Not written in English and cannot determine eligibility 

Subhedar NV and Shaw NJ. Neurodevelopmental outcome 

with inhaled nitric oxide therapy.. The Journal of pediatrics 

1999; 135(2 Pt 1):266-7. 

No abstractable data 

Subhedar, N. and Dewhurst, C.. Is nitric oxide effective in 

preterm infants?. Arch Dis Child Fetal Neonatal Ed 2007; 

92(5):F337-41. 

No original data 

Subhedar, N. V. and Shaw, N. J.. Changes in oxygenation 

and pulmonary haemodynamics in preterm infants treated 

with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed 

1997; 77(3):F191-7. 

No abstractable data 

Subhedar, N. V. and Shaw, N. J.. Inhaled nitric oxide in 

preterm infants at high risk of developing chronic lung 

disease (CLD). Early Hum. Dev. 1997; 49(3):211-212. 

Article does not address any of the Key Questions 

Subhedar, N. V., Jauhari, P., and Natarajan, R.. Cost of 

inhaled nitric oxide therapy in neonates [8]. Lancet 2002; 

359(9319):1781-1782. 

No original data 

Article does not address any of the Key Questions 

D‐19
 
 

 

 

 

Appendix D: List of Excluded Articles
 

Sun, B.. Current progress of clinical trials for new drug 

evaluation in neonatal and pediatric clinics in China. 

Zhongguo Yao Li Xue Bao 1997; 18(6):537-9. 

No original data 

Susan RH. Neurodevelopmental Outcomes of the NICHD 

Randomized Controlled Trial of iNO for Premature Infants 

with Severe Respiratory Failure. American Pediatric 

Society/SocieTY for Pediatric Research Abstract. 2006. 

CODEN: RCT; ISSN: CN-00711875. 

Unobtainable 

Tang, S. F. and Miller, O. I.. Inhaled nitric oxide during 

emergency neonatal transportation. J Paediatr Child Health 

1996; 32(6):539-41. 

Article does not include infants born at less than 34 

weeks gestation 

Tang, S. F. and Miller, O. I.. Low-dose inhaled nitric oxide 

for neonates with pulmonary hypertension. J Paediatr Child 

Health 1996; 32(5):419-23. 

Article does not include infants born at less than 34 

weeks gestation 

Tavares, A. P., Pimenta Junior, A. G., and Evora, P. R.. 

Basis for the therapeutic use of inhaled nitric oxide: 

Fundamentos para o uso terapeutico do oxido nitrico pela 

via inalatoria.. Arq. Bras. Cardiol. 1995; 64(1):45-52. 

Not written in English and cannot determine eligibility 

Ten Eick, A. P. and Gormley, A.. Phosphodiesterase 

inhibitors and persistent pulmonary hypertension of the 

newborn. Hosp. Pharm. 2004; 39(9):831-834. 

No original data 

Article does not address any of the Key Questions 

Tolsa, J. F.. [Physiologic aspects of lung circulation in 

adjustment to extra-uterine life]. Arch Pediatr 2000; 7 

Suppl 2:269s-270s. 

Not written in English and cannot determine eligibility 

Tommasoni, N., Gamba, P. G., Midrio, P., Biban, P., 

Pettenazzo, A., Zanon, G. F., and Guglielmi, M.. 

Congenital diaphragmatic hernia: the use of ECMO and 

other modern therapeutic strategies: Ernia congenita 

diaframmatica: impiego dell'ECMO e di altre moderne 

strategie terapeutiche.. Pediatr Med Chir 1996; 18(3):295­

300. 

Not written in English and cannot determine eligibility 

Trevisanuto, D., Ferrarese, P., Biban, P., Cantarutti, F., and 

Zanardo, V.. Oxygenation response to NO in newborns 

with severe pulmonary hypertension [3]. Acta Paediatr. Int. 

J. Paediatr. 1996; 85(11):1387. 

Article does not address any of the Key Questions 

Truffert, P., Llado-Paris, J., Mercier, J. C., Dehan, M., and 

Breart, G.. Early inhaled nitric oxide in moderately 

hypoxemic preterm and term newborns with RDS: the RDS 

subgroup analysis of the Franco-Belgian iNO Randomized 

Trial. Eur J Pediatr 2003; 162(9):646-7. 

No abstractable data 

Truog, W. E., Ballard, P. L., Norberg, M., Golombek, S., 

Savani, R. C., Merrill, J. D., Parton, L. A., Cnaan, A., 

Luan, X., and Ballard, R. A.. Inflammatory markers and 

mediators in tracheal fluid of premature infants treated with 

inhaled nitric oxide. Pediatrics 2007; 119(4):670-678. 

No abstractable data 

Truog, W. E., Pallotto, E., Clark, P., Banks, B., Kaftan, H. 

A., Ekekezie, I. I., Norberg, M., and Ballard, R. A.. 

Interaction of endogenous endothelin-1 and inhaled nitric 

oxide in term and preterm infants. Clin. Sci. 2002; 

103(SUPPL. 48):294S-297S. 

Article does not address any of the Key Questions 

Tung, B. J.. The use of nitric oxide therapy in the transport 

of newborns with persistent pulmonary hypertension. Air 

Med J 2001; 20(5):10-1. 

No original data 

Article does not include infants born at less than 34 

weeks gestation 

Turanlahti, M., Pesonen, E., Pohjavuori, M., Lassus, P., 

Fyhrquist, F., and Andersson, S.. Plasma cyclic guanosine 

monophosphate reflecting the severity of persistent 

pulmonary hypertension of the newborn. Biol Neonate 

2001; 80(2):107-12. 

No abstractable data 

Turbow, R., Waffarn, F., Yang, L., Sills, J., and Hallman, 

M.. Variable oxygenation response to inhaled nitric oxide 

in severe persistent pulmonary hypertension of the 

newborn. Acta Paediatr 1995; 84(11):1305-8. 

Article does not include infants born at less than 34 

weeks gestation 

Van Marter, L. J.. Epidemiology of bronchopulmonary 

dysplasia. Semin Fetal Neonatal Med 2009; 14(6):358-66. 

No original data 

Van Meurs, K. P., Rhine, W. D., Asselin, J. M., Durand, D. 

J., Peverini, R., Dudell, G., Butler, S., Durand, D., Asselin, 

J., Van Meurs, K., and Rhine, W.. Response of premature 

infants with severe respiratory failure to inhaled nitric 

oxide. PEDIATR. PULMONOL.1997; 24(5):319-323. 

No abstractable data 

Vento, M., Aguar, M., and Brugada, M.. Extremely 

premature infant: Overcoming inflammation and oxidative 

stress. Pediatr. Health 2008; 2(4):397-400. 

No original data 

Vieux, R., Fresson, J., Hascoet, J. M., Blondel, B., Truffert, 

P., Roze, J. C., Matis, J., Thiriez, G., Arnaud, C., Marpeau, 

L., and Kaminski, M.. Improving perinatal regionalization 

by predicting neonatal intensive care requirements of 

preterm infants: an EPIPAGE-based cohort study.. 

Pediatrics 2006; 118(1):84-90. 

D‐20
 
 

 

 

Appendix D: List of Excluded Articles
 

Article does not address any of the Key Questions 

Von Buch, Ch. and Kachel, W.. Initiative application of 

nitric oxide in the treatment of persistent pulmonary 

hypertension of the newborn pretem baby - A case report: 

Inhalative stickoxid (NO)-anwendung zur behandlung der 

persistierenden pulmonalen hypertonie des fruhgeborenen 

fallberich. Monatsschr. Kinderheilkd. 1997; 145(7):708­

711. 

Not written in English and cannot determine eligibility 

Article does not address any of the Key Questions 

Vosatka, R. J.. Persistent pulmonary hypertension of the 

newborn [3]. New Engl. J. Med. 2002; 346(11):864. 

No original data 

Vyas, J. R., Currie, A. E., Shuker, D. E., Field, D. J., and 

Kotecha, S.. Concentration of nitric oxide products in 

bronchoalveolar fluid obtained from infants who develop 

chronic lung disease of prematurity. Arch Dis Child Fetal 

Neonatal Ed 1999; 81(3):F217-20. 

Article does not include pre-term infants who were 

treated with inhaled nitric oxide 

Article does not address any of the Key Questions 

Westrope, C., Roberts, N., Nichani, S., Hunt, C., Peek, G. 

J., and Firmin, R.. Experience with mobile inhaled nitric 

oxide during transport of neonates and children with 

respiratory insufficiency to an extracorporeal membrane 

oxygenation center. Pediatr Crit Care Med 2004; 5(6):542­

6. 

Article does not include infants born at less than 34 

weeks gestation 

Article does not address any of the Key Questions 

Whitelaw, A.. Towards a molecular basis for 

intraventricular haemorrhage: nitric oxide and impaired 

cerebral autoregulation. Acta Paediatr 2002; 91(4):373-4. 

No original data 

Wilkowski, J.. [Inhaled nitric oxide in the therapy of acute 

hypoxemic respiratory failure of newborn]. Med Wieku 

Rozwoj 2001; 5(4):301-14. 

Not written in English and cannot determine eligibility 

Williams, O., Hutchings, G., Debieve, F., and Debauche, 

C.. Contemporary neonatal outcome following rupture of 

membranes prior to 25 weeks with prolonged 

oligohydramnios. Early Hum. Dev. 2009; 85(5):273-277. 

No abstractable data 

Xiao, Z. H., Andre, P., Lacaze-Masmonteil, T., Audibert, 

F., Zupan, V., and Dehan, M.. Outcome of premature 

infants delivered after prolonged premature rupture of 

membranes before 25 weeks of gestation. Eur. J. Obstet. 

Gynecol. Reprod. Biol. 2000; 90(1):67-71. 

No abstractable data 

Yamaguchi, N. and Togari, H.. A multicenter clinical 

retrospective study of inhaled nitric oxide in neonates. 

ACTA NEONATOL. JPN. 1996; 32(3):464-471. 

Not written in English and cannot determine eligibility 

Yamaguchi, N., Togari, H., Takase, M., Hattori, S., 

Yamanami, S., Hasegawa, H., Hoshino, R., Tamura, M., 

Mimura, S., Suzuki, S., Futamura, M., Aotani, H., Sumi, 

K., Kusuda, S., Ichiba, H., Yong-Kye, L., Uetani, Y., 

Nakao, H., and Higuchi, R.. A prospective clinical study on 

inhaled nitric oxide therapy for neonates in Japan. Pediatr 

Int 2001; 43(1):20-5. 

Article address Key Question 1 or 2 ONLY and is not a 

randomized controlled trial 

Yao, C.-T., Wang, J.-N., Lin, C.-H., Yeh, C.-N., Tai, Y.-T., 

Wu, M.-H., and Wu, J.-M.. Prediction of outcome in 

infants with congenital diaphragmatic hernia or severe 

diaphragmatic eventration. Acta Paediatr. Taiwan. 2004; 

45(3):131-135. 

Article does not address any of the Key Questions 

Yao, C.-T., Wang, J.-N., Lin, C.-H., Yeh, C.-N., Tai, Y.-T., 

Wu, M.-H., and Wu, J.-M.. Prediction of outcome in 

infants with congenital diaphragmatic hernia or severe 

diaphragmatic eventration. Acta Paediatr. Taiwan. 2004; 

45(3):131-135. 

Other reason 

Yeh, T.-F.. Persistent pulmonary hypertension in preterm 

infants with respiratory distress syndrome. Pediatr. 

Pulmonol. 2001; 32(Suppl. 23):103-106. 

No original data 

Young, J. D.. The use of inhaled nitric oxide in the acute 

respiratory distress syndrome. Br J Hosp Med 1997; 

57(4):126-7. 

No original data 

Yu, V. Y. H.. Persistent pulmonary hypertension in the 

newborn. Early Hum. Dev. 1993; 33(3):163-175. 

No original data 

Zamakhshary, M., Mah, K., Mah, D., Cameron, B., Bohn, 

D., Bass, J., Scott, L., and Kim, P. C. W.. Physiologic 

predictors for the need for patch closure in neonatal 

congenital diaphragmatic hernia. Pediatr. Surg. Int. 2008; 

24(6):667-670. 

Article does not include infants born at less than 34 

weeks gestation 

Zamakhshary, M., Mah, K., Mah, D., Cameron, B., Bohn, 

D., Bass, J., Scott, L., and Kim, P. C.. Physiologic 

predictors for the need for patch closure in neonatal 

congenital diaphragmatic hernia. Pediatr Surg Int 2008; 

24(6):667-70. 

Article does not address any of the Key Questions 

Zecca, E., De Luca, D., Costa, S., Marras, M., and 

Romagnoli, C.. Neonatal intensive care and outcomes of 

extremely preterm infants: Changes over a decade. Ital. J. 

Pediat. 2006; 32(1):48-54. 

Other reason 

D‐21
 
 

Appendix D: List of Excluded Articles
 

Zhan, Q. Y.. [The role of high frequency oscillatory 

ventilation in the treatment of acute respiratory distress 

syndrome]. Zhonghua Jie He He Hu Xi Za Zhi 2007; 

30(10):740-1. 

Not written in English and cannot determine eligibility 

Ziebinski, M. and Walas, W.. The use of nitric oxide during 

transport of newborns with critical respiratory 

insufficiency: own experience, preliminary report: Wstepne 

doswiadczenia wlasne w stosowaniu tlenku azotu podczas 

transportu noworodkow z krytyczna niewydolnoscia 

oddechowa.. Prz. Lek. 2002; 59 Suppl 1:60-62. 

Not written in English and cannot determine eligibility 

Zorc, J. J. and Kanic, Z.. A cyanotic infant: True blue or 

otherwise?. Pediatr. Ann. 2001; 30(10):597-601. 

No original data 

D‐22
 
Appendix E. Evidence Tables 

Evidence Table 1: Risk of bias in randomized controlled trials. 

Author, year 

Followup studies 

sequence adequately generated 

allocation adequately concealed 

allocated intervention adequately prevented for personnel during the study(ST) 

allocated intervention adequately prevented for outcome assessors during the study (LT) 

allocated intervention adequately prevented for personnel during the study(LT) 

allocated intervention adequately prevented for outcome assessors during the study (LT) 

incomplete outcome data adequately addressed (ST) 

incomplete outcome data adequately addressed (LT) 

Ballard, 20061 

HIbbs, 20072 

Walsh, 20103 

+ + + + + + + + 

Dani, 20064 

0 + - -

+ 

FancoBelgium, 19995

 + + - - 0 0 

Field, 20056 

Huddy, 20087 

- + - - - - - - 

Hascoet, 20058 

Hamon, 2005 9 

+ + 0 0 0 0 + + 

Kinsella, 199910 

+ + + + + + + + 

KinsellaM, 200611 

Watson, 200912 

+ + + + + 

Mercier, 2010{#122 62} 

+ + + + + + + 0 

E‐1
Appendix E. Evidence Tables 

Evidence Table 1: Risk of bias ion randomized controlled trials (continued). 

Author, year 

Followup studies 

sequence adequately generated 

allocation adequately concealed 

allocated intervention adequately prevented for personnel during the study(ST) 

allocated intervention adequately prevented for outcome assessors during the study (LT) 

allocated intervention adequately prevented for personnel during the study(LT) 

allocated intervention adequately prevented for outcome assessors during the study (LT) 

incomplete outcome data adequately addressed (ST) 

incomplete outcome data adequately addressed (LT) 

Schreiber, 200313 

Mestan, 200514 

+ + + + + 

Srisuparp, 200215 

+ 0 0 0 0 0 - + 

Su, 200816 + 0 - 0 - 0 - 0 Subhedar, 199717 

Bennett, 200118 

+ 0 - - 0 0 + 0 

Van Meurs, 200519 

Chock, 200920 

+ + + + + 

Hintz, 2007 21 

Van Chock20 + + + + + + + + 

Meurs, 200722 

E‐2
Appendix E. Evidence Tables 

Evidence Table 1: Risk of bias ion randomized controlled trials (continued). 

KEY Category Question Yes No Unclear 

Sequence generation: Was the allocation sequence adequately generated? + - 0 

Allocation concealment: Was the allocation adequately concealed + - 0 

Blinding of personnel (shortterm outcomes) Was knowledge of the allocation intervention adequately prevented for personnel during the study? + - 0 

Blinding of outcome assessors (short-term outcomes) 

Was knowledge of the allocated intervention adequately preventes for outcome assessors during the study? 

+ - 0 

Blinding of personnel longterm outcomes) Was knowledge of the allocation intervention adequately prevented for personnel during the study? + - 0 

Blinding of outcome assessors Long-term outcomes) 

Was knowledge of the allocated intervention adequately preventes for outcome assessors during the study? 

+ - 0 

Incomplete outcome data (short-term) 

Were incomplete data adequately addressed? + - 0 

Incomplete outcome data (short-term) 

Were incomplete data adequately addressed? + - 0 

Selective outcome reporting Are reports of the study free of suggestion of selective 

outcome reporting? 

+ - 0 

Other sources of bias Was the study apparently free of other problems that could 

put it at high risk of bias? 

+ - 0 

good = all criteria were present "yes" fair = greater than or equal to 50% of criteria are present poor = less than 50% of criteria are present or unclear 

E‐3
Appendix E. Evidence Tables 

Reference List 

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm infants 

undergoing mechanical ventilation. New Engl. J. Med. 2006; 355(4):343-53. 

2. Hibbs AM, Walsh MC, Martin RJ et al. One Year Respiratory Outcomes of 12. 

the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). N/A 2007. 

3. Walsh MC, Hibbs AM, Martin CR et al. Two-year neurodevelopmental 13. 

outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 2010; 156(4):556-61.e1. 

4. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled 14. 

nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr 2006; 95(9):1116-23. 

5. Franco-Belgium Collaborative NO Trial Group. Early compared with 15. 

delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. 16. 

6. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for 17. Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 18. 

7. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre 

randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure 19. in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

8. Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide 20. 

therapy in premature infants. J. Pediatr. 2005; 146(3):318-23. 

9. Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. 

Early inhaled nitric oxide improves oxidative balance in very preterm 21. infants. Pediatr Res 2005; 57(5 Pt 1):637-43. 

10. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 

neonates with severe hypoxaemic respiratory failure: A randomised 22. controlled trial. Lancet 1999; 354(9184):1061-5. 

11. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N 

355(4):354-64. 

Watson RS, Clermont G, Kinsella JP et al. Clin

iNO in premature newborns with respiratory fai2009; 124(5):1333-43. 

Schreiber MD, Gin-Mestan K, Marks JD, Huo D

Inhaled Nitric Oxide in Premature Infants with Syndrome. New Engl. J. Med. 2003; 349(22):20

Mestan KK, Marks JD, Hecox K, Huo D, Schre

Neurodevelopmental outcomes of premature infnitric oxide. N Engl J Med 2005; 353(1):23-32. 

Srisuparp P, Heitschmidt M, Schreiber MD. Inh

premature infants with mild to moderate respiraMed Assoc Thai 2002; 85 Suppl 2:S469-78. 

Su PH, Chen JY. Inhaled nitric oxide in the man

with severe respiratory failure. J Perinatol 2008

Subhedar NV, Ryan SW, Shaw NJ. Open rando

inhaled nitric oxide and early dexamethasone in Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F

Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. 

outcome in high-risk preterm infants treated witPaediatr 2001; 90(5):573-6. 

Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature infants with severe respiratory failure353(1):13-22. 

Chock VY, Van Meurs KP, Hintz SR et al. Inha

premature rupture of membranes, oligohydramnhypoplasia. Am J Perinatol 2009; 26(4):317-22. 

Hintz SR, Van Meurs KP, Perritt R et al. Neuro

premature infants with severe respiratory failure controlled trial of inhaled nitric oxide. J Pediatr 

Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

E‐4
Appendix E. Evidence Tables 

Evidence Table 2: Risk of bias in observational studies. 

Author, year 

Representativeness of the treated cohort 

Selection of the control cohort 

Selection of treated patients 

Demonstration that outcome of interest was present at start of study 

Comparability of cohorts on the basis of the design or analysis 

Assessment of outcome 

Was followup long enough for outcomes to occur? 

Banks, 19991 

+ 0 + 0 0 

Cheung, 19982 

- - - 0 - 

Clark, 20023 

0 + + 0 + 

Dewhurst, 20104 

0 0 0 0 0 0 

Kumar, 20075 

+ - + + + 0 0 

Uga, 20046 0 + 0 + 0 0 + Tanaka, 20077 

+ + + + 0 0 + 

Yadav, , 19998 

- + + 0 0 

E‐5
Appendix E. Evidence Tables 

Evidence Table 2: Risk of bias in observational studies (continued). 

KEY Category Question Score 

Selection 

Representativeness of treated cohort 

Truly representative 

Somewhat representative 

No description 

+ - 0 

Selection of control cohort 

Same NICU or group of NICUs 

Different source 

No description 

+ - 0 

Selection of treated patients 

Medical record other 

no description 

+ - 0 

Demonstration that outcoems of interest was not present at start of study Yes No Unclear 

+ - 0 

Comparability 

Comparability of cohorts on the basis of the design or analysis Yes No Unclear 

+ - 0 

Outcome 

Assessment of outcome 

Independent blind assessment record linkage 

parent report 

teacher report 

not description 

+ + - - 0 

Was follow-up long enough four outcomes to occur? Yes 

Yes for at least 1 outcome of interest No Unclear 

+ + - 0 

Were incomplete outcome data adequately addressed Yes No unclear 

+ - 0 

good = all criteria were present "yes" fair = greater than or equal to 50% of criteria are present poor = less than 50% of criteria are present or unclear 

E‐6
Appendix E. Evidence Tables 

Reference List 

1. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in 

oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999; 103(3):610-8. 

2. Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth 

weight neonates ((less-than or equal to)1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998; 133(6):735-9. 

3. Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy 

of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002; 86(1):F41-5. 

4. Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled 

nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010; 99(6):854-60. 

. 

5. Kumar VH, Hutchison AA, Lakshminrusimha S, M

Ryan RM. Characteristics of pulmonary hypertensPerinatol 2007; 27(4):214-9. 

6. Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitric 

very low-birthweight infants with hypoplastic lung Pediatr. Int. 2004; 46(1):10-4. 

7. Tanaka Y, Hayashi T, Kitajima H, Sumi K, Fujimu

therapy decreases the risk of cerebral palsy in pretepulmonary hypertension of the newborn. Pediatrics 

8. Yadav M, Emmerson AJ. Inhaled nitric oxide in pr

1999; 354(9196):2162-3 

E‐7
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics Author, Year Study 

Design 

Study siteStudy location Recruitment date Planned length of 

follow-up 

Inclusion criteria Exclusio

Ballard, 20061 RCT Multi-Center -

North America 

Start date: May-2000 – End date: Apr-2005 

60 Weeks PMA 

Age: 7-21 days GA:<= 32 weeks BW: 500-1250 Vent support: "undergoing mechanical ventilation" between 7-21 days of age Other: NCPAP for those with BW 500-799g 

Congen: anomalieIVH: bilatOther: prexposure 

Follow-up of Ballard, 20061 

Hibbs, 20072 

RCT Multi-Center -

North America 

12 Months Age: 7-21 days of age 

BW: 500-1250 grams Vent support: required vent support via CPAP or tracheal intubation 

Follow-up of Ballard 20061 

Walsh, 20103 

RCT Multi-Center -

North America 

Age: 7-21 days from birth 

BW: <1250 g Vent support: intubated and on mechanical ventilation 

E‐8
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

Banks, 19994 Phase II 

open label, noncontrolled pilot study 

Single Center -North America 

Start date: Oct-1995 – End date: Aug-1997 

Age: >4 weeks chronologic age FiO2: >/=45% MAP: >/=10mmHg BPD: vent dependent Other: No improvement in resp. status in previous 3 days with optimal use of all standard BPD therapy: glucocorticoids, bronchodilators, diuretics per attending physician 

Congen: heart dise

Cheung, 19985 Prospective cohort Single Center - North America Start date: Dec-1993 – End date: Oct-1997 Early childhood GA:24-30 weeks 

BW: </=1500 grams Hypoxemia: hypoxemia with FiO2 > 90%, and MAP 15+/- 2 

Congen: anomalie

Clark, 20026 Multi-Center -

North America 

Start date: Jun-97— End date: Jun-99 

44 wks PMA Age: < 30 days but > 10 

days; BW: <1250; FiO2: > 40% w/o fluctuations of > 25% in the preceding 24 hours; Oligho: clinical and radiographic finding consistent with CLD 

Bleeding100,000; Congen: lethal anoiBetaAnt: within prehours; IVH: progCorticost

E‐9
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

of drug wpreceding Sepsis: 2 cultures yorganism 48 hours 

Dani, 20067 RCT Single Center -

Europe 

Start date: Jan-2001 – End date: Jun-2004 

Age: <=7 days GA:< 30 wks; Inborn RDS: Classic symptoms (need for O2, tachypnea, retractions, and grunting) and typical Xray findings (reduced air content, reticulogranular pattern of lungs and air bronchograms) FiO2: FIO2>0.5 (50%) and arterial-alveolar oxygen ratio <0.15 Surfactant Vent support 

Bleedingcount <50and bleed(hematurETT; gasor stools; puncture Congen: congenitamalformaHydrops 

Dewhurst, 2010 8 Retrospecti ve Cohort Multi-Center - Europe Start date: Jan- 2006 End date: Dec- 2007 Age: <10 days 

GA: <31 weeks 

Field, 20059 RCT Multi-Center -

Europe 

Start date: Feb-1997 – End date: Dec-2001 

1 year Corrected age 

Age: <28 days GA:<34 weeks Surfactant: treatment if appropriate 

Bleeding50,000 asec IVH: GraOther: se

E‐10
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

anomaliechromoso

Follow-up of Field 20059 Huddy, 200810 

RCT Multi-Center -

Europe 

Start date: Feb-1997 – End date: Dec-2001 

4-5 Years Age: <28 days 

GA:<34 wks Respfail: severe Vent support: intubation and mechanical ventilation 

FrancoBelgium Collaborative NO Trial Group, 199911 

RCT Multi-Center -

Europe 

Start date: Apr-1995 – End date: Jun-1997 

Until hospital discharge 

Age: <7 days of age GA:<33 weeks OI: 12.5-30 

OI: > the requiring oxide; acFrench DrecommeCongen: anomalieanomalieDshuntinsevere leshunting Hypoxemforms of hypoplasIVH: gradPulmonaraised publood flow Refractorshock Other: ab

E‐11
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

exam due asphyxia IVH 

Hascoet, 200512 

RCT Multi-Center -

Europe 

Start date: Jul-1999 – End date: Feb-2001 

28 Days GA:<32 weeks Bleeding

<50,000/Congen: abnormaHypoxemhypoxemmmHg & <50mmH100% priof age) 

Follow-up of Hascoet 200512 

Hamon, 200513 

RCT Single Center -

Europe 

Start date: Jul-1999 – End date: Feb-2001 

28 Days Age: < 48 hours 

GA:< 32 wks FiO2: > 0.40 Other: aAO2 < 0.22 

Bleeding50,000 Congen: abnormaRefractor

Kinsella, 199914 

RCT Multi-Center -

North America 

Hospital discharge 

Age: =< 7 days chronological age GA: 34 weeks or less Hypoxemia: Arterial/alveolar oxygen ratio <0.1 on 2 sequential ABGs despite mechanical vent and surfactant Vent Support: mechanical ventilation 

Congen: congenitacongenitadisease (VSD) 

E‐12
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

Kinsella, 200615 

RCT Multi-Center -

North America 

Start date: Mar- 2001 – End date: Jun -2005 

Age: <48 hours GA:<=34 wks BW: 500-1250g Respfail: requiring intubation and mechanical vent Vent Support: intubation & mechanical ventilation 

Congen: congenitadisease eseptal deor ventricdefect <=PneumotunevaluaPulmhemVent Supexpected mechanicof <48 ho

Follow-up of Kinsella 200615 

Watson, 200916 

RCT Multi-Center -

North America 

Start date: Mar 2001 – End date: Jun- 2005 

1 Year Age: <48 hours 

GA:<=34 weeks BW: 500-1250g Vent Support: mechanical ventilation 

Congen: anomaliePneumotunevacuaPulmhemhemorrhaVent Supexpected ventilatiohours 

Mercier, 2010

17 

RCT Multi-center - 

Europe 

Start date: May-2005 End date: May-2008 

1, 2 and 7 years 

GA: <34 weeks 

Schreiber, 200318 

RCT Single Center -

North America 

Start date: Oct-1998 – End date : Oct-2001 

Age: <72 hours GA:<34 weeks BW: <2000 g RDS: clinical diagnosis 

Congen: congenitamalformaHydrops 

E‐13
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria ExclusioSurfactant: Must be treated with surfactant Vent support: Require intubation and mechanical ventilation 

Follow-up of Schreiber, 200318 

Mestan, 200519 

RCT Single Center -

North America 

Start date: Oct-1998 – End date : Oct-2001 

Two years of age 

Srisuparp, 200220 

RCT Single Center -

North America 

Start date: Jul-1997 – End date: Jan-1998 

Neonatal period, to 28 days of age 

Age: < 72 hours BW: <2000g OI: >=4 if birthweight (BW) <= 1000g; >=6 if BW 1001-1250g; >= 8 of BW 1251-1500g; >= 10 if BW 1501-1750 g; >=12 if BW 1751-2000g ArtrCath RDS Vent Support: mechanical ventilation 

Congen: anomalieHydrops 

Su, 200821 RCT Single center -

Asia 

Start date: Jul-2000 – End date: Jul-2006 

GA:</= 31 weeks BW: </= 1500g RDS: severe RDS - clinical signs (IC rtxs, flaring, grunting) or CXR findings severe diffuse reticuloBleeding

uncorrecCongen: congenitaabnormaIVH: Sev

E‐14
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusiogranular infiltrates w/low lung volumes Respfail: OI >/=25 Vent Support: mechanical ventilation 

Other: letchromosoanomalie

Subhedar, 199722 

RCT Single Center -

Europe 

Start date: Aug-1995 – End date: Sep-1996 

Not specified in article 

Age: 96 hours of age GA:<32 weeks RDS: requiring mechanical ventilation Surfactant Vent Support: mechanically ventilated since birth Other: high risk for CLD by prediction score 

BleedingCongen: anomaliecardiac aDshuntinIVH: with involvemPulmhem Sepsis: Cpositive Other: G

Follow-up of Subhedar, 199722 

Bennett, 200123 

RCT Single Center -

Europe 

30 Months corrected age 

GA:<32 weeks Intrprncy

parenchyinvolvementry 

Tanaka, 200724 Retrospecti ve cohort Single Center - Asia Start date: Jan-1988 – End date: Dec-1999 3 Years GA:< 34 weeks 

Shuting: Rt-to-L shunt at PDA or R-to-L at arterial level Hypoxemia: due to PPHN

 Multiple Singleton Congen: heart dise

E‐15
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria ExclusioPPHN: Clinical: >5% difference in Pre- & Postductal SaO2, or recurrent desats <85% over 12hours despite optimal treatment of lung disease, AND Echo evidence (w/o structural heart disease): peak systolic PAP >35mmHg or >2/3 systemic systolic pressure - indicated by R-to-L shunting at PDA or arterial level 

Uga, 200425 Retrospecti 

ve cohort 

Single Center -Asia 

Start date: Jan-1999 End date: NS 

NS BW: <1500 grams 

FiO2: 100% MAP: >8 Oligho: >5 days with PROM PPHN: defined by no response to surfactant,  oligohydramnios/PROM>5 days, refractory hypoxemia PPROM: >5 days Respfail: insufficient arterial oxygenation on 100% FiO2, MAP >8cmH20 Surfactant: with no response 

Van Meurs, 200526 

RCT Multi-Center -

North America 

Start date: Jan-2001 – End date: Sep-03 

Age: 4 to 120 hours after birth GA:< 34 weeks 

Bleedingdiathesis count at o50,000 p

E‐16
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) Author, Year 

Study Design 

Study siteStudy location Recruitment date 

Planned length of follow-up 

Inclusion criteria ExclusioBW: 401-1500g OI: at least 10 on 2 ABGs between 30 min and 12 hours apart; revised to OI of at least 5.0 followed within 30 min to 12 hours of OI of at least 7.5 ArtrCath: eligible from 4 to 120 hours after birth Congen: Ventricular Septal Defect, patent ductus arteriosus and atrial level shunt permitted PPHN: idiopathic Pneumonia Pulmonary hypoplasia: suspected RDS Sepsis Surfactant: at least 4 hours before Vent Support: required assisted ventilation Other: Aspiration Syndrome 

(thromboCongen: Heart Discongenitainvolving system 

Sub analysis of 

RCT Multi-Center -

North America 

Start date: Jan- 2001 – End date: Sep- 2003 

18 to 22 Months 

GA:<34 wks; <34 wks 

Good 

E‐17
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusio

Van Meurs, 200526 

Chock, 200927 

BW: 401-1500g (iNO trial); some >1500g (larger Preemie Pilot study) Oligho: documented on U/S 5+ days prior to delivery Pulmhyp: interpretation of CXR w/small, hypoplasticappearing lungs Respfail: 4 hours following surfactant 

Follow-up of Van Meurs, 200526 

Hintz, 200728 

RCT Multi-Center -

North America 

Start date: Jan -2001– End date: Sep- 03 

18 - 22 Months corrected age 

GA:< 34 wks BW: 401 - 1500 g OI: >/=10 on 2 consecutive blood gases 30 min to 12 h apart; revised to OI >/=5 followed by OI>/=7.5 w/in 30 min to 24 hours Respfail: severe (defined in original iNO trial) Surfactant:x1 dose at least 4hr before meeting OI criteria Vent support: Mechanical 

Van Meurs, 200729 

RCT Multicenter -

North America 

Start date: Jan- 2001– End date: Sep- 2003 

18-22 Months GA:<34 wks 

BW: >1500 g OI: OI >/=15 x2 ABGs 30 min-12 hrs apart; OI >/=10 then OI>/=12.5 within 30 

Bleeding<50,000; diathesis Congen hOther: de

E‐18
Appendix E. Evidence Tables 

Evidence Table 3: Study characteristics (continued) 

Planned 

Study Study site- length of 

Author, Year Design Study location Recruitment date follow-up 

Inclusion criteria Exclusiomin-24 hrs PPHN: idiopathic Pneumonia Pulmonary hypoplasia Sepsis RDS Surfactant: at least 1 dose >4hrs prior Vent Support: mechanical ventilation Other: Aspiration syndromes 

provide f

Yadav, 199930 

Retrospecti ve cohort 

Single Center -Europe 

Start year: 1993 – End year: 1997 

Hospital discharge 

GA: "preterm" Hypoxemia: "severe hypoxemia despite max therapy 

Congen: malforma

ArtrCath: Arterial catheter, BPD: Bronchopulmonary dysplasia , BW: Birth weight, Congen: Congenital anomaly/malformation, Dshunting: Ductal SInspired Oxygen, g:grams, GA: Gestational age, iNO: inhaled Nitric Oxide, intrprncyml:Intraparenchymal lesion, IVH: Intraventricular Hemorrhagepressure, OI: Oxygenation Index, Oligho : Oligohydramnios, PMA: post menstrual age, PPHN: Persistent Pulmonary Hypertension of the Newborn, 

hypoplasia, RDS: Respiratory distress syndrome, Respfail: Respiratory failure , Vent Support: Ventilation Support 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. New 

E‐19
Appendix E. Evidence Tables 

355(4):343-53. 

2. Hibbs AM, Walsh MC, Martin RJ et al. One Year Respiratory Outcomes of 

the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). N/A 2007. 

3. Walsh MC, Hibbs AM, Martin CR et al. Two-year neurodevelopmental 

outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 2010; 156(4):556-61.e1. 

4. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes 

in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999; 103(3):610-8. 

5. Cheung P-Y, Peliowski A, Robertson CMT. The outcome of very low birth 

weight neonates ((less-than or equal to)1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998; 133(6):735-9. 

6. Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and 

efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002; 86(1):F41-5. 

7. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled 

nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr 2006; 95(9):1116-23. 

8. Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled 

nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010; 99(6):854-60. 

9. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

10. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre 

randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure 

in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

11. Franco-Belgium Collaborative NO Trial Group. Early compared with 

delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. 

12. Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide 

therapy in premature infants. J. Pediatr. 2005; 146(3):318-23. 

13. Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. 

Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 2005; 57(5 Pt 1):637-43. 

14. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 

neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet 1999; 354(9184):1061-5. 

15. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N 355(4):354-64. 

16. Watson RS, Clermont G, Kinsella JP et al. Clin

iNO in premature newborns with respiratory fai2009; 124(5):1333-43. 

17. Mercier JC, Hummler H, Durrmeyer X et al. Inh

prevention of bronchopulmonary dysplasia in prandomised controlled trial. Lancet 2010. 

18. Schreiber MD, Gin-Mestan K, Marks JD, Huo D

Inhaled Nitric Oxide in Premature Infants with Syndrome. New Engl. J. Med. 2003; 349(22):20

19. Mestan KK, Marks JD, Hecox K, Huo D, Schre

Neurodevelopmental outcomes of premature infnitric oxide. N Engl J Med 2005; 353(1):23-32. 

20. Srisuparp P, Heitschmidt M, Schreiber MD. Inh

premature infants with mild to moderate respiraMed Assoc Thai 2002; 85 Suppl 2:S469-78. 

21. Su PH, Chen JY. Inhaled nitric oxide in the man

with severe respiratory failure. J Perinatol 2008

22. Subhedar NV, Ryan SW, Shaw NJ. Open rando

inhaled nitric oxide and early dexamethasone in Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F

23. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. 

outcome in high-risk preterm infants treated witPaediatr 2001; 90(5):573-6. 

24. Tanaka Y, Hayashi T, Kitajima H, Sumi K, Fuji

therapy decreases the risk of cerebral palsy in ppulmonary hypertension of the newborn. Pediat

25. Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitr

very low-birthweight infants with hypoplastic luPediatr. Int. 2004; 46(1):10-4. 

26. Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature infants with severe respiratory failure353(1):13-22. 

27. Chock VY, Van Meurs KP, Hintz SR et al. Inha

premature rupture of membranes, oligohydramnhypoplasia. Am J Perinatol 2009; 26(4):317-22

28. Hintz SR, Van Meurs KP, Perritt R et al. Neuro

premature infants with severe respiratory failure controlled trial of inhaled nitric oxide. J Pediatr 

29. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

30. Yadav M, Emmerson AJ. Inhaled nitric oxide in 

1999; 354(9196):2162-3. 

E‐20
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Ballard, 20061 

Placebo 288 Mean: 26 

SD: 1.5 

Mean: 759 SD: 155 

W: 145 (50.3) 

HFV: 74 (25.7) 

Median:16 Range:13-19 IQR 

NA 

B: 90 (31.3) 

CMV: 191 (66.3) 

Units: Days 

H: 43 CPAP: 23 (14.9) Other: 10 

(8) 

(3.) 

iNO 294 Mean: 26 

SD: 1.5 

Mean: 766 SD: 161 

W: 170 (57.8) B: 76 (25.9) H: 32 

HFV: 65 (22.1) CMV: 202 (68.7) CPAP: 27 

Median:16 Range:12-19 IQR Units: Days 

NA 

(10.9) (9.2) Other: 16 (5.4) 

E‐21
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Follow-up of Ballard, 20061 

Hibbs, 20072 

Placebo 225 Mean: 25.7 

SD: 1.5 

Mean: 762 SD: 150 

W: 121 (53.8) B: 64 (28.4) H: 31 (13.8) Other: 9 (4) 

NA NA NA 

iNO 230 Mean: 25.8 

SD: 1.4 

Mean: 769 SD: 163 

W: 141 (61.3) B: 56 (24.2) H: 22 (9.5) Other:: 11 (4.8) 

NA NA NA 

Follow-up of Ballard 20061 

Walsh, 20103 

Placebo gas 234 Mean: 25.7 

SD:1.5 

Mean: 764 SD: 153 

W: 124(53) Other: 110(47) 

NA Median: 16 

Range: 13-20 IQR Unit: days 

NA 

iNO 243 Mean:25.8 

SD: 1.4 

Mean: 765 SD:163 

W: 151(62) Other: 92(38) 

NA Median: 17 

Range: 13-19 IQR Unit: days 

NA 

Banks, 19994 

iNO 16 Median: 25.5 

Range: 24-

Median: 787 Range: 

NA HFV: 5 

(31.25) 

Median: 2.5 Range: 1-7 

NA 

E‐22
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

 29 448-1790 

CMV :11 (68.75) 

Units: Months 

Cheung, 19985 

iNO treated cohort 

24 Median: 25 

Range: 24-27 (25% and 75 %) 

Median: 860 Range: 668-1068 (25% and 75 %)

 NA CMV : 24 

(100) NA 

Median:32 Range: 28- 52 (25% and 75 %) 

Clark, 20026 

iNO 33 Mean: 25.3; 

Range: 23-29 

Mean: 736 Range: 509-1250 

W: 11 (33) B: 21 (64) H: 1 (3) 

 Mean: 19 

Range: 9-29 Units: Days

 

Dani, 20067 Control 20 Mean: 26.7 

SD: 1.9 

Mean: 825 SD: 299

 NA HFV: 11 (55) NA Mean: 15.1 

SD: 4.9 

iNO 20 Mean: 26.3 

SD: 2.6 

Mean: 937 SD: 298

 NA HFV: 10 (50) 

NA 

Mean:16.4 SD: 5.1 

No responders 

6 Mean: 25.4 

SD: 2.6 

Mean: 748 SD: 321.4

 NA CPAP: 4 

(67) NA 

Mean:18.1 SD: 4.2 

Responders 14 Mean: 26.7 

SD: 1.9 

Mean: 1022.7 SD: 243.1

 NA CPAP: 13 

(93) NA 

Mean:14.7 SD: 3.9 

E‐23
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Dewhurst, 2010 8 Responders 26 Median: 26 Range: 25-

29 

Median: 920 Range: 655-1538 

NA Median: 53 

Range: 37-217 Units: Hours 

Median: 47 Range: 30-78 

Nonresponders 8 Median: 29 Range: 27-

30 

Median: 915 Range: 723-183 

NA Median: 75 

Range: 20-183 Units: Hours 

Median: 23 Range: 8-54 

Field, 20059 Control 53 Mean: 26.3 

SD: 2.4 

Mean: 890 SD: 343

 NA HFV: 39 

(74%) 

Median:1 Range:1-5 IQR Units: Days 

Median:31.9 Range: 17.4-51.8 IQR 

iNO 55 Mean: 27.4 

SD: 2.6 

Mean: 1006 SD: 395

 NA HFV: 33 (60) Median:1 

Range:0-6 IQR Units: Days 

Median:32.9 Range: 22.2-49.8 IQR, 

Follow-up of Field 20059 

Huddy, 200810 

Control 16 Mean: 28.2 

SD: 2.7 

Mean: 1142 SD: 440

 NA NA Median: 1 

Range: IQR 1.5 Units: Days 

Median: 25.9 Range: IQR 41.3 

iNO 22 Mean: 28.5 

SD: 2.4 

Mean: 1191 SD: 403

 NA NA Median: 1 

Range: IQR 3 Units: Days 

Median: 30.1 Range: IQR 20.5 

FrancoBelgium Collaborativ e NO Trial Group, 

Control 45 Median: 29 

Range: 3.1 IQR 

Median: 1150 Range: 520 IQR 

NA HFV: 34 (76) 

CMV : 11 (24) 

Median:1 Range: 1 IQR Units: Days 

Median: 18 Range: 7.4 IQR 

E‐24
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

199911 

iNO 40 Median: 29.6 

Range: 2.6 IQR 

Median: 1200 Range: 570 IQR 

NA HFV: 30 (75) 

CMV : 10 (25) 

Range: 1.5 Units: Days 

Median:20.2 Range: 8.3 IQR 

Hascoet, 200512 

Control with hypoxemic respiratory failure 

84 NA BW<750: 

19 (22) BW 750-999: 17 (20), BW 1000-1500: 32 (39) BW >1500: 16 (19)

 NA NA NA Mean:12 

SD: 5.6 

iNO with hypoxemic respiratory failure 

61 NA BW <750g: 

10 (16.5) BW 750-999g: 14 (23) BW 1000-1500g: 27 (44) BW >1500g: 10 (16.5)

 NA NA NA OI 

Mean:14.6 SD: 8.9 

E‐25
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Follow-up of Hascoet 200512 

Hamon, 200513 

Hypoxemic respiratory failure, no iNO 

39 Mean: 27.9 

SD: 0.4 

Mean: 1102 SD: 54 

NA NA Mean:15.9 

SD: 1.8 Units: Hours 

NA 

iNO treated hypoxemic respiratory failure 

37 Mean: 27.3 

SD: 0.4 

Mean: 1083 SD: 58 

NA NA Mean:14.1 

SD:1.4 Units: Hours 

NA 

Kinsella, 199914 

Control 32 Mean: 26.8 

SD: 2.5 

Mean: 988 SD: 387

 NA NA Mean: 27 

SD:37 Units: Hours 

NA 

iNO 48 Mean: 27.1 

SD: 2.5 

Mean: 1040 SD: 461

 NA NA Mean:30 

SD: 38 Units: Hours 

NA 

Kinsella, 200615 Placebo gas, Total sample 395 Mean: 25.6 SD: 1.8 Mean: 788 SD: 185 W: 234 of 394 (59.4) 

B: 98 of 394 (24.9) H: 48 of 394 (12.2) Other: 14 of 394 (3.6) 

HFV: 113 of 389 (29) CMV : 276 of 389 (71) 

Mean:30.1 SD:13.2 Units: Hours 

Mean:5.8, SD:6.7 

iNO, Total 398 Mean: 25.6 Mean: 796 W: 249 of HFV: 113 of Mean:30.5 Mean:5.4 

E‐26
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

sample SD: 1.7 SD: 190 397(62.7) 

B: 94 of 397(23.7) H: 41 of 397(10.3) Other: 13 of 397 (3.3) 

393 (28.8) CMV : 280 of 393 (71.2) 

SD:13.4 Units: Hours 

SD: 5.2 

Follow-up of Kinsella 200615 

Watson, 200916 

Control -detailed outcome cohort 

320 Mean: 25.7 

SD: 1.9 

Mean: 791 SD: 186 

W: 192 (60) B: 71 (22.2) H: 44 (13.8) Asian/Oth er: 13 (4.1) 

NA NA Median:4.1

 Range: 2.7-6.4 IQR 

iNO- detailed outcome cohort 

332 Mean: 25.6 

SD: 1.7 

Mean: 797 SD: 190 

W: 205 (61.8) B: 76 (22.9) H: 38 (11,5) Asian/Oth er: 13 (3.9) 

NA NA Median:4.1 

Range: 2.8-6.2 IQR 

Mercier, 2010 17 

Control 401 Mean: 26.6 

SD: 1.3 

Mean: 864 SD: 192 

W: 328 (82) 

CPAP: 42 (10) 

NA Mean: 8.6 

SD: 12.7 

B: 48 (12) 

E‐27
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

A: 2 (<1) Other: 23 (6) 

iNO 399 Mean: 26.4 

SD: 1.3 

Mean: 851 SD: 207 

W: 329 (82) B: 39 (10) A: 4 (1) Other: 27 (7) 

CPAP: 41 (10) 

NA Mean: 8.0 

SD: 10.7 

Schreiber, 200318 

Placebo 102 Mean: 27 

SD: 2.8 

Mean: 949 SD: 387 

W: 12 (11.8) B: 74 (72.6) Other: 16 (15.7) 

HFV: 48 (47) CMV : 54 (52.9) 

Median:14 Range: IQR 7.6-28.5 

Median:6.8 Range: 4.4-12.7 IQR 

iNO 

105 Mean: 27.4 

SD: 2.5 

Mean: 1017 SD: 369 

W: 18 (17.1) B: 71 (67.6) Other: 16 (15.2) 

HFV: 54 (51.4) CMV : 51 (48.6) 

Median: 12.9 Range: IQR 7.0-25.2 

Median:7.3 Range: IQR 4.1-12.3 

Follow-up Control 68 Mean: 27.2 Mean: 958 W: 8 (12) NA SD: 8.4 Median: 7.2 

E‐28
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

of Schreiber, 200318 

Mestan, 200519 

SD: 2.6 SD: 356 

B: 52 (76) Other:: 8 (12)

 Units: 

Months

 Range: IQR 4.5-14.3 

iNO 70 Mean: 27.5 

SD: 2.4 

Mean: 1026 SD: 366 

W: 14 (20) B: 44 (63), Other:: 12 (17)

 NA Mean: 24.9 

SD: 7.9 Units: Months 

Median: 6.6 Range: IQR 4-11.5 

Srisuparp, 200220 

Control 18 Mean: 27.2 

SD: 0.5 

Mean: 901 SD: 73 

B: 16 (89) HFV: 7 

(38.9) 

NA Mean:11.9 

SD: 2.2 

iNO 16 Mean: 26.8 

SD: 0.5 

Mean: 874 SD: 70 

B: 16 (100) 

HFV: 7 (43.8) 

NA Mean:10.8 

SD: 1.5 

Su, 200821 Received 

inhaled oxygen placebo only 

33 Mean: 27.9 

SD: 1.8 

Mean: 1050 SD: 210 

NA NA Mean:2.5 SD: 1.8 

Units: Days 

Mean: 30.5 SD: 4.7 

iNO 32 Mean: 27.4 

SD: 2.3 

Mean: 1020 SD: 230

 NA CMV : 

32(100) 

Mean: 2.45 SD: 1.7 Units: Days 

Mean:30.3 SD: 3.5 

E‐29
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Subhedar, 199722 

Dexamethaso ne and standard of care 

22 Median: 27 

Range: 22-31 

Median: 750 Range: 520-1400

 NA NA Median: 104 

Range: 96-120 Units: Hours 

Median: 3.9 Range: 1.2-11.5 

iNO + iNO and dexamethaso ne) 

20 Median: 27 

Range: 24-30 

Median: 882 Range: 416-1354

 NA NA Median: 99 

Range: 96-113 IQR Units: Hours 

Median: 7.9 Range: 1.6-46.7 

Dexamethaso ne alone AND dex + iNO) 

21 Median: 27 

Range: 22-31 

Median: 870 Range: 530-1400

 NA NA Median: 104 

Range: 96-120 Units: Hours 

Median: 7.9 Range: 1.2-46.7 

iNO AND 21 Median: 27 Median: NA NA Median: 98 Median: 4.1 

E‐30
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

standard of care 

Range: 22-31 

818 Range: 520-1222 

Range: 96-114 Units: Hours

 Range: 1.4-28 

Follow-up of Subhedar, 199722 

Bennett, 200123 

Control 22 NA NA NA CMV :22 

(100) 

Mean: 96 Units: Hours 

NA 

iNO 20 NA NA NA CMV :20 

(100) 

Mean: 96 Units: Hours 

NA 

Tanaka, 200724 

Control 15 Median: 26 

Range: 24-30 

Median: 818 Range: 720-1400 IQR 

NA HFV: 9 (60) NA Median: 23.3 Range:16-45 

iNO 16 Median: 25.5 

Range: 25-28.8 

Median: 838 Range: 628-1144 IQR 

NA HFV: 14 (87.5) NA Median: 23.3 Range: 16-45 

IQR 

Uga, 200425 Control 10 Mean: 25.8 

SD: 2.4 Range: 24-30 

Mean: 809 SD: 316 Range: 426-1453

 NA NA NA Mean: 13.9 

SD: 10.2 

iNO 8 Mean: 27.2 

SD: 2.2 Range: 24-30 

Mean: 996 SD: 294 Range: 570-1317

 NA NA NA Mean: 28.8 

SD: 18.3 

E‐31
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

Van Meurs, 200526 

Control 210 Mean: 26 

SD: 2 

Mean: 837 SD: 260 

W: 96 (46) B: 78 (37) H: 32 (15) Other: 4 (2) 

HFV: 124 (59) CMV: 86 (41) 

Mean:28 SD: 22 Units: Hours 

Mean:22 SD:17 

iNO 210 Mean: 26 

SD: 2 

Mean: 840 SD: 264 

W: 95 (45) B: 69 (33) H: 36 (17) Other: 10 (5) 

HFV: 125 (59) CMV : 85 (40) 

Mean:26 SD: 23 Units: Hours 

Mean:23 SD:17 

Sub analysis of Van Meurs, 200526 

Chock, 200927 

Control 6 Mean: 29 

SD: 3 

Mean: 1179 SD: 369 

W: 4 (67) B: 1 (17) H: 0 (0) Other: 1 (17) 

HFV: 6 (100) Mean:11 

SD: 4 Units: Hours 

Mean:44 SD: 30 Median:39 Range:10-100 

iNO 6 Mean: 27 

SD: 2 

Mean: 1039 SD: 355 

W: 2 (33) B: 1 (17) H: 2 (33) Other: 1 (17) 

HFV: 6 (100) Mean:12 

SD: 8 Units: Hours 

Mean:20 SD:27  Median: 19 Range: 11-64 

Follow-up of Van Meurs, 200526 

Hintz, 200728 

Placebo 102 Mean: 26.2 

SD: 2.2 

Mean: 864 SD: 271 

W: 46 (45) B: 35 (34) H: 18 (18) Other: 1 (1) 

HFV: 57 (56) NA Mean: 18.1 

SD:11.3 Median: 14.9 Range:.5 -21.6 

E‐32
Appendix E. Evidence Tables 

Evidence Table 4. Participant Characteristics (continued) Author, year 

Control Interventions 

N at baseline 

Gestational age (weeks) 

Birth weight (grams) 

Race n(%) 

Mode of Ventilation, n(%) 

Participant age at enrollment 

Oxygenation Index 

 iNO Followup of group 91 Mean: 26.8 SD: 2.3 Mean: 958 SD: 276 W: 43 (47) 

B: 27 (30) H: 17 (19) 

HFV: 61 (67) NA Mean: 20 

SD:12.9 Median: 16.3 Range: 12-24 

Van Meurs, 200729 

Control 15 Mean: 31.4 

SD: 1.1 

Mean: 2168 SD: 441 

W: 5 (33) HFV: 11 (73) 

NA 

Mean: 28.2 SD:17.3 

B: 4 (27) CMV : 2(13) H: 6 (40) HFFI: 2 (13) 

iNO 14 Mean: 31.1 

SD: 1.2 

Mean: 1970 SD: 391 

W: 7 (50) B: 5 (36) H: 1 (7) Other:1 (7) 

HFV: 6 (43) CMV : 8 (57) HFFI 0 (0) 

NA 

Mean:25.1 SD:19.4 

Yadav, 199930 

iNO 41 Mean:27 

SD:2.6 

Mean: 1000 

NA NA NA Mean: 40 

SD: 17 

SD: 46 

B:Non-hispanic black; H:Hispanic; W:non-hispanic white; HFV: High-frequency ventilation; CMV: Conventional mechanical ventilation; CPAP: Con

Pressure; HFFI: High-frequency flow interruption; mmHg: millimeters of mercury; ppm: parts per million; iNO: inhaled nitric oxide 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm infants 

undergoing mechanical ventilation. New Engl. J. Med. 2006; 355(4):343-53. 

2. Hibbs AM, Walsh MC, Martin RJ et al. One Year Respiratory Outcomes of 

the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide (iNO). N/A 2007. 

3. Walsh MC, Hibbs AM, Martin CR et al. Two-year neurodevelopmental 

outcomes of ventilated preterm infants treated wiPediatr 2010; 156(4):556-61.e1. 

4. Banks BA, Seri I, Ischiropoulos H, Merrill J, Ryc

in oxygenation with inhaled nitric oxide in severe dysplasia. Pediatrics 1999; 103(3):610-8. 

5. Cheung P-Y, Peliowski A, Robertson CMT. The 

E‐33
Appendix E. Evidence Tables 

weight neonates ((less-than or equal to)1500 g) rescued by inhaled nitric oxide: Neurodevelopment in early childhood. J. Pediatr. 1998; 133(6):735-9. 

6. Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy 

of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002; 86(1):F41-5. 

7. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled 

nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr 2006; 95(9):1116-23. 

8. Dewhurst C, Ibrahim H, Gothberg S, Jonsson B, Subhedar N. Use of inhaled 

nitric oxide in the new born period: Results from the European inhaled nitric oxide registry. Acta Paediatr. Int. J. Paediatr. 2010; 99(6):854-60. 

9. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

10. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

11. Franco-Belgium Collaborative NO Trial Group. Early compared with delayed 

inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. 

12. Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide 

therapy in premature infants. J. Pediatr. 2005; 146(3):318-23. 

13. Hamon I, Fresson J, Nicolas MB, Buchweiller MC, Franck P, Hascoet JM. 

Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 2005; 57(5 Pt 1):637-43. 

14. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 

neonates with severe hypoxaemic respiratory failure: A randomised controlled 

trial. Lancet 1999; 354(9184):1061-5. 

15. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N Engl J Med 2006; 355(4):354-64. 

16. Watson RS, Clermont G, Kinsella JP et al. Clinical and economic effects of 

iNO in premature newborns with respiratory failure at 1 year. Pediatrics 2009; 124(5):1333-43. 

17. Mercier JC, Hummler H, Durrmeyer X et al. Inhaled nitric oxide for 

. 

prevention of bronchopulmonary dysplasia in prerandomised controlled trial. Lancet 2010. 

18. Schreiber MD, Gin-Mestan K, Marks JD, Huo D

Nitric Oxide in Premature Infants with the RespirNew Engl. J. Med. 2003; 349(22):2099-107. 

19. Mestan KK, Marks JD, Hecox K, Huo D, Schreib

outcomes of premature infants treated with inhale2005; 353(1):23-32. 

20. Srisuparp P, Heitschmidt M, Schreiber MD. Inha

premature infants with mild to moderate respirato

Assoc Thai 2002; 85 Suppl 2:S469-78. 

21. Su PH, Chen JY. Inhaled nitric oxide in the mana

with severe respiratory failure. J Perinatol 2008; 

22. Subhedar NV, Ryan SW, Shaw NJ. Open random

inhaled nitric oxide and early dexamethasone in Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F1

23. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. N

in high-risk preterm infants treated with inhaled n2001; 90(5):573-6. 

24. Tanaka Y, Hayashi T, Kitajima H, Sumi K, Fujim

therapy decreases the risk of cerebral palsy in prepulmonary hypertension of the newborn. Pediatri

25. Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitri

very low-birthweight infants with hypoplastic lunPediatr. Int. 2004; 46(1):10-4. 

26. Van Meurs KP, Wright LL, Ehrenkranz RA et al

premature infants with severe respiratory failure. 353(1):13-22. 

27. Chock VY, Van Meurs KP, Hintz SR et al. Inhal

premature rupture of membranes, oligohydramnihypoplasia. Am J Perinatol 2009; 26(4):317-22. 

28. Hintz SR, Van Meurs KP, Perritt R et al. Neurod

premature infants with severe respiratory failure controlled trial of inhaled nitric oxide. J Pediatr 2

29. Van Meurs KP, Hintz SR, Ehrenkranz RA et al. I

>1500 g and <34 weeks gestation with severe res2007; 27(6):347-52. 

30. Yadav M, Emmerson AJ. Inhaled nitric oxide in 

1999; 354(9196):2162-3 

E‐34
Appendix E. Evidence Tables 

Evidence Table 5. Death and survival outcomes for KQ1. Author, Year 

Outcome Time of 

outcome measure 

Arm Description N 

(Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) OR (95% CI) 

Adjusted Relat

Effect (95% CI) Adjusted OR (9

Ballard, 20061 

Death 36 weeks 

PMA 

Control 288 18 (6.3) 

iNO 294 16 (5.4) 

40 weeks PMA 

Control 288 19 (6.6) 

iNO 294 19 (6.5) 

44 wks PMA 

Control 288 20 (6.9) 

iNO 294 20 (6.8) 

Dani, 20062 

NICU Control 20 6 (30) P-value: 0.494 

iNO 20 4 (20) Nonresponders 6 4 (66) P-value: 0.078 

Responders 14 3 (21) 

Field, 20053 1 year Control 53 34 (64) 

iNO 55 30 (55) 

FrancoBelgium Collaborati ve NO Trial Group, 19994 

in NICU Control 45 16 (35) P-value: Not 

significant 

iNO 40 11 (27) 

Hascoet, 20055 7 days of life Control with HRF 84 14 (17) P-value: 0.58 1 iNO with HRF 61 8 (13) 

28 days of life 

Control with HRF 84 26 (31) P-value: Not 

significant 

E‐35
Appendix E. Evidence Tables 

Evidence Table 5. Death and survival outcomes for KQ1 (continued) Author, Year 

Outcome Time of 

outcome measure 

Arm Description N 

(Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) OR (95% CI) 

Adjusted Relat

Effect (95% CI) Adjusted OR (9

iNO with HRF 61 25 (41) 

Kinsella, 19996 Discharge Control 32 17 (53) P-value: 0.65 RR: 1.11(0.7-1.8) 

iNO 48 23 (48) 

Kinsella, 20067

 36 wks 

PMA 

Control 392 98 (25) P-value: 0.08 

RR: 0.79 (0.61-

iNO, Total sample) 

394 78 (19.8) 

Mercier, 2010 8

 24-28 

weeks 

Control 401 42 (10.5) iNO 399 56 (14) 

Schreiber, 20039 

NICU Control 102 23 (22.5) P-value: 0.18 

RR: 0.68 (0.38-1.20)

 RR: 0.68 (0.38-

iNO 105 16 (15.2) 

Srisuparp, 200210 7 days Control 22 2 (11.1) P-value: 1 

iNO 16 2 (12.5) 

Su, 200811 During 

Study (9 death within 96 hours) 

Control 33 10 (30.3) 

iNO 32 6 (18.8) 

E‐36
Appendix E. Evidence Tables 

Evidence Table 5. Death and survival outcomes for KQ1 (continued) Author, Year 

Outcome Time of 

outcome measure 

Arm Description N 

(Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) OR (95% CI) 

Adjusted Relat

Effect (95% CI) Adjusted OR (9

groups 1&3; iNO + iNO and dexamethasone) 

20 10 (50) 

Van Meurs, 200513

 death 

before discharge to home or within 365 

Control 208 93 (45) P-value: 0.11 

RR:1.16 (0.96-1

iNO) 210 109 (52) 

Van Meurs, 200714 

Death before discharge to home or within 365 

Control 15 4 (27) P-value: 0.7 

RR: 1.34 (0.45-4.0) 

p-value: 0.65 RR: 1.26 (0.47-3

iNO 14 5 (36) 

Ballard, 20061 

Survival without BPD 

36 weeks PMA 

Control 288 105 (36.5) p-value:0.04 

RR: 1.26 (1.02-1.55)

 RR: 1.45 (1.03-

iNO 294 129 (43.9) 

E‐37
Appendix E. Evidence Tables 

Evidence Table 5. Death and survival outcomes for KQ1 (continued) Author, 

Year 

Outcome Time of 

outcome measure 

Arm Description N 

(Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) OR (95% CI) 

Adjusted Relat

Effect (95% CI) Adjusted OR (9

Hascoet, 20055 28 days Control with HRF 84 18 (21.4) p-value:NS iNO with HRF 61 14 (23) p-value:NS 

Schreiber, 20039

 Survived 

NICU 

iNO 89 54 (60.7) 

Control 79 37 (46.8) 

Schreiber, 20039 

Survival with BPD 

Survived NICU 

Control 102 42 (53.2) p-value:0.07 

RR:0.74 (0.53-1.03) 

iNO 105 35 (39.3) 

Subhedar, 199712 

Not Specified 

Control dexamethasone and standard of care 

22 14 (64) RR: 1.07 (0.71-

1.37) RR: 0.92 (0.67-

1.28) 

Groups 1&3; iNO + iNO and dexamethasone 

10 10 (100) 

Dexamethasone alone AND dex + iNO 

21 11 (52) 

iNO AND standard of care 

21 13 (62) 

Schreiber, 20039 

Survival, BPD not specific 

Survived NICU 

Control 102 79 (77.5) 

iNO 105 89 (84.8) 

E‐38
Appendix E. Evidence Tables 

BPD: Bronchopulmonary Dysplasia, CI: Confidence Interval, GEE: Generalized estimating equation, HRF: Hypoxemic Respiratory Failure , iNO: InhNeonatal intensive care unit, NS: Not significant, OI: Oxygenation Index, OR: Odds ratio, PMA: Post-menstrual age , RR: Relative risk 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm 

infants undergoing mechanical ventilation. New Engl. J. Med. 2006; 

355(4):343-53. 

2. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled 

nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr 2006; 95(9):1116-23. 

3. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

4. Franco-Belgium Collaborative NO Trial Group. Early compared with 

delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomised controlled trial. The Franco-Belgium Collaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. 

5. Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide 

therapy in premature infants. J. Pediatr. 2005; 146(3):318-23. 

6. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 

neonates with severe hypoxaemic respiratory failure: A randomised 

controlled trial. Lancet 1999; 354(9184):1061-5. 

7. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N Engl J Med 2006; 

355(4):354-64. 

8. Mercier JC, Hummler H, Durrmeyer X et al. Inh

prevention of bronchopulmonary dysplasia in prandomised controlled trial. Lancet 2010. 

9. Schreiber MD, Gin-Mestan K, Marks JD, Huo D

Inhaled Nitric Oxide in Premature Infants with Syndrome. New Engl. J. Med. 2003; 349(22):20

10. Srisuparp P, Heitschmidt M, Schreiber MD. Inh

premature infants with mild to moderate respiraMed Assoc Thai 2002; 85 Suppl 2:S469-78. 

11. Su PH, Chen JY. Inhaled nitric oxide in the man

with severe respiratory failure. J Perinatol 2008

12. Subhedar NV, Ryan SW, Shaw NJ. Open rando

inhaled nitric oxide and early dexamethasone in Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F

13. Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature infants with severe respiratory failure353(1):13-22. 

14. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

E‐39
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffe in Dur(p-v

Ballard, 20061 

36 weeks PMA 

Control 288 164 (56.9) 

iNO 294 149 (50.7) 

Dani, 20062 

36 weeks PMA 

Control 20 12 (60) P-value: 

0.067 

Mean: 69.4 SD: 30.2 

0.0

iNO 20 6 (30) Mean: 

47.3 SD: 39.4 

Nonrespond ers 

6 2 (33) Mean: 

19.8 SD: 11.5 

0.0

Responders 14 7 (50) Mean: 

48.6 SD: 37.3 

Field, 20053 

36 weeks PMA 

Control 55 15 (27) Mean: 6 

IQR:1.0-17.0 

iNO 53 26 (49) Mean: 15 

IQR:2-71 

E‐40
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

FrancoBelgium Collabor ative NO Trial Group, 19994 

during hospitalizati on 

Control 29 8 (29) p-value: NS Median: 

23 IQR:41 

0.38 

iNO 29 7 (24) p-value: NS 

OR: 0.95 (0.44–2.04) 

Median: 

14 IQR:43 

Kinsella, 20065 

36 weeks PMA 

Control 309 210 (68) P-value: 0.43 RR:0.96 

(0.86–1.09) 

randomizati on strata, study sight 

iNO 326 212 (65) 

Kinsella, 19996 

36 weeks PMA 

Control 15 12 (80) p-value: 0.3 

RR: 0.75(0.5-1.13) iNO 25 15 (60) 

Mercier, 2010 7 

24-28 weeks 

Control 358 96 (27) iNO 339 81(24) 

Schreib er, 20038 

36 weeks PMA 

Control 102 42 (53.2) P-value: 

0.07 RR: 0.74 (0.53–1.03) 

type of ventilation 

iNO 105 35 (39.3) 

Su, 20089 

36 weeks PMA 

Control 33 11 (33.3) 

E‐41
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

iNO 32 10 (31.3) 

Subhed ar, 1997

10 

36 weeks PMA 

Dexamethas one and standard of care 

22 14 (64) 

Groups 1&3; iNO + iNO and dexamethas one 

20 10 (50) 

Dexamethas one alone AND dex + iNO 

21 11 (52) 

iNO AND standard of care 

21 13 (62) 

Van Meurs, 200711 

36 weeks PMA 

Control 11 5 (45) p-value: 0.66 

RR: 0.66 (0.21-2.08) 

p-value: 0.21 RR: 0.40 (0.09-1.71) 

OI stratum Mean: 32 

SD: 23 

0.45 

iNO 10 3 (30) Mean: 

23.8 SD: 24.4 

Van Meurs, 200512 

36 weeks PMA 

Control 127 86 (68) P-value: 0.26 RR: 0.90 

(0.75–1.08) iNO 109 65 (60) 

Ballard, 20061 

40 weeks PMA 

Control 288 84 (29.2) iNO 294 66 (22.4) 

44 weeks PMA 

Control 288 35 (12.2) iNO 294 27 (9.2) 

Dani, 2006 2 

Duration of supplement 

Control 20 69.4 days* iNO 20 47.3 days* 

E‐42
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure al oxygen 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

Nonrespond 

ers 

6 19.8 days* 

Responders 14 48.6 days* 

Field, 20053 1 year corrected 

age 

Control 18 

survivors 

1 (6) 

iNO 20 

survivors 

3 (15) 

At term (EDC) 

Control 53 12 (23) Median: 

81 IQR:14-100 

iNO 55 16 (29) Median: 

59 IQR:30-78 

FrancoBelgium Collabor ative NO Trial Group, 19994 

28 days Control 29 14 (48) p-value: NS 

iNO 29 13 (45) 

Kinsella, 19996 Hospital discharge Control 15 12 (80) p-value: 0.1 RR: 0.65 

(0.41-1.02) 

iNO 25 13 (54) p-value: 0.1 

1.02) RR: 0.65(0.41-

Kinsella, 2006 5 

Post-natal corticostero ids 

Control 365 204 (56) p-value: 0.24 

iNO 369 222 (60) 

Schreib Duration of Control 102 28.5 days* 

E‐43
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year er, 2003

8 

Time of outcome measure Mechanical Ventilation 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

iNO 105 16 days 

Su, 20089 

Duration of Mechanical Ventilation 

Control 33 14.2 days* iNO 32 12.8 days * 

Van Meurs, 200512 

Days on Mechanical Ventilation 

Control 210 47 days* iNO 210 39 days* 

Van Meurs, 2007 11 

Physiologic BPD as per Walsh criteria 

Control 10 4 (40) p-value: 1 

RR: 0.91 (0.31-2.70)

 p-value: 0.61 RR: 0.74 (0.26-2.09) iNO 11 4 (36) 

Ballard, 20061 

40 weeks PMA, severe 

Control 288 30 (10.4) iNO 294 18 (6.1) 

44 weeks PMA, severe 

Control 288 12 (4.2) iNO 294 6 (2) 

Dani, 20062 

In NICU, severe 

Control 20 20 (100) 14.9 

(Mean) 18.1 (SD) 

iNO 20 20 (100) 1 12.5 

(Mean) 

0.60

E‐44
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

10.1 (SD) 

Nonrespond ers 

6 6 (100) 19 

(Mean) 12.7 (SD) 

Responders 14 14 (100) 1 15.8 

(Mean) 17.3 (SD) 

0.69 

Field, 20053 During hospitalizati 

on, severe 

Control 53 4 (Mean) 

1.0-9.0 IQR 

iNO 55 7 

(Median) 2-26 IQR 

Hascoet , 200513 

48 hours of life, severe 

Control with HRF 

84 30 (35.7) 0.024 

iNO with HRF 

61 49 (80.3) 0.024 

FrancoBelgium , 19994 

during hospitalizati on, severe 

Control 29 16 

(Median) 14 IQR 

ns 

iNO 29 12 

(Median) 32 IQR 

0.78 

E‐45
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

Schreib er, 20038 

Before Discharge, severe 

Control 79 

survivors 

28.5 

(Median) IQR 8-48 

iNO 89 

survivors 

16 

(Median) IQR 8-37 

0.19 

Subhed ar, 199710 

Before Discharge, severe 

Dexamethas one and standard of care 

22 19 

(Median) 5-39 range 

Groups 1&3; iNO + iNO and dexamethas one 

20 11 

(Median) 5-44 range 

Dexamethas one alone AND dex + iNO 

21 23 

(Median) 6-44 range 

iNO AND standard of care 

21 13 

(Median) 5-39 range 

Time to extubation, severe 

Dexamethas one and standard of care 

22 11 

(Median) range 5-

E‐46
Appendix E. Evidence Tables 

Evidence Table 6. BPD for KQ1 (continued)

Author, Year 

Time of outcome measure 

Study Arm N 

(number of participan ts measured ) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Adjustmen ts 

Duration (days) 

Diffee in Dura(p-va

35 

Groups 1&3; iNO + iNO and dexamethas one 

20 6.5 

(Median) range 5-28 

Dexamethas one alone AND dex + iNO 

21 8.5 

(Median) 5-35 range 

iNO AND standard of care 

21 11 

(Median) 5-28 range 

Van NICU, Control 117 Mean:47 

Meurs, 200512 

severe SD: 53 

iNO 101 Mean:39 

SD:45 

0.56 

* Measure given in days, not number of participants BPD: Bronchopulmonary Dysplasia, EDC: Estimated date of confinement, HFOV: High-frequency oscillatory ventilation, HRF: HypoxemiInhaled Nitric Oxide, IQR: Inter-quartile range, NICU: Neonatal Intensive Care Unit, NS: Not significant, PMA: Post-menstrual age, SD: S

E‐47
Appendix E. Evidence Tables 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm controlled trial. Lancet 1999; 354(9184):1061-5

infants undergoing mechanical ventilation. New Engl. J. Med. 2006; 7. Mercier JC, Hummler H, Durrmeyer X et al. In

355(4):343-53. prevention of bronchopulmonary dysplasia in p

2. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled randomised controlled trial. Lancet 2010. 

nitric oxide in very preterm infants with severe respiratory distress 8. Schreiber MD, Gin-Mestan K, Marks JD, Huo Dsyndrome. Acta Paediatr 2006; 95(9):1116-23. Inhaled Nitric Oxide in Premature Infants with 

3. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled Syndrome. New Engl. J. Med. 2003; 349(22):20

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for 9. Su PH, Chen JY. Inhaled nitric oxide in the manPreterm Infants With Severe Respiratory Failure: the INNOVO multicentre with severe respiratory failure. J Perinatol 2008randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 10. Subhedar NV, Ryan SW, Shaw NJ. Open rando115(4):926-36. inhaled nitric oxide and early dexamethasone in 

4. Franco-Belgium Collaborative NO Trial Group. Early compared with Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F

delayed inhaled nitric oxide in moderately hypoxaemic neonates with 11. Van Meurs KP, Hintz SR, Ehrenkranz RA et alrespiratory failure: a randomised controlled trial. The Franco-Belgium infants >1500 g and <34 weeks gestation with sCollaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. Perinatol 2007; 27(6):347-52. 

5. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 12. Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature newborns with respiratory failure. N Engl J Med 2006; premature infants with severe respiratory failure355(4):354-64. 353(1):13-22. 

6. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 13. Hascoet JM, Fresson J, Claris O et al. The safet

neonates with severe hypoxaemic respiratory failure: A randomised therapy in premature infants. J. Pediatr. 2005; 1

E‐48
Appendix E. Evidence Tables 

Evidence Table 7. Death of BPD outcomes for KQ1 Author, Year Time of 

outcome measure 

Arm Description 

N (Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) 

Adjusted Relative 

Effect (95% CI) 

Ad

OR (95% CI) Adjusted OR (95% CI) 

Ballard, 20061 36 weeks 

PMA 

Control 288 182 (63.2) iNO 294 165 (56.1) 

Dani, 20062 NICU Control 20 18 (90) P-value: 0.016 

OR: 0.111 (0.02-0.610) 

iNO 20 10 (50) 

Nonresponders 6 6 (100) P-value: 0.035 

Responders 14 10 (71) 

Field, 20053 36 weeks 

PMA 

Control 53 48 (91) iNO 55 49 (89) 

FrancoBelgium Collaborative NO Trial Group, 19994 

In NICU Control 45 24 (53) 

iNO 40 18 (45) 

Kinsella, 19995 Discharge Control 32 29 (91) P-value: 0.14 RR: 0.85(0.7-

iNO 48 37 (77) 1.03)

Kinsella, 20066 

36 wks PMA 

Control 392 295 (75.3) P-value: 0.24 RR: 0.95 (0.87-1.03) St

ra

iNO 394 282 (71.6) 

Mercier, 2010

7 

24-28 weeks 

Control 400 138 (35) 

E‐49
Appendix E. Evidence Tables 

Evidence Table 7. Death of BPD outcomes for KQ1 (continued) Author, Year Time of 

outcome measure 

Arm Description 

N (Number of Participants Measured) 

Participants with Outcome n (%) 

Relative Effect (95% CI) 

Adjusted Relative 

Effect (95% CI) 

Ad

OR (95% CI) Adjusted OR (95% CI) 

iNO 395 137 (35) 

Schreiber, 20038 

NICU Control 102 65 (63.7) P-value: 0.03 

RR: 0.76 (0.60-0.97) 

RR: 0.77 (0.60-0.98) typ

iNO 105 51 (48.6) 

Su, 2008 9 36 weeks 

PMA 

Control 33 21 (64) 

iNO 32 16 (50) 

Subhedar, 1997 10 

Before Discharge 

Control 22 21 (95) RR = 1.05 

(0.84-1.25) iNO 20 20 (100) 

Van Meurs, 200711 

Death before discharge to home or within 365 

Control 15 9 (60) P-value: 0.87 

RR: 0.83 (0.43-1.62) 

p-value: 0.5 RR: 0.80 (0.43-1.48)

 O

iNO 14 7 (50) 

Van Meurs, 200512 

before discharge to home or within 365 days among hospitalized infants 

Control 208 170 (82) P-value: 0.52 RR: 0.97 

(0.86-1.06)

 BOx

iNO 210 167 (80) 

BPD: Bronchopulmonary Dysplasia, iNO: Inhaled nitric oxide, NICU: Neonatal intensive care unit, OI: Oxygenation Index, OR: Odds ratio

age , RR: Relative risk 

E‐50
Appendix E. Evidence Tables 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm premature newborns with respiratory failure. N 

infants undergoing mechanical ventilation. New Engl. J. Med. 2006; 355(4):354-64. 

355(4):343-53. 7. Mercier JC, Hummler H, Durrmeyer X et al. Inh

2. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled prevention of bronchopulmonary dysplasia in p

nitric oxide in very preterm infants with severe respiratory distress randomised controlled trial. Lancet 2010. syndrome. Acta Paediatr 2006; 95(9):1116-23. 8. Schreiber MD, Gin-Mestan K, Marks JD, Huo D

3. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled Inhaled Nitric Oxide in Premature Infants with 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Syndrome. New Engl. J. Med. 2003; 349(22):20Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre 9. Su PH, Chen JY. Inhaled nitric oxide in the man

randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; with severe respiratory failure. J Perinatol 2008115(4):926-36. 10. Subhedar NV, Ryan SW, Shaw NJ. Open rando

4. Franco-Belgium Collaborative NO Trial Group. Early compared with inhaled nitric oxide and early dexamethasone in 

delayed inhaled nitric oxide in moderately hypoxaemic neonates with Arch Dis Child Fetal Neonatal Ed 1997; 77(3):Frespiratory failure: a randomised controlled trial. The Franco-Belgium 11. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

Collaborative NO Trial Group. Lancet 1999; 354(9184):1066-71. infants >1500 g and <34 weeks gestation with s

5. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature Perinatol 2007; 27(6):347-52. 

neonates with severe hypoxaemic respiratory failure: A randomised 12. Van Meurs KP, Wright LL, Ehrenkranz RA et a

controlled trial. Lancet 1999; 354(9184):1061-5. premature infants with severe respiratory failure

6. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 353(1):13-22. 

E‐51
Appendix E. Evidence Tables 

Evidence Table 8. Brain injury outcomes for KQ2. 

Author, Year Outcomes 

Time of outcome measure Arm Description 

N (number of participants measured) 

Participants with outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative E(95% CI) 

Dani, 20061 Brain injury, 

any IVH 

before discharge 

Control 20 4 (20) P-value: 

iNO 20 5 (25) 0.725

Hascoet, 20052 28 days Control 84 6 (7) P-value: iNO 61 4 (6) NS

Kinsella, 19993 7 days or 36 weeks 

postconception al age 

iNO 32 18 (56) P-value: Control 17 10 (59) NS

Su, 20084 Not specified Control 33 12 (36.3) 

iNO 32 8 (25) 

Dani, 20061 Brain injury, 

IVH grades 3 and 4 

Before discharge 

Control 20 2 (10) P-value: iNO 20 2 (10) 1

Nonresponders 6 3 (50) P-value: 

Responders 14 3 (21) 0.225

Kinsella, 1999 3 7 days Control 43 16 (37) iNO 26 10 (40) 

Kinsella, 20065 7 to 14 days of age and / or at 

more than 30 days of age 

Control 394 63 (16) p-value 0.

RR: 0.77 (1.09) 

iNO 398 49 (12.3) 

Mercier, 2010 6 

24-28 weeks Control 397 32 (8) 

iNO 395 24 (6.1) 

Srisuparp, 20027 

72 hours Control 18 5 (27.8) 

iNO 16 4 (25.1) 

Su, 20084 Not specified Control 33 8 (24.2) 

iNO 32 4 (12.5) 

E‐52
Appendix E. Evidence Tables 

Evidence Table 8. Brain injury outcomes for KQ2 (continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm Description N (number 

of participants measured) 

Participants with outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative (95% CI) 

Ballard, 20068 Brain Injury, IVH Grades 3 

or 4 and / or PVL 

after study entry 

Control 288 10 (4.1) P-value: 0.67 

RR:1.21(0.53-2.76) 

iNO 294 13 (5) 

FrancoBelgium Collaborativ e NO Trial Group, 19999 

during hospitalization 

Control 45 12 (27) P-value: NS iNO 40 13 (32) 

Kinsella, 2006 5 

21 days until extubation 

Control 364 87 (24) 

iNO 366 64 (17) 

Schreiber, 200310 

NICU Control 102 24 (23.5) P-value: 0.04 

RR: 0.53 (0.28-0.98) 

iNO 105 13 (12.4) 

Van Meurs, 200711 28 +/- 3 days Control 9 (HUS available) 2 (22) P-value: 0.47 

iNO 9 0 (0) 

Van Meurs, 200512 Not specified Control 155 50 (32) P-value: 0.11 RR: 1.25 (0.95-

1.66) 

iNO 170 69 (39) 

Dani, 20061 Brain Injury, 

PVL 

Before discharge 

Control 20 1 (5) P-value: iNO 20 0 (0) 0.5Nonresponders 6 0 (0) P-value: Responders 14 0 (0) 1

Kinsella, 20065 7 to 14 days of age and / or at 

more than 30 days of age 

Control 356 32 (9) P-value: 0

RR: 0.58 1.00)

iNO 365 19 (5.2) 

Kinsella, 7 days or 36 

weeks 

Control 15 2 (13) P-value: 0.62 iNO 25 2 (8) 

E‐53
Appendix E. Evidence Tables 

Evidence Table 8. Brain injury outcomes for KQ2 (continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm Description N (number 

of participants measured) 

Participants with outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative (95% CI) 

19993 postconception 

al age 

Mercier, 2010 6 

24-28 weeks Control 397 1 (0.2) 

iNO 395 7 (1.7) 

Su, 20084 Not specified Control 33 4 (12.1) 

iNO 32 3 (9.4) 

CI: Confidence Interval, iNO: Inhaled nitric oxide, IVH: Intraventricular hemorrhage, NS: Not significant, PVL: Periventricular leukomalaci

Reference List

1. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi A, Rubaltelli FF. Inhaled 

nitric oxide in very preterm infants with severe respiratory distress syndrome. Acta Paediatr 2006; 95(9):1116-23. 

2. Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide 

therapy in premature infants. J. Pediatr. 2005; 146(3):318-23. 

3. Kinsella JP, Walsh WF, Bose CL et al. Inhaled nitric oxide in premature 

neonates with severe hypoxaemic respiratory failure: A randomised controlled trial. Lancet 1999; 354(9184):1061-5. 

4. Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants 

with severe respiratory failure. J Perinatol 2008; 28(2):112-6. 

5. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N Engl J Med 2006; 355(4):354-64. 

6. Mercier JC, Hummler H, Durrmeyer X et al. Inhaled nitric oxide for 

prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 2010. 

7. Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in 

premature infants with mild to moderate respiratory distress syndrome. J 

Med Assoc Thai 2002; 85 Suppl 2:S469-78. 

8. Ballard RA, Truog WE, Cnaan A et al. Inhaled 

infants undergoing mechanical ventilation. New 355(4):343-53. 

9. Franco-Belgium Collaborative NO Trial Group

delayed inhaled nitric oxide in moderately hyporespiratory failure: a randomised controlled triaCollaborative NO Trial Group. Lancet 1999; 35

10. Schreiber MD, Gin-Mestan K, Marks JD, Huo D

Inhaled Nitric Oxide in Premature Infants with Syndrome. New Engl. J. Med. 2003; 349(22):20

11. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

12. Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature infants with severe respiratory failure353(1):13-22. 

E‐54
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me

Author, Year Outcomes 

Time of outcome measure 

Arm Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) Adjusted Relative 

Effect (95% CI) 

Ballard, 20061 

Cardiac Outcomes, PDA Requiring Medical or Surgical Treatment 

after study entry 

Control 288 55 (19.1) P-value: 0.85 

RR: 0.96 (0.68-1.35) 

iNO 294 54 (18.4) 

Field, 20052 during 

hospitalizatio n 

Control 53 13 (25) iNO 55 9 (16) 

Schreiber, 20033 

Before discharge 

Control 102 26 (25.5) P-value: 0.27 

RR: 0.75 (0.45-

1.25) 

iNO 105 20 (19) 

Kinsella, 20064 

Cardiac Outcomes, PDA Requiring Medical Treatment 

Before discharge 

Control 395 212 (53.7) P-value: 0.92 iNO 398 215 (54) 

Srisuparp, 20025 

Before discharge 

Control 18 1 (5.6) P-value: 1 iNO 16 0 (0) 

Su, 20086 Before 

discharge 

Control 33 8 (24.2) 

iNO 32 9 (28.1) 

Subhedar, 19977 

Before discharge 

Control dexamethaso ne and standard of care 

22 1 (5) 

E‐55
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

 Groups 1&3; 

iNO + iNO and dexamethaso ne 

20 3 (15) 

Dexamethaso ne alone AND dex + iNO 

21 1 (5) 

iNO AND standard of care 

21 2 (10) 

Kinsella, 20064 

Cardiac Outcomes, PDA requiring surgical treatment 

Before discharge 

Control 395 86 (21.8) P-value: 0.96 iNO 398 86 (21.6) 

Mercier, 2010 8 

24-28 weeks Control 397 45 (11.3) 

iNO 395 59 (14.9) 

Srisuparp, 20025 

Before discharge 

Control 18 0 (0) P-value: 0.47 iNO 16 1 (6.3) 

Subhedar, 19977 

Before discharge 

Control dexamethaso ne and standard of care 

22 2 (10) 

Groups 1&3; iNO + iNO and dexamethaso ne 

20 1 (5) 

Dexamethaso ne alone AND 

21 2 (10) 

E‐56
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

dex + iNO iNO AND standard of care 

21 2 (10) 

Dani, 20069 Cardiac 

Outcomes, Incidence of PDA 

Before discharge 

Control 20 18 (90) P-value: 0.421 iNO 20 16 (80) Nonresponde rs 

6 5 (60) P-value: 0.657 

Responders 14 11 (80) 

Kinsella, 199910 

Cardiac Outcomes, Symptomatic PDA 

Before discharge 

Control Unclear Unclear (19) P-value: NS iNO Unclear (21) 

Subhedar, 19977 

Before discharge 

Control dexamethaso ne and standard of care 

22 3 (15) 

Groups 1&3; iNO + iNO and dexamethaso ne 

20 4 (20) 

Dexamethaso ne alone AND dex + iNO 

21 3 (14) 

iNO AND standard of care 

21 4 (19) 

Hascoet, 200511 

Cardiac Outcomes, Undefined PDA 

28 days Control with 

Hypoxemic Respiratory Failure 

84 31 (37) P-value: NS 

iNO with Hypoxemic Respiratory 

61 20.74 (34) 

E‐57
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

Failure 

Dani, 2006 9 Sepsis 

Defined by Positive Culture 

before discharge 

Control 20 10 (50) iNO 20 8 (40) 0.751 Responders 6 2 (33) Nonresponde rs 

14 6 (43) 0.545 

Field, 2005 2 during 

hospitalizatio n 

Control 53 21 (40) iNO 55 23 (42) 

Srisuparp, 

2002 5 Unspecified Control 18 7 (38.9) 1 iNO 16 7 (43.8) 1 

Field, 2005 2 Sepsis 

Defined by Clinician 

during hospitalizatio n 

Control 53 iNO 55 12 (22) 

Su, 2008 

{#200) 

Undefined Sepsis 

Unspecified Control 33 2 (6.1) 

iNO 32 3 (9.4) 

Kinsella, 

2006 4 Unspecified Control 369 118 (32) iNO 381 139 (0.365) 0

Ballard, 

2006 1 after study entry Control 288 118 (41) 0.91 0.98(0.80-1.20) 

iNO 294 121 (41.2) 0.91 

0.98(0.80-1.20) 

Schreiber, 

2003 3 

After 24 hours of age 

Control 102 50 (49) iNO 105 54 (51.5) 0.73 

1.05 (0.80-1.38) 

Ballard, Cardiac after study Control 288 19 (6.6) P-value: 0.63 

E‐58
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 20061

Outcomes

 Outcomes, 

NEC requiring surgical treatment 

 Time of 

outcome measure entry 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

RR: 1.17(0.64-

2.13) 

Adjusted Relativ

Effect (95% CI) 

iNO 294 23 (7.8) 

Ballard, 20061 

Cardiac Outcomes, NEC requiring medical treatment 

after study entry 

Control 288 8 (2.8) P-value: 0.84 

RR:1.20(0.46-3.13) 

iNO 294 10 (3.4) 

Dani, 20069 Cardiac 

Outcomes, NEC diagnosed by clinical criteria 

Before discharge 

Control 20 0 (0) P-value: 0.5 

iNO 20 1 (5) 

Before discharge 

Nonresponde rs 

6 0 (0) P-value: 0.7 

Responders 14 1 (7) 

Hascoet, 200511 

Cardiac Outcomes, NEC undefined 

28 days of life Control with 

Hypoxemic Respiratory Failure 

84 (6) NS 

iNO with Hypoxemic Respiratory Failure 

61 (8) 

Kinsella, 20064 

Before discharge 

Control 369 46 (12.5) 

0.54 

iNO 379 53 (14) 

Mercier, 2010 8 

Before discharge 

Control 397 7 (1.8) iNO 395 11 (2.8) 

Schreiber, before Control 102 6 (5.9) P-value: 0.11 

E‐59
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 20033 

Outcomes Time of 

outcome measure discharge 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

RR: 2.10 (0.83-

5.32) 

Adjusted Relativ

Effect (95% CI) 

iNO 105 13 (12.4) 

Su, 20086 Before 

discharge 

Control 33 2 (6.1) iNO 32 2 (6.3) 

Subhedar, 19977 

before discharge 

Control dexamethaso ne and standard of care 

22 2 (10) 

Groups 1&3; iNO + iNO and dexamethaso ne 

20 1 (5) 

Dexamethaso 

ne alone AND 

dex + iNO 

21 2 (10) 

iNO AND standard of care 

21 1 (5) 

Ballard, 2006 1 

ROP requiring treatment by cryo or laser 

After study entry 

Control 288 68 (23.6) p-value: 0.95 

RR = 0.97 (0.72-1.31) 

iNO 294 72 (24.5) 

Field, 20052 Before 

hospital discharge 

Control 49 4 (8) iNO 50 8 (16) 

Kinsella, 199910 

Before hospital discharge 

Control 15 3 (20) P-value: 0.1 iNO 25 1 (4) 

Kinsella, 20064 

Before Discharge 

Control 395 60 (15.2) P-value: 0.59 iNO 398 66 (16.6) 

Schreiber, Before Control 102 10 (9.8) P-value: 0.27 

E‐60
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 20033

Outcomes Time of 

outcome measure 

 hospital 

discharge 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

iNO 105 6 (5.7) 

Subhedar, 19977 

Before Hospital Discharge 

Control dexamethaso ne and standard of care 

22 0 (0) 

Groups 1&3; iNO + iNO and dexamethaso ne 

20 2 (10) 

Dexamethaso ne alone AND dex + iNO 

21 2 (10) 

iNO AND standard of care 

21 0 (0) 

Van Meurs, 200712 

Before Discharge 

Control 5 2 (40) P-value: 0.44 

iNO 5 0 (0) 

Van Meurs, 200513 

before hospital discharge 

Control 112 36 (32) P-value: 0.42 

iNO 98 29 (30) 

Field, 20052 Pulmonary 

Hemorrhage 

Hospital discharge 

Control 53 5 (9) 

iNO 55 4 (7) 

Kinsella, 20064 

Before discharge 

Control 395 26 (6.6) 0.75 

iNO 398 24 (6) 

Mercier, 2010 8 Discharge Control 397 14 (3.5) iNO 395 12 (3) 

Schreiber, Before Control 102 4 (3.8) P-value: 0.37 

E‐61
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 20033 

Outcomes Time of 

outcome measure discharge 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

RR:0.56 (0.17-

1.84) 

Adjusted Relativ

Effect (95% CI) 

iNO 105 7 (6.9) 

Su, 20086 Before 

discharge 

Control 33 2 (6.1) 

iNO 32 3 (9.4) 

Field, 20052 Air Leak Hospital 

discharge 

Control 53 20 (38) iNO 55 20 (36) 

Kinsella, 1999 10 

Kinsella, 20064 

Before discharge 

Control 395 24 (6.1) P-value: 0.94 

iNO, Total sample) 

398 25 (6.3) 

Mercier, 2010 8 

24-28 weeks Control 397 13(3) 

iNO 395 12 (2) 

Schreiber, 20033 

Before discharge 

Control 102 16 (15.7) P-value: 

0.27 RR: 0.67 (0.33-1.37) 

iNO 105 11 (10.5) 

Before discharge 

Control 102 Pulmonary 

interstitial emphysema 35 (34.3) 

P-value: 0.23 RR: 0.78 (0.51-1.18) 

iNO 105 Pulmonary 

interstitial emphysema 28 (26.7) 

Srisuparp, 2002 5 

72 hours Control 18 1 (5.6) p-value: 0.59 

iNO 16 2 (12.5) 

Su, 20086 Before 

discharge 

Control 33 2 (6.1) 

iNO 32 2 (6.3) 

E‐62
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

Subhedar, 19977 

Before discharge 

Control dexamethaso ne and standard of care 

22 1 (5) 

Groups 1&3; iNO + iNO and dexamethaso ne 

20 3 (15) 

Dexamethaso ne alone AND dex + iNO 

21 3 (14) 

iNO AND standard of care 

21 1 (5) 

Van Meurs, 200513 

Before discharge 

Control 117 37 (32) P-value: 0.55 

RR: 1.12 (0.78-1.

iNO 101 35 (35) 

Van Meurs, 200712 discharge Control 11 2 (18) P-value:0.48 iNO 9 0 (0) 

Schreiber, 20033 

Cardiac Outcomes, Methemoglobi nemia >4% 

Before discharge 

Control 102 0 (0) iNO 105 3 (2.9) 

Van Meurs, 200712 

Before discharge 

Control 14 0 (0) iNO 14 0 (0) 

Van Meurs, 200513 

Before discharge 

Control 210 2 (1) 

iNO 210 2 (1) 

E‐63
Appendix E. Evidence Tables 

Evidence Table 9. Other short term outcomes addressing KQ2 including PDA, sepsis, NEC, ROP, Pulmonary outcomes, and me(continued) Author, Year 

Outcomes Time of 

outcome measure 

Arm 

Description 

N (number of participants measured) 

Participants with outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relativ

Effect (95% CI) 

Schreiber, Cardiac Before Control 102 0 (0) 20033 Outcomes, 

Methemoglobi 

discharge iNO 105 0 (0) 

Van Meurs, 200513 

nemia >8% Before 

discharge 

Control 210 0 (0) P-value: 0.99 

CI: Confidence Interval; HRF: Hypoxemic respiratory failure; iNO: Inhaled nitric oxide; NEC: Necrotizing enterocolitis; NS: Not significant,: Relativ

Arteriosis; ROP: Retinopathy of Prematurity; RR: Relative risk; 

Reference List

1. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm 

infants undergoing mechanical ventilation. New Engl. J. Med. 2006; 355(4):343-53. 

2. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

3. 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 Engl. J. Med. 2003; 349(22):2099-107. 

4. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N Engl J Med 2006; 355(4):354-64. 

5. Srisuparp P, Heitschmidt M, Schreiber MD. Inhaled nitric oxide therapy in 

premature infants with mild to moderate respiratory distress syndrome. J Med Assoc Thai 2002; 85 Suppl 2:S469-78. 

6. Su PH, Chen JY. Inhaled nitric oxide in the management of preterm infants 

with severe respiratory failure. J Perinatol 2008; 28(2):112-6. 

7. Subhedar NV, Ryan SW, Shaw NJ. Open randomised controlled trial of 

inhaled nitric oxide and early dexamethasone in Arch Dis Child Fetal Neonatal Ed 1997; 77(3):F

8. Mercier JC, Hummler H, Durrmeyer X et al. Inh

prevention of bronchopulmonary dysplasia in prandomised controlled trial. Lancet 2010. 

9. Dani C, Bertini G, Pezzati M, Filippi L, Cecchi 

nitric oxide in very preterm infants with severe syndrome. Acta Paediatr 2006; 95(9):1116-23. 

10. Kinsella JP, Walsh WF, Bose CL et al. Inhaled 

neonates with severe hypoxaemic respiratory facontrolled trial. Lancet 1999; 354(9184):1061-5

11. Hascoet JM, Fresson J, Claris O et al. The safet

therapy in premature infants. J. Pediatr. 2005; 1

12. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

13. Van Meurs KP, Wright LL, Ehrenkranz RA et a

premature infants with severe respiratory failure353(1):13-22. 

E‐64
Appendix E. Evidence Tables 

Evidence Table 10. Death and survival beyond the NICU for KQ3. Study, year Outcomes 

Time of outcome measure Study Arm 

N (Participant Measured) 

Participants with Outcome—n (%) 

Relative Effect (95% CI) 

AdjusteRelative (95% CI

Bennett, 20011 

Death 30 months 

corrected age 

Control 22 7 (32) P-value: 0.13 

RR: 1.65 (0.87–3.3) 

iNO 20 10 (50) 

Hintz, 2007 2 18-22 months Control 98 210 (47) 

iNO 109 210 (52) 

Huddy, 20083 4-5 years, median 4.52 

(IQR 0.9) 

Control 19 0 (0) 

4-5 years, median 4.63, IQR 0.84) 

iNO 25 1 (4) 

Walsh, 20104 2 years Control 288 23 (8) RR: 1.02 iNO 294 24 (8.2) (0.59-1.77) 

Watson, 20095 1 year corrected age Control 384 98 (25.5) P-value: 0.12 iNO 385 80 (20.8) 

Mestan KK, 20056 

Survival 25.2+/-8.4 

months corrected age 

Control 102 79 (0.775) 

24.9 +/-7.9 months corrected age 

iNO 105 89 (84.8) 

CP: Cerebral palsy, iNO: Inhaled nitric oxide, IQR: Inter-quartile range, MDI: Mental developmental index, NDI: Neurodevelopmental impairment, N

Oxygenation index, PDI: Physical developmental index 

E‐65
Appendix E. Evidence Tables 

Reference List

1. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome 

in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr 2001; 90(5):573-6. 

2. Hintz SR, Van Meurs KP, Perritt R et al. Neurodevelopmental outcomes of 

premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 2007; 151(1):16-22, 22.e1-3. 

3. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

4. Walsh MC, Hibbs AM, Martin CR et al. Two-year 

outcomes of ventilated preterm infants treated with Pediatr 2010; 156(4):556-61.e1. 

5. Watson RS, Clermont G, Kinsella JP et al. Clinica

iNO in premature newborns with respiratory failur124(5):1333-43. 

6. Mestan KK, Marks JD, Hecox K, Huo D, Schreibe

outcomes of premature infants treated with inhaled 2005; 353(1):23-32. 

E‐66
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 11. Cerebral palsy outcomes in KQ3. Refid Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Bennett, 20011 

Moderate / Severe CP 

18 to 22 months 

Control 14 2 (14.3) iNO 7 0 (0) 

Hintz SR, 20072 

Moderate / Severe CP 

3 years Control 102 11 (11) P-value; 0.11 

RR: 1.85 (0.93-3.71) 

P-value: Model #1: 0.0453; Model #2: 0.048 RR: Model #1: 2.01 (1.01-3.98); Model #2: 2.41 (1.01-5.75) 

iNO 90 18 (20) 

Huddy, 20083 Mild CP 4-5 years 

iNO 16 4 (25) Control 22 6 (27.3) 

Moderate / Severe CP 

4-5 years Control 16 2 (12.5) 

iNO 22 3 (13.6) 

Mestan KK, 20054 Any CP 25.2+/-8.4 months 

corrected age 24.9+/-7.9 months corrected age 

Control 68 7 (10) P-value: 0.78 

iNO 70 6 (9) 

E‐67
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 11. Cerebral palsy outcomes in KQ3 (continued) Author, Year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Tanaka, 2007 5 

Any CP 3 years Control 15 7 (46.7) 

iNO 16 2 (12.5) 

Van Meurs, 2007 6 

Moderate/Severe CP 

18-22 months 

Control 0 8 (0) 

iNO 0 9 (0) 

Walsh, 20107 

Moderate / Severe CP 

2 years Control 234 12 (5.1) RR: 1.23 

(0.59-2.55) 

24.9+/-7.9 months corrected age 

iNO 243 15 (6.2) 

CI: Confidence Interval, CP: Cerebral Palsy, iNO: Inhaled Nitric Oxide, OI: Oxygenation Index, RR: Risk Ratio 

Reference List

1. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome 

in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr 2001; 90(5):573-6. 

2. Hintz SR, Van Meurs KP, Perritt R et al. Neurodevelopmental outcomes of 

premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 2007; 151(1):16-22, 22.e1-3. 

3. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

4. Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental 

outcomes of premature infants treated with inhaled 

2005; 353(1):23-32. 

5. Tanaka Y, Hayashi T, Kitajima H, Sumi K, Fujimu

therapy decreases the risk of cerebral palsy in pretepulmonary hypertension of the newborn. Pediatrics 

6. Van Meurs KP, Hintz SR, Ehrenkranz RA et al. In

>1500 g and <34 weeks gestation with severe resp2007; 27(6):347-52. 

7. Walsh MC, Hibbs AM, Martin CR et al. Two-year 

outcomes of ventilated preterm infants treated with Pediatr 2010; 156(4):556-61.e1. 

E‐68
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Hintz, 20071 NDI: any of the 

following: modsevere CP, blind, deaf, MDI<70 or PDI<70 

18-22 months 

Control 102 48 (47) P-value:0.74 

RR: 1.07 (0.80 - 1.44) 

iNO 89 45 (51) 

Isolated delay = MDI<70 or PDI<70 in absence of modsevere CP, deafness or blindness 

Control 102 35 (34) P-value:0.37 

RR:0.79 (0.51-1.23) 

P-value: Model #1: 0.78: Model #2 0.37 RR: Model #1: 1.04 (0.79-1.36); Model #2: 1.19 (0.81-1.73) 

iNO 88 24 (27) 

Huddy, 20082 Any cognitive disability 

(GCAS<85) 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 9 (56.2) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 11 (50) 

E‐69
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

 Moderate or 

severe cognitive disability (GCAS<70) 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 6 (37.5) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 6 (27.3) 

Severe cognitive disability (GCAS <50) 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 3 (18.7) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 3 (13.6) 

GCAS>84 4-5 yrs, 

median 4.52 (IQR 0.9) 

Control 16 7 (43.7) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 11 (50) 

Overall outcome: severe disability 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 3 (18.7) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 3 (13.6) 

Overall outcome: Moderate disability 

4-5 yrs, median 4.52 

Control 16 4 (25) 

E‐70
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

 (IQR 0.9) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 5 (22.7) 

Overall outcome: Normal 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 3 (18.7) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 5 (22.7) 

Overall outcome: mild disability 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 4 (25) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 6 (27.3) 

Mestan, 20053 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 24.9 +/-7.9 months corrected age 

Control 67 31 (46) P-value:0.01 

RR: 0.53 (0.33-0.87) 

P-value: Model #1: 0.50: Model #2: 0.79 RR: Model #1: 0.85 (0.54-1.35); Model #2: 0.91 (0.46-1.81) 

iNO 70 17 (24) 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 

24.9 +/- iNO 70 

E‐71
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

7.9 months corrected age 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.002 

RR:0.57(0.35-0.93 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.006 

RR:0.52 (0.32-0.82) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.007 

RR:0.48 (0.28-0.82) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome 

25.2+/-8.4 months 

Control 67 P-value:0.006 

RR:0.49 (0.29-0.82) 

E‐72
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

(any disability or any BSID II score <70) 

corrected age 24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.01 

RR:0.53 (0.33-0.87) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.03 

RR:0.6 (0.38-0.96) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.01 

RR:0.53 (0.33-0.87) 

24.9 +/-7.9 months corrected age 

iNO 70 

E‐73
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.01 

RR:0.55 (0.35-0.99) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopme ntal outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 67 P-value:0.01 

RR:0.55 (0.34-0.89) 

24.9 +/-7.9 months corrected age 

iNO 70 

Delay without disability 

25.2+/-8.4 months corrected age 

Control 67 23 (34) P-value:0.03 

RR:0.59 (0.36-0.95) 

24.9 +/-7.9 months corrected age 

iNO 69 11 (16) 

Disability (CP, bilateral blindness or bilateral hearing loss) 

25.2+/-8.4 months corrected age 

Control 68 8 (12) 

24.9 +/-7.9 

iNO 67 6 (9) 

E‐74
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

months corrected age 

MDI or PDI < 70 25.2+/-

8.4 months corrected age 

Control 67 28 (42) P-value: 0.03 

24.9 +/-7.9 months corrected age 

iNO 69 16 (23) 

MDI and PDI < 70 

25.2+/-8.4 months corrected age 

Control 67 8 (12) P-value: 0.58 

24.9 +/-7.9 months corrected age 

iNO 69 6 (9) 

Van Meurs, 20074 NDI = any one of the following: 

moderate to severe CP, blind, deaf, MDI <70, or PDI <70 

18 to 22 months 

Control 8 2 (25) P-value:0.58 

RR: 0.44 (0.05-4,02)

 

iNO 9 1 (11) 

Walsh, 20105 

MDI>85 2 years Control 214 83 (35) 

24.9 +/-7.9 months corrected age 

iNO 210 95 (45.2) 

PDI>85 2 years Control 212 73 (31) 

E‐75
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 12. Cognitive outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcom e Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (95% CI) 

 iNO 207 75 (36.2) 

NDI in subset with complete evaluations 

2 years Control 212 (51) RR:0.93 

iNO 207 (48) (0.76-1.14) 

Neurodevelopme ntal Impairment (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS>=2), bilateral blindness, or bilateral deafness requiring amplification). 

2 years Control 234 114 (49) RR: 0.92 

(0.75-1.12) 

iNO 243 109 (44.8) 

BSID: Bayley Scale of Infant Development, BW: Birth weight, CP: Cerebral Palsy, GCAS: General conceptual ability score, GMFCS: Gross Motor F

System, iNO: Inhaled Nitric Oxide, IQR: Inter-quartile range, IVH: Intravascular hemorrhage, MDI: Mental Development Index, NDI: NeurodevelopmOxygenation Index, PDI: Psychomotor Development Index, PVL: Periventricular leukomalacia, RR: Relative Risk 

Reference List

 1. Hintz SR, Van Meurs KP, Perritt R et al. Neurodevelopmental outcomes of support without nitric oxide for severe respiratory 

premature infants with severe respiratory failure enrolled in a randomized follow up at 4-5 years. Arch Dis Child Fetal Neonacontrolled trial of inhaled nitric oxide. J Pediatr 2007; 151(1):16-22, 22.e1-3. 3. Mestan KK, Marks JD, Hecox K, Huo D, Schreibe

2. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised outcomes of premature infants treated with inhaled 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory 2005; 353(1):23-32. 

E‐76
Evidence Table : Cerebral Palsy for KQ3 continued 

4. Van Meurs KP, Hintz SR, Ehrenkranz RA et al. Inhaled nitric oxide in infants 

>1500 g and <34 weeks gestation with severe respiratory failure. J Perinatol 2007; 27(6):347-52. 

5. Walsh MC, Hibbs AM, Martin CR et al. Two-year neurodevelopmental 

outcomes of ventilated preterm infants treated with Pediatr 2010; 156(4):556-61.e1.

E‐77
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 13. Sensory impairment for KQ3. Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (9CI) 

Bennett, 2001 1 

Sensorineural Impairment 

 Control 22 1 (5) 

iNO 20 0 (0) 

Field, 2005 2 Visual 

Impairment 

1 year corrected age 

Control 53 0 (0) iNO 55 1 (2) 

Hearing Impairment 

Control 53 0 (0) iNO 55 3 (5) 

Huddy, 20083 

Visual Impairment 

4-5 years Control 16 7 (43.7) 

iNO 22 13 (59.1) 

Hearing Impairment 

4-5 years Control 16 0 (0) 

iNO 22 2 (9.1) 

Mestan KK, 20054 Hearing Aid 25.2+/-8.4 months 

corrected age 24.9+/-7.9 months corrected age 

Control 68 1 (1) P-value: 0.49 

iNO 70 0 (0) 

Blindness 25.2+/-8.4 

months corrected age 24.9+/-7.9 

Control 68 2 (3) P-value: 0.24 

iNO 70 0 (0) 

Van Meurs, 20075 

Deafness 4-5 years Control 16 0 (0) 

iNO 22 1 (4.5) 

E‐78
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 13. Sensory impairment for KQ3 (continued) Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (9CI) 

 No 

recognizable speech 

4-5 years Control 16 0 (0) 

iNO 22 3 (13.6) 

Any disability of hearing or communication 

4-5 years Control 16 3 (18.7) 

iNO 22 3 (13.6) 

Deafness 18 to 22 

months 

Control 8 0 (0) 

iNO 9 0 (0) 

Walsh, 20106 

Deafness 2 years Control 234 3 (1) RR: 2.56 (0.68-

9.52) 

24.9+/-7.9 months corrected age 

iNO 243 8 (3.2) 

Blindness 2 years Control 234 9 (4) RR: 0.97 (0.40-

2.40) 

24.9+/-7.9 iNO 243 9 (3.7) 

Watson, 2009 7 Sensory impairment included in NDI but not individually. 

CI: Confidence Interval, iNO: Inhaled nitric oxide, NDI: Neurodevelopmental Impairment, RR: Relative Risk 

E‐79
Evidence Table : Cerebral Palsy for KQ3 continued 

Reference List

1. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome 

in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr 2001; 90(5):573-6. 

2. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

3. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

4. Mestan KK, Marks JD, Hecox K, Huo D, Schreibe

outcomes of premature infants treated with inhaled 2005; 353(1):23-32. 

5. Van Meurs KP, Hintz SR, Ehrenkranz RA et al. In

>1500 g and <34 weeks gestation with severe resp2007; 27(6):347-52. 

6. Walsh MC, Hibbs AM, Martin CR et al. Two-year 

outcomes of ventilated preterm infants treated with Pediatr 2010; 156(4):556-61.e1. 

7. Watson RS, Clermont G, Kinsella JP et al. Clinica

iNO in premature newborns with respiratory failur124(5):1333-43. 

E‐80
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 13. Sensory impairment for KQ3. Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Effect (9CI) 

Bennett, 2001 1 

Sensorineural Impairment 

 Control 22 1 (5) 

iNO 20 0 (0) 

Field, 2005 2 Visual 

Impairment 

1 year corrected age 

Control 53 0 (0) iNO 55 1 (2) 

Hearing Impairment 

Control 53 0 (0) iNO 55 3 (5) 

Huddy, 20083 

Visual Impairment 

4-5 years Control 16 7 (43.7) 

iNO 22 13 (59.1) 

Hearing Impairment 

4-5 years Control 16 0 (0) 

iNO 22 2 (9.1) 

Mestan KK, 20054 Hearing Aid 25.2+/-8.4 months 

corrected age 24.9+/-7.9 months corrected age 

Control 68 1 (1) P-value: 0.49 

iNO 70 0 (0) 

Blindness 25.2+/-8.4 

months corrected age 24.9+/-7.9 

Control 68 2 (3) P-value: 0.24 

iNO 70 0 (0) 

Van Meurs, 20075 

Deafness 4-5 years Control 16 0 (0) 

iNO 22 1 (4.5) 

E‐81
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 13. Sensory impairment for KQ3 (continued) Author, year Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted Relative (95% CI) 

No 

recognizable speech 

4-5 years Control 16 0 (0) 

iNO 22 3 (13.6) 

Any disability of hearing or communication 

4-5 years Control 16 3 (18.7) 

iNO 22 3 (13.6) 

Deafness 18 to 22 

months 

Control 8 0 (0) 

iNO 9 0 (0) 

Walsh, 20106 

Deafness 2 years Control 234 3 (1) RR: 2.56 (0.68-

9.52) 

24.9+/-7.9 months corrected age 

iNO 243 8 (3.2) 

Blindness 2 years Control 234 9 (4) RR: 0.97 (0.40-

2.40) 

24.9+/-7.9 iNO 243 9 (3.7) 

Watson, 2009 7 Sensory impairment included in NDI but not individually. 

CI: Confidence Interval, iNO: Inhaled nitric oxide, NDI: Neurodevelopmental Impairment, RR: Relative Risk 

E‐82
Evidence Table : Cerebral Palsy for KQ3 continued 

Reference List

1. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental outcome 

in high-risk preterm infants treated with inhaled nitric oxide. Acta Paediatr 2001; 90(5):573-6. 

2. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

3. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre randomised 

controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

4. Mestan KK, Marks JD, Hecox K, Huo D, Schreibe

outcomes of premature infants treated with inhaled 2005; 353(1):23-32. 

5. Van Meurs KP, Hintz SR, Ehrenkranz RA et al. In

>1500 g and <34 weeks gestation with severe resp2007; 27(6):347-52. 

6. Walsh MC, Hibbs AM, Martin CR et al. Two-year 

outcomes of ventilated preterm infants treated with Pediatr 2010; 156(4):556-61.e1. 

7. Watson RS, Clermont G, Kinsella JP et al. Clinica

iNO in premature newborns with respiratory failur124(5):1333-43. 

E‐83
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3. Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

Bennett, 20011 

Severe neurodisability - one or more of: moderate or 

30 months corrected age 

Control 14 5 (36) P-value: 0.12 

severe developmental delay; CP; sensorineural impairment (hearing loss requiring hearing aids and blindness) 

iNO 7 0 (0) 

Hintz SR, 20072 NDI: any of the following: modsevere CP, blind, 

deaf, MDI<70 or PDI<70 

18-22 months 

Control 102 48 (47) P-value:0.74 

RR: 1.07 (0.80 - 1.44) 

iNO 89 45 (51) 

E‐84
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

 Isolated delay = 

MDI<70 or PDI<70 in absence of modsevere CP, deafness or blindness

 Control 102 35 (34) P-value:0.37 

RR:0.79 (0.51-1.23) 

P-value: Model #1: 0Model #2 0RR: Model 1.04 (0.79-Model #2: 1(0.81-1.73) 

iNO 88 24 (27) 

Unimpaired = MDI & PDI>85, no mod-severe CP, and not blind or deaf

 Control 102 26 (25) P-value:0.86 

RR:0.92 (0.56 - 1.51) 

P-value: Mo#1: 0.10; M#2: 0.43 RR: Model 0.72 (0.48-Model #2: 0(0.44-1.42) 

Huddy, 20083 

Overall outcome: severe disability 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 3 (18.7) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 3 (13.6) 

Overall outcome: Moderate disability 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 4 (25) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 5 (22.7) 

Overall outcome: Normal 

4-5 yrs, median 

Control 16 3 (18.7) 

E‐85
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

 4.52 (IQR 

0.9) 4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 5 (22.7) 

Overall outcome: mild disability 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 4 (25) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 6 (27.3) 

Mestan, 20054 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 24.9 +/-7.9 months corrected age 

Control 68 31 (46) P-value:0.01 

RR: 0.53 (0.33-0.87) 

P-value: Mo#1: 0.50: M#2: 0.79 RR: Model 0.85 (0.54-Model #2: 0(0.46-1.81) ) 

iNO 70 17 (24) 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment 

25.2+/-8.4 months 

Control 68 P-value:0.0

RR:0.57(0.3

E‐86
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

al outcome (any disability or any BSID II score <70) 

corrected age 24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.52 (00.82) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.48 (00.82) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.49 (00.82) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.53 (00.87) 

24.9 +/-7.9 months corrected 

iNO 70 

E‐87
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcome Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

age 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.6 (0.3

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.53 (00.87) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.55 (00.99) 

24.9 +/-7.9 months corrected age 

iNO 70 

Abnormal neurodevelopment al outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 

Control 68 P-value:0.0

RR:0.55 (00.89) 

24.9 +/-7.9 months corrected age 

iNO 70 

Van Meurs, 20075 NDI = any one of the following: 

moderate to severe CP, blind, 

18 to 22 months 

Control 8 2 (25) P-value:0.58 

RR: 0.44 (0.05-4.02)

 

iNO 9 1 (11) 

E‐88
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcomedeaf, MDI <70, or PDI <70 

 Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

Walsh, 20106 

NDI in subset with complete evaluations 

2 years Control 212 (51) RR:0.93 (0.76-

24.9 +/-7.9 1.14)months corrected age 

iNO 207 (48) 

Neurodevelopment al Impairment (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS>=2), bilateral blindness, or bilateral deafness requiring amplification). 

2 years Control 234 114 (49) RR: 0.92 (0.75-

1.12) 

iNO 243 109 (44.8) 

Watson, 20097 NDI (CP, severe hearing loss, MDI 

or PDI< 70,or blindness) 

1 year corrected age 

Control 218 73 (33.5) P-value: 0.66 

iNO 237 84 (35.4) 

Van Meurs, 20075 

Death or NDI, Death and/or NDI 

18 to 22 months 

Control 12 6 (50) P-value: 1 

RR: 0.86 (0.37-1.96) 

P-value: 0.8 RR: 0.90 (02.02) 

iNO 14 6 (43) 

Van Meurs, 20075 

Death or NDI, Death and/or moderate to severe CP 

18 to 22 months 

Control 12 4 (33) P-value: 1 

RR: 1.07 (0.37-3.11)

 P-value: 0.RR: 1.08 (03.03) 

iNO 14 5 (36) 

Bennett, 20011 

Death or NDI, Death or severe neurodisability 

30 months corrected age 

Control 22 13 (59) P-value: 0.79 

RR: 1.1 (0.57-2.3) 

iNO 19 12 (63) 

Watson, 20097 

Death or NDI, Death or NDI (CP, severe hearing 

1 year corrected age 

Control 384 171 (44.5) P-value: 0.55 

iNO 387 164 (42.4) 

E‐89
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 14. NDI and death or NDI outcomes for KQ3 (continued) Author, year 

Outcome

loss, MDI or PDI< 70,or blindness) 

 Time of 

Outcome Measure 

Study Arm N 

(Participants Measured) 

Number of Participants with Outcome—n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Ef(95% CI) 

Watson, 20097 

Death or NDI, Death, on oxygen, or NDI (CP, severe hearing loss, MDI or PDI< 70,or blindness) 

1 year corrected age 

Control 384 175 (45.6) P-value: 0.65 

iNO 387 170 (43.9) 

Hintz SR, 20072 

Death or NDI, Death or NDI:any of the following: mod-severe CP, blind, deaf, MDI<70 or PDI<70 

18-22 months 

Control 200 146 (73) P-value: 0.32 

RR:1.07 (0.95-1.19) 

P-value: 0.3 RR: Model 1.06 (0.95-

iNO 198 154 (78) 

Hintz SR, 20072 

Death or NDI, Death or moderate to severe CP 

18-22 months 

Control 200 109 (54) P-value: 0.07 

RR:1.17 (0.99-1.38) 

P-value: 0.0RR: Model 1.15 (0.99-

iNO 199 127 (64) 

CI: Confidence Interval; CP: Cerebral Palsy; GMFCS: Gross motor function classification system; iNO: Inhaled nitric oxide; IQR: Inter-quartile range

developmental index; NDI: Neurodevelopmental impairment; NS: Not significant,OI: Oxygenation index; OI: Oxygenation Index; PDI: Physical deve

Reference List

1. Bennett AJ, Shaw NJ, Gregg JE, Subhedar NV. Neurodevelopmental premature infants with severe respiratory failure 

outcome in high-risk preterm infants treated with inhaled nitric oxide. Acta controlled trial of inhaled nitric oxide. J Pediatr 

Paediatr 2001; 90(5):573-6. 3. Huddy CL, Bennett CC, Hardy P et al. The INN

2. Hintz SR, Van Meurs KP, Perritt R et al. Neurodevelopmental outcomes of randomised controlled trial: neonatal ventilation 

E‐90
Evidence Table : Cerebral Palsy for KQ3 continued 

versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

6. 

Perinatol 2007; 27(6):347-52. 

Walsh MC, Hibbs AM, Martin CR et al. Two-y

outcomes of ventilated preterm infants treated w

4. 5. 

Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. 

Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353(1):23-32. 

Van Meurs KP, Hintz SR, Ehrenkranz RA et al. Inhaled nitric oxide in 

7. 

Pediatr 2010; 156(4):556-61.e1. 

Watson RS, Clermont G, Kinsella JP et al. Clin

iNO in premature newborns with respiratory fai2009; 124(5):1333-43. 

infants >1500 g and <34 weeks gestation with severe respiratory failure. J 

E‐91
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes. Refid Outcome 

Time of Outcome Measure Study Arm 

N (Participants Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement 

ReEfCI

Field, 20051 Seizures 1 year 

corrected age 

Control 18 0 (0) 

iNO 25 3 (12) 

Huddy, 20082 

Seizures 4-5 years Control 16 2 (9.1) 

iNO 22 3 (13.6) 

Field, 20051 Oral feeding 1 year 

corrected 

Control 53 20 (38) 

iNO 55 28 (51) 

Huddy, 20082 

Steroids, Inhaled 

4-5 years Control 16 3 (18.8) 

iNO 22 4 (18.2) 

Field, 20051 Steroids, 

Unspecified 

1 year corrected age 

Control 18 5 (28) 

iNO 25 5 (20) 

Hibbs, 2007

3 

12 +/- 3 months 

Control 225 (17.7) OR

0.7

E‐92
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes (Refid Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement Re

EfCI

iNO 230 (11) 

12 +/- 3 months 

Control 225 (32.4) OR

(0

iNO 230 (19.8) 

Cheung, 19984 

Bronchodilator s 

iNO 10 1 (10) 

Field, 20051 1 year 

corrected age 

Control 18 7 (39) 

1 year corrected age 

iNO 25 10 (40) 

Hibbs, 2007

3 

12 +/- 3 months 

Control 225 (54.1) OR

0.7

iNO 230 (40.1) 

Huddy, 20082 

4-5 years Control 16 4 (25) 

iNO 22 7 (31.8) 

Hibbs AM, 20073 

Diuretics 12 +/- 3 

months 

Control 225 (28.4) O

(0

iNO 230 (18.6) 

Huddy, 20082 Long-Term Pulmonary 

Outcomes, Asthma 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 4 (25) 

4-5 yrs, median 4.63, 

iNO 22 9 (40.9) 

E‐93
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes (Refid Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement Re

EfCI

IQR 0.84) 

Huddy, 20082 Long-Term Pulmonary 

Outcomes, Respiratory Disability 

4-5 yrs Control 16 1 (6.2) 

iNO 22 2 (9.1) 

Field, 20051 Long-Term 

Pulmonary Outcomes, Feeding tube 

1 year corrected age 

Control 18 1 (6) 

iNO 25 1 (4) 

Cheung, 19984 Long-Term Pulmonary 

Outcomes, Wheezing 

> 1 year corrected age 

iNO 10 4 (40) 

Field, 20051 1 year 

corrected age 

Control 18 5 (28) 

iNO 25 13 (52) 

Hibbs, 20073 12 +/- 3 

months 

Control 225 (56.4) OR

iNO 230 (49.6) 1.0

Huddy, 20082 4-5 yrs, median 4.52 

(IQR 0.9) 

Control 16 6 (50) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 9 (40.9) 

Cheung, 19984 Long-Term Pulmonary 

Outcomes, Recurrent Aspiration Pneumonia 

> 1 year corrected age 

iNO 10 1 (10) 

Clark, 2002 5 Long-Term 

Pulmonary Outcomes, Supplemental Oxygen 

6 months PCA 

iNO 25 10 (40) 

Field, 2005 1 1 year 

corrected age 

Control 18 1 (6) iNO 25 3 (12) 

Hibbs, 2007 Any Home Control 225 (49.5) 

E‐94
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes (Refid 3

Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement Re

EfCI

 Oxygen Use iNO 230 (38.4) 

Persistent Oxygen use at time of followup 

Control 225 (9.4) 

iNO 230 (3) 

Huddy, 2008 2 4-5 years (Oxygen 

discontinued prior to follow-up) 

Control 16 4 (25) 

iNO 22 4 (18) 

Watson, 2009 6 1 year corrected age 

500-749g 

Control 192 3 (2) iNO 192 13 (7) 

1 year corrected age 750-999g 

Control 139 5 (4) iNO 141 4 (3) 

1 year corrected age 1000-1250g 

Control 64 3 (5) 

iNO 65 0 (0) 

Huddy, 20082 Height 4-5 years Control 16 -0.68 

iNO 22 -0.9 

Mestan KK, 20057 2 years Control 79 68 (86) -0.59 (IQR -

1.25 to 0.41) 

Median:83.9 cm IQR 81-88.3 cm 

0.5

iNO 138 70 (51) -0.23 

(IQR -0.83 to 0.36) 

Median:84.5 cm IQR 81.2-88.5 

Walsh, 20108 2 Years Control 234 Mean: 85.3 

cm SD:6 cm 

E‐95
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes (Refid Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement Re

EfCI

iNO 243 Mean: 85.2 

cm SD:5.2 cm 

Hintz SR, 20079 Weight 2 Years Control 102 Mean 10.6 kg SD:1.7 kg 0.7

iNO 91 Mean:10.6 kg 

SD:1.4 kg 

Huddy, 20082 

4-5 years Control 16 -1.02 

iNO 22 -0.86 

Mestan KK, 20057 2 years Control 79 68 (.86) -1.07 (IQR -

2.25 to -0.38) 

Median:10.8 kg IQR 9.5-12.2 kg

 0

iNO 138 70 () -0.49 

(IQR -1.51 to 0.61 

Median:1.17 kg IQR 1.05-1.35 k g 

Walsh, 20108 2 Years Control 234 Mean:11.5 kg 

SD:1.7 kg 

iNO 243 Mean:11.4 kg 

SD:1.7 

513 Field, 20051 

Head Circumferance 

1 year Control 18 15 (83) Mean:45.2 

cm SD:1.6 cm 

iNO 25 23 (92) 45.5 SD:1.8 

cm 

Hintz SR, 20079 

18-22 Months Control 102 Mean:46.7 

cm SD:1.9 cm 

0.6

E‐96
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 15. Other long term outcomes included in KQ3 including seizures, growth, oral feeding, pulmonary outcomes (Refid Outcome Time of 

Outcome Measure 

Study Arm N (Participants 

Measured) 

Number of Participants with Outcome—n (%) 

Zscore Measurement Re

EfCI

iNO 91 Mean:46.8 

cm SD:1.7 cm 

160 Huddy, 20082 

4-5 years Control 16 -1.53 

iNO 22 -1.48 

Walsh, 20108 2 Years Control 234 Mean:47.8 

cm SD:1.9 cm 

iNO 243 Mean:47.6 

cm SD:2.1 cm 

Cheung, 1998 4 Slow Weight, Height or Head 

Circumference Development 

1 year iNO 10 4 

CI: Confidence Interval; CP: Cerebral Palsy; iNO: Inhaled Nitric Oxide; IQR: Inter-quartile range; OI: Oxygenation Index; RR: Risk Ratio 

Reference List

1. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

2. Huddy CL, Bennett CC, Hardy P et al. The INNOVO multicentre 

randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years. Arch Dis Child Fetal Neonatal Ed 2008; 93(6):F430-5. 

3. Hibbs AM, Walsh MC, Martin RJ et al. One Year Respiratory Outcomes of 

the Preterm Infants Enrolled in the NO CLD Trial of Inhaled Nitric Oxide 

(iNO). N/A 2007. 

4. Cheung P-Y, Peliowski A, Robertson CMT. Th

weight neonates ((less-than or equal to)1500 g) oxide: Neurodevelopment in early childhood. J. 

5. Clark PL, Ekekezie II, Kaftan HA, Castor CA, T

efficacy of nitric oxide in chronic lung disease. Neonatal Ed 2002; 86(1):F41-5. 

6. Watson RS, Clermont G, Kinsella JP et al. Clin

iNO in premature newborns with respiratory fai2009; 124(5):1333-43. 

7. Mestan KK, Marks JD, Hecox K, Huo D, Schre

Neurodevelopmental outcomes of premature inf

E‐97
Evidence Table : Cerebral Palsy for KQ3 continued 

nitric oxide. N Engl J Med 2005; 353(1):23-32. 9. Hintz SR, Van Meurs KP, Perritt R et al. Neuro

8. Walsh MC, Hibbs AM, Martin CR et al. Two-year neurodevelopmental premature infants with severe respiratory failure 

outcomes of ventilated preterm infants treated with inhaled nitric oxide. J controlled trial of inhaled nitric oxide. J Pediatr 

Pediatr 2010; 156(4):556-61.e1. 

E‐98
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy. 

Author, Year Outcomes 

Time of outcome measure Study Arm 

N (number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Ef(95% CI) 

Chock, 2009 

1 

BPD at 36 weeks 36 weeks PMA Control 2 2 (100) P-value: 0.43 

iNO 5 2 (40) 

Field, 20052 36 weeks PMA Control 55 15 (27) 

iNO 53 26 (49) 

Kinsella, 20063 

36 weeks PMA Control 309 210 (68) P-value: 0.43 RR:0.96 (0

1.09) 

iNO 326 212 (65) 

36 weeks PMA Control 

Birth weight of 500–749 g 

189 66 (34.9) P-value: 0.2

RR: 0.82 (01.11) 

iNO Birth weight of 500–749 g 

191 55 (28.8) 

36 weeks PMA Control Birth 

weight of 750–999 g 

139 24 (17.3) P-value: 0.1

RR: 0.63 (01.15) 

iNO Birth weight of 750–999 g 

138 15 (10.9) 

36 weeks PMA Control Birth 

weight of 1000–1250 g 

64 8 (12.5) P-value: 0.9

RR: 0.98 (02.46) 

iNO Birth weight of 1000–1250 g 

65 8 (12.3) 

E‐99
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

Schreiber, 20034 

36 weeks PMA Control 102 42 (53.2) P-value: 0.07 

RR: 0.74 (0.1.03) 

iNO 105 35 (39.3) 

Van Meurs, 20055 

36 weeks PMA Control 127 86 (68) P-value: 0.26 RR: 0.90 (0.

1.08) 

iNO 109 65 (60) Control BW<=1000g 

88 64 (73) P-value: 0.84 RR: 1.02 (0.

1.23) 

Arm B BW<=1000 g 

67 49 (73) 

Control BW>1000 g 

37 21( 57) P-value: 0.08 RR: 0.68 (0.4

1.05) 

iNO BW>1000g 

42 16 (38) 

Control OI<=17 

76 50 (66) P-value: 0.12 RR: 0.80 (0.

1.06) 

iNO OI<=17 59 30 (51) Control OI>17 

49 36 (72) P-value: 0.85 RR: 0.98 (0.

1.24) 

iNO OI>17 50 35 (70) 

Ballard, 20066 

Survival without BPD 36 weeks PMA Control 288 105 (36.5) P-value: 0.04 

RR: 1.45 (1.03-2.04) iNO 294 129 (43.9) 

36 weeks PMA Control 500-

799 g) 

197 74 (37.6) P-value: 0.07 

RR: 1.20 

iNO 500-799 (0.94–1.54) g 

197 85 (43.1) 

36 weeks PMA Control 800- 91 32 (35.2) P-value: 0.14 

E‐100
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

1250 grams birth weight) 

RR: 1.30 (0.91-1.87) 

iNO 800-1250 grams birth weight 

97 44 (45.4) 

36 weeks PMA Control OI at 

study entry < 3.5 

149 68 (45.6) RR: 

1.28(1.02-1.61) 

iNO OI at study entry < 3.5 

162 92 (56.8) 

36 weeks PMA Control OI at 

study entry >= 3.5) 

139 37 (26.6) RR: 

1.11(0.74-1.66) 

iNO OI at study entry >= 3.5 

132 37 (28) 

Schreiber, 20034 

Survived NICU Control 79 37 (46.8) 

iNO 89 54 (60.7) 

Survived NICU Control 

BW<=750 g 

40 4 (10) 

iNO BW<=750 g 

32 7 (21.9) 

Survived NICU iNO BW 

751-1000 g 

28 14 (50) 

Control BW 751-1000 g 

29 11 (37.9) 

Survived NICU Control BW 

1001-1500 g 

21 12 (57.1) 

iNO BW 1001-1500 g 

30 18 (60) 

Survived NICU Control BW 12 10 (83.3) 

E‐101
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

>1500 g iNO BW >1500 g 

15 15 (100) 

Survived NICU Control OI 

<6.94 (median) 

49 16 (32.7) 

iNO OI <6.94 (median) 

50 32 (64) 

Survived NICU Control 

OI>=6.94 (median) 

48 20 (41.7) 

iNO 0I>=6.94 (median)) 

51 21 (41.2) 

Schreiber, 2003 4 

Survival with BPD Survived NICU Control 102 42 (53.2) p-value = 

0.07 RR = 0.74 (0.53-1.03) 

0.75 (0.54-1

iNO 105 35 (39.3) 

Banks, 19997 

Death 3-24 months 

from enrollment 

iNO 16 7 (44) iNO responders 

11 4 (36) 

iNO nonresponders 5 3 (60) 

Chock, 20091 

Death prior to discharge home or within 365 days 

Control 6 4 (67) P-value: 0.57 iNO 6 2 (33) 

Field, 2005 2 36 weeks Control 53 34 (64) 

iNO 55 30 (55) 

Hintz SR, 18-22 months Control Birth 152 79 (52) P-value: 0.04 RR: 1.22 (1.

E‐102
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

20078 weight 

</=1000g, F/U cohort 

1.46) 

iNO tx, Birth weight </= 1000gm 

152 98 (64) 

Control Birth weight >1000g, F/U Cohort 

48 19 (40) P-value: 0.08 RR: 0.58 (0.

1.07) 

iNO Tx, Birth weight >1000g 

48 11 (23) 

Control Placebo, Birth weight 401-750grams 

99 55 (56) P-value: 0.01 

iNO tx, Birth weight 401-750grams 

94 / 400 (for analysis cohort) 

69 (73) 

Control Placebo, Birth weight 751-1000grams 

53 24 (45) P-value: 0.63 

iNO tx, Birth weight 751-1000grams) 

58 / 400 (analysis cohort) 

29 (50) 

Control Placebo, Birth weight 1001 -1500 grams 

48 / 400 (analysis cohort) 

19 (40) P-value: 0.07 

iNO tx. Birth weight 1001-1500grams 

48 / 400 (analysis cohort) 

11 (23) 

E‐103
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

Kinsella, 20063 

36 wks PMA Control 392 98 (25) P-value: 0.0

RR: 0.79 (0.1.03)

iNO 394 78 (19.8) 

36 wks PMA Control BW 

500-749 g; mean 639, SD 71 

189 66 (34.9) P-value:0.2

 RR: 0.82 (01.11)

iNO BW 500-749 g; mean 642, SD 76 

191 55 (28.8) 

36 wks PMA Control BW 

750-999 g; mean 843, SD 71 

139 24 (17.3) P-value: 0.1

RR: 0.63 (01.15)

iNO BW 750-999 g; mean 851, SD 71 

138 15 (10.9) 

36 wks PMA Control BW 

1000-1250 g; mean 1113 g, SD 77g 

64 8 (12.5) P-value: 0.97 

RR: 0.98 (0.2.46) 

iNO BW 1000-1250 g; mean 1129 g, SD 68g 

65 8 (12.3) 

Kumar, 2007 

9 

Control iNO 23 

E‐104
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

Schreiber, 20034 

NICU Control 102 23 (22.5) P-value: 0.1

RR: 0.68 (0.1.20) 

iNO 105 16 (15.2) 

Van Meurs, 20055 

Death before discharge to home or within 365 days among hospitalized infants 

Control 208 93 (44) P-value: 0.1

RR: 1.16 (0.1.39)

iNO 210 109 (52) 

Death before discharge to home or within 365 days among hospitalized infants 

Control BW<=1000g 

158 76 (48) P-value: 0.0

RR: 1.28 (1.1.54) 

iNO BW<=1000 g 

158 98 (62) 

Death before discharge to home or within 365 days among hospitalized infants 

Control BW>1000 g) 

52 17 (33) P-value: 0.16 

RR: 0.65 (0.1.18) 

iNO BW>1000g 

52 11 (21) 

Death before Control 

OI<=17 

110 40 (36) P-value: 0.09 

E‐105
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

RR: 1.27 (0.

1.68) 

discharge to home or within 365 days among hospitalized infants 

iNO OI<=17 100 45 (45) 

Death before discharge to 

Control OI>17 

100 53 (53) P-value: 0.39 

RR: 1.11 (0.1.4) 

home or within 365 days among hospitalized infants 

iNO OI>17 110 64 (58) 

Yadav, 199910 

Prior to hospital discharge 

iNO 41 25 (61) iNO responders to iNO based on decrease in IO by 10 in first 60 minutes of treatment 

26 11 (42) 

iNO noesponders based on failure to decrease OI by 10 in 60 minutes of 

15 14 (93) 

E‐106
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

treatment 

Chock, 20091 

Death or BPD Death prior to 

discharge home or within 365 days 

Control 6 6 (100) 

P-value: 0.18 

iNO 6 3 (50) 

Field, 20052 36 weeks PMA Control 53 48 (91) 

iNO 55 49(89) 

36 weeks PMA Control 

acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) 

36 32 (89) RR: 0.98(0.8

1.11) 

iNO acute diagnosis at study entry(lung disease immediately 

35 30 (86) 

E‐107
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

after birth and randomizing at <= 3 days) 

36 weeks PMA Control 9 9 (100) 

chronic diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) iNO chronic 10 10 (100) 

diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) 

36 weeks PMA Control other 

diagnosis (developed lung disease after initial 

8 7 (88) RR: 0.98(0.8

1.12) 

recovery 

E‐108
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

from respiratory problems) iNO other diagnosis (developed lung disease after initial recovery from respiratory problems) 

10 9 (10) 

36 weeks PMA Control 

OI<=30 at study entry 

25 22 (88) 

iNO OI<=30 at study entry 

25 22 (88) 

36 weeks PMA Control 

OI>30 at study entry 

28 26 (93) RR: 0.98(0.

1.12) 

E‐109
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

iNO OI>30 at study entry 

30 27 (90) 

Term EDC Control 

acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) 

36 29 (81) 

iNO acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) 

35 22 (63) 

Term EDC Control 

chronic 

9 9 (100) 

E‐110
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days) iNO chronic 10 10 (100) 

diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days) 

Term EDC Control other 

diagnosis (developed lung disease after initial 

8 7 (88) 

recovery from respiratory problems) iNO other 10 7 (70) diagnosis (developed lung disease 

E‐111
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

after initial recovery from respiratory problems) 

Term EDC Control 

OI<=30 at study entry 

25 20 (80) 

iNO OI<=30 at study entry 

25 17 (68)

 Control 

OI>30 at study entry 

28 25 (89) 

iNO OI>30 at study entry 

30 22 (73) 

Kinsella, 20063 

36 wks PMA Control 392 295 (75.3) P-value: 0.24 

RR: 0.95 (0.1.03) 

iNO 394 282 (71.6) 

36 wks PMA Control BW 

500-749 g; mean 639, SD 71) 

189 159 (84.1) P-value: 0.85 

RR: 1.01 (0.1.1) 

iNO BW 500-749 g; mean 642, SD 76 

191 162 (84.8) 

36 wks PMA Control BW 139 95 (68.3) P-value: 0.93 

E‐112
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

750-999 g; mean 843, SD 71 

RR: 1.01 (0.1.18) 

iNO BW 750-999 g; mean 851, SD 71 

138 95 (68.8) 

36 wks PMA Control BW 

1000-1250 g; mean 1113 g, SD 77 g) 

64 41 (64.1) P-value: 0.00

RR: 0.6 (0.420.86) 

BW 1000-1250 g; mean 1129 g, SD 68g 

65 25 (38.5) 

Schreiber, 2003 4 

Survived NICU Control 102 51 (48.6) p = 0.03 

RR = 0.76 (0.60-0.97) 

0.77 (0.60-0

iNO 105 65 (63.7) 

Van Meurs, 200711 

Death before discharge to home or within 365 

Control 15 9 (60) P-value: 0.87 

RR: 0.83 (0.43-1.62) 

p-value: 0.5 RR: 0.80 (0.41.48) 

iNO 14 7 (50) 

E‐113
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

Van Meurs, 20055 

Before discharge to home or within 365 days among hospitalized infants 

Control 208 170 (82) P-value: 0.52 

RR: 0.97 (0.1.06) 

iNO 210 167 (80) 

Before discharge to home or within 365 days among hospitalized infants 

Control BW<=1000 g 

158 133 (85) P-value: 0.29 

RR: 1.04 (0.1.13) 

iNO BW<=1000 g 

158 141 (89) 

Before discharge to home or within 365 days among hospitalized infants 

Control BW>1000 g 

52 35 (69) P-value: 0.03 

RR: 0.72 (0.0.96) 

iNO BW>1000 g 

52 26 (50) 

Before discharge to home or within 365 days among hospitalized infants 

Control OI<=17 

110 83 (75) P-value: 0.37 

RR: 0.93 (0.1.08) 

iNO OI<=17 100 71 (71) 

E‐114
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

Before discharge to home or within 365 days among hospitalized infants 

Control OI>17 

100 85 (86) P-value: 0.75 

RR: 1.02 (0.1.12) 

iNO OI>17 110 96 (87) 

Watson, 200912 

1 year corrected age 

Control 383 110 (28.7) P-value: 0.29 

iNO 384 97 (25.3) 

1 year corrected age 

Control birth weight 500-749 g 

187 70 (37.4) P-value: 0.99 

iNO birth weight 500-749 g 

187 70 (37.4) 

1 year corrected age 

Control birth weight 750-999 g 

133 29 (21.8) P-value: 0.08 

iNO birth weight 750-999 g 

139 19 (13.7) 

1 year corrected age 

Controlbirth weight 1000-1250 g 

64 11 (17.2) P-value: 0.61 

E‐115
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

iNO birth weight 1000-1250 g 

58 8 (13.8) 

Van Meurs, 2005 5 

Brain Injury, Severe IVH (grades 3-4) or PVL 

36 weeks Control 210 50 (32) p-value = 

0.11 RR= 1.25 (0.95-1.66) 

iNO 210 69 (39) 

Kinsella, 20063 

Death or Brain Injury, Death or grade 3 or 4 ICH or PVL 

30 days Control 391 151 (38.6) P-value: 0.02 

RR: 0.79 (0.0.96) 

iNO 392 120 (30.6) 

30 days Control BW 

500-749 g; mean 639, SD 71 

189 89 (47.1) P-value: 0.18 

RR: 0.86 (0.1.08) 

iNO BW 500-749 g; mean 642, SD 76 

191 77 (40.3) 

30 days Control BW 

750-999 g; mean 843, SD 71 

139 47 (33.8) P-value: 0.02 

RR: 0.63 (0.40.93) 

E‐116
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

iNO BW 750-999 g; mean 851, SD 71) 

137 29 (21.2) 

30 days Control BW 

1000-1250 g; mean 1113 g, SD 77 g 

63 15 (23.8) P-value: 0.8 

RR: 0.92 (0.4

1.74) 

iNO BW 1000-1250 g; mean 1129 g, SD 68 g) 

64 14 (21.9) 

Field, 20052 Death or NDI 1 year 

corrected 

Control acute diagnosis at study entry(lung disease immediately after birth and randomizing at <= 3 days) 

36 24 (67) RR: 0.99(0.7

1.28) 

iNO acute diagnosis at study entry(lung disease immediately 

35 23 (66) 

E‐117
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

after birth and randomizing at <= 3 days) 

1 year Control 9 7 (78) corrected chronic 

diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) iNO chronic 10 8 (10) diagnosis (presenting with lung disease immediately after birth with continuing problems and randomizing >3 days)) 

1 year Control other 8 5 (63) 

corrected diagnosis 

(developed lung disease after initial recovery 

E‐118
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

from respiratory problems) iNO other diagnosis (developed lung disease after initial recovery from respiratory problems) 

10 6 (60) 

1 year corrected 

Control OI<=30 at study entry 

25 15 (60) RR: 

0.99(0.76-1.28)

 

iNO OI<=30 at study entry 

25 16 (64) 

1 year corrected 

Control OI>30 at study entry 

28 21 (75) 

iNO OI>30 at study entry 

30 21 (70) 

iNO 387 164 (42.4) 

Hintz SR, 20078 

18-22 months Control 196 146 (73) P-value: 0.32 

RR: 1.07 (0.95-1.19) 

P-value: 0.3 RR: Model #1.06 (0.95-1

E‐119
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

 iNO 198 154 (78) 

18-22 months Control Birth 

weight </=1000g, F/U cohort 

152 120 (79) P-value: 0.12 

RR: 1.08 (0.1.20) 

iNO tx, Birth weight </= 1000gm 

151 131 (87) 

18-22 months Control Birth 

weight >1000g, F/U Cohort 

48 26 (54) P-value: 0.63 

RR: 0.91 (0.1.33) 

iNO Tx, Birth weight >1000g 

47 23 (49) 

18-22 months Control 

Placebo, Birth weight 401-750grams 

99 / 400 (analysis cohort) 

81 (82) P-value 0.05

iNO tx, Birth weight 401-750grams 

94 / 400 (for analysis cohort) 

86 (91) 

E‐120
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

18-22 months Control 

Placebo, Birth weight 751-1000grams 

53 39 (74) P-value: 0.5

iNO tx, Birth weight 751-1000grams 

58 / 400 (analysis cohort) 

45 / 57 (79) 

18-22 months Control 

Placebo, Birth weight 1001 -1500 grams 

48 / 400 (analysis group) 

26 (54) P-value: 0.54 

iNO tx. Birth weight 1001-1500grams 

48 / 400 (analysis group) 

23 / 47 (49) 

18-22 months Control 200 109 (54) P-value: 0.07 

1.17 RR: (0.99-1.38) 

P-value: 0.07 RR: Model #1.15 (0.99-1

iNO 199 127 (64) 

18-22 months Control Birth 

weight </=1000g, F/U cohort 

152 89 (59) P-value: 0.01 RR: 1.22 (1.

1.43) 

iNO tx, Birth weight </= 

152 111/151 (74) 

E‐121
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

1000gm 

18-22 months Control Birth 

weight >1000g, F/U Cohort 

48 20 (42) P-value: 0.39 RR: 0.80 (0.4

1.33) 

iNO Tx, Birth weight >1000g 

48 16 (33) 

18-22 months Control 

Placebo, Birth weight 401-750grams 

99 / 400 (analysis cohort) 

61 (62) 

iNO tx, Birth weight 401-750grams 

94 / 400 (for analysis cohort) 

75 / 93 (81) 

18-22 months Control 

Placebo, Birth weight 751-1000grams 

53 28 (53) 

iNO tx, Birth weight 751-1000grams) 

58 / 400 (analysis cohort) 

36 (62) 

18-22 months Control 

Placebo, Birth weight 1001 -1500 grams) 

48 / 400 (analysis group) 

20 (42) 

E‐122
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

iNO tx. Birth weight 1001-1500grams) 

48 / 400 (analysis group) 

16 (33) 

Watson, 200912 

1 year corrected age 

Control birth weight 500-749 g 

187 96 (51.3) P-value: 0.57 

iNO birth weight 500-749 g 

188 102 (54.3) 

1 year corrected age 

Control birth weight 750-999 g 

133 59 (44.4) P-value: 0.04 

iNO birth weight 750-999 g) 

140 45 (32.1) 

1 year corrected age 

Control birth weight 1000-1250 g 

64 16 (25) P-value: 0.63 

iNO birth weight 1000-1250 g 

59 17 (28.8) 

1 year corrected age 

Control 384 171 (44.5) P-value: 0.55 iNO 387 164 (42.4) 

1 year corrected age 

Control 384 175 (45.6) P-value: 0.65 

iNO 387 170 (43.9) 

1 year corrected age 

Control birth weight 500-749 g 

187 98 (52.4) P-value: 0.38 

iNO birth weight 500-749 g 

188 107 (56.9) 

E‐123
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 16. All outcomes addressing the KQ4 populations subgroups including death, BPD at 36 weeks PMA, death or 

BPD, Survival with BPD, NDI, death or NDI, Dath, ICH, and PVL, death or disability, cerebral palsy (continued) Author, Year 

Outcomes Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted 

Relative Eff(95% CI) 

1 year corrected age 

Control birth weight 750-999 g 

133 60 (45.1) P-value: 0.04 

iNO birth weight 750-999 g 

140 46 (32.9) 

1 year corrected age 

Control birth weight 1000-1250 g 

64 17 (26.6) P-value: 0.78 

iNO birth weight 1000-1250 g) 

59 17 (28.8) 

Uga, 2004 13 Survival 28 days Control 5 10 (50) 

iNO 8 8 (100) 

Field, 2005 2 Severe Disability 1 year Control 53 2 (4) 

iNO 55 7 (13) 

Yadav, 1999 

10 Survival to Discharge 27 weeks Responders 15 26 

Nonresponders 1 15 

Hintz, 2007 8 Death or Moderate to 

severe CP 

18-22 months Control 109 (54) P = 0.07 RR 

= 1.17 (0.99-1.38) iNO 199 127 (64) 

Watson, 2009 12 Death/Oxygen/NDI 1 year Control 175 (45.6) P = 0.65 iNO 170 (43.9) 

BW: 500-749g Control 98 (52.4) 

iNO 107 (56.9) 

BW: 750-999g Control 60 (45.1) 

iNO 46 (32.9) 

BW: 1000-1250g 

Control 17 (26.6) 

iNO 17 (28.8) 

BPD: Bronchopulmonary Dysplasia; BPD: Bronchopulmonary Dysplasia; BSID: Bayley scale of infant development; BW: Birth weight; CI: Confiden

palsy; DQ: Developmental quotient; EDC: Estimated date of confinement; F/U: Follow: up; GEE: Generalized estimated equations; HFOV: High-freq

E‐124
Evidence Table : Cerebral Palsy for KQ3 continued 

HFV: High-frequency ventilation; HRF: Hypoxemic respiratory failure; ICH: Intracranial Hemorrhage; iNO: Inhaled nitric oxide; IQR: Inter-quartile hemorrhage ; MDI: Mental developmental scale; NDI: Neurodevelopmental impairment; NICU: Neonatal intensive care unit; NS: Not significant; OI: 

Postmenstrual age; PVL: Periventricular leukomalacia; RR: Relative risk; SD: Standard deviation; tx: treatment; 

Reference List

1. Chock VY, Van Meurs KP, Hintz SR et al. Inhaled nitric oxide for preterm 

premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol 2009; 26(4):317-22. 

2. Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled 

Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4):926-36. 

3. Kinsella JP, Cutter GR, Walsh WF et al. Early inhaled nitric oxide therapy in 

premature newborns with respiratory failure. N Engl J Med 2006; 355(4):354-64. 

4. 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 Engl. J. Med. 2003; 349(22):2099-107. 

5. Van Meurs KP, Wright LL, Ehrenkranz RA et al. Inhaled nitric oxide for 

premature infants with severe respiratory failure. N Engl J Med 2005; 353(1):13-22. 

6. Ballard RA, Truog WE, Cnaan A et al. Inhaled nitric oxide in preterm 

infants undergoing mechanical ventilation. New Engl. J. Med. 2006; 355(4):343-53. 

7. Banks BA, Seri I, Ischiropoulos H, Merrill J, Ry

in oxygenation with inhaled nitric oxide in sevedysplasia. Pediatrics 1999; 103(3):610-8. 

8. Hintz SR, Van Meurs KP, Perritt R et al. Neuro

premature infants with severe respiratory failure controlled trial of inhaled nitric oxide. J Pediatr 

9. Kumar VH, Hutchison AA, Lakshminrusimha S

Ryan RM. Characteristics of pulmonary hypertePerinatol 2007; 27(4):214-9. 

10. Yadav M, Emmerson AJ. Inhaled nitric oxide in 

1999; 354(9196):2162-3. 

11. Van Meurs KP, Hintz SR, Ehrenkranz RA et al

infants >1500 g and <34 weeks gestation with sPerinatol 2007; 27(6):347-52. 

12. Watson RS, Clermont G, Kinsella JP et al. Clin

iNO in premature newborns with respiratory fai2009; 124(5):1333-43. 

13. Uga N, Ishii T, Kawase Y, Arai H, Tada H. Nitr

very low-birthweight infants with hypoplastic luPediatr. Int. 2004; 46(1):10-4. 

E‐125
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI 

Author, Year Outcome 

Time of outcome measure Study Arm 

N (number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust ments Du

Ballard, 20061 

BPD 36 weeks 

PMA 

Control 288 164 (56.9) 

iNO 294 149 (50.7) 

Dani, 20062 

36 weeks PMA 

Control 20 12 (60) P-value: 

0.067 

Me

SD

iNO 20 6 (30) Me

SD

Nonrespon ders 

6 Me

SD

Responder s 

14 Me

SD

Field, 20053 

36 weeks PMA 

Control 49 15 (28) Me

IQ

iNO 50 26 (47) Me

IQ

FrancoBelgium Collabor ative NO Trial Group, 19994 

during hospitaliza tion 

Control 29 8 (29) p-value: NS Me

IQ

iNO 29 7 (24) p-value: NS 

OR: 0.95 (0.44–2.04) 

Me

IQ

Kinsella, 19995 

36 weeks PMA 

Control 15 12 (80) p-value: 0.3 

RR: 0.75(0.5-1.13) iNO 25 15 (60) 

E‐126
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Kinsella, 20066

 36 weeks 

BDP at 36 weeks PMA 

Control 309 210 (68) P-value: 0.43 RR:0.96 (0.86– 

1.09) 

randomi zation strata, study sight 

iNO 326 212 (65) 

Mercier, 2010 7 

36 weeks PMA 

Control 358 96 (27) iNO 339 81(24) 

Schreib er, 20038 

36 weeks PMA 

Control 102 42 (53.2) P-value: 0.07 

RR: 0.74 (0.53– 1.03) 

type of ventilati on 

iNO 105 35 (39.3) 

Su, 20089 

36 weeks PMA 

Control 33 11 (33.3) 

iNO 32 10 (31.3) 

Subhed ar, 199710 

36 weeks PMA 

Control dexametha sone and standard of care 

22 14 (64) 

Groups 1&3; iNO + iNO and dexametha sone 

20 10 (50) RR: 

0.79(0.44-1.33) 

Dexametha sone alone AND dex + iNO 

21 11 (52) 

iNO AND standard of care 

21 13 (62) RR: 

0.85(0.48-1.44) 

Van Meurs, 

36 weeks PMA 

Control 11 5 (45) p-value: 0.66 p-value: 0.21 OI 

stratum 

Me23 

E‐127
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 200711 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

RR: 0.66 

(0.21-2.08) 

Adjusted Relative Effect (95% CI) RR: 0.40 (0.09-1.71)

Adjust 

ments 

Dur

iNO 10 3 (30) Me

SD

Van Meurs, 200712 

36 weeks PMA 

Control 127 86 (68) P-value: 0.26 RR: 0.90 (0.75– 

1.08) iNO 109 65 (60) 

Ballard, 20061 

40 weeks PMA 

Control 288 84 (29.2) iNO 294 66 (22.4) 

Control 288 35 (12.2) 

iNO 294 27 (9.2) 

Field, 20053 

At term (EDC) 

Control 53 12 (23) Me

IQR

iNO 55 16 (29) Me

IQR

Field, 20053 1 year corrected 

age 

Control 18 survivors 1 (6) 

iNO 20 survivors 3 (15) 

FrancoBelgium Collabor ative NO Trial Group, 19994 

28 days Control 29 14 (48) p-value: NS 

iNO 29 13 (45) 

Hamon, 200513 28 days Control Hypoxemic 

Respiratory Failure, no iNO 

29 15 (55.6) 

E‐128
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

iNO treated Hypoxemic Respiratory Failure 

22 8 (36.4) 

Kinsella, 19995 Hospital discharge Control 15 12 (80) p-value: 0.1 RR: 0.65 

(0.41-1.02) 

iNO 25 13 (54) p-value: 0.1 

1.02) RR: 0.65(0.41-

Van Meurs, 200512 

Physiologi c BPD as per Walsh criteria 

Control 115 69 (60) P-value: 0.17 RR: 0.87 (0.68– 

1.10) 

center, birthweight group, and oxygena tionindex entry stratum 

iNO 100 50 (50) 

OR (95% CI) Adjusted OR 

(95% CI) 

Ballard, 20061 

Death 36 weeks 

PMA 

Control 288 18 (6.3) iNO 294 16 (5.4) 

40 weeks PMA 

Control 288 19 (6.6) iNO 294 19 (6.5) 

44 wks PMA 

Control 288 20 (6.9) iNO 294 20 (6.8) 

E‐129
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

36 weeks PMA 

Control 7-14 days age at study entry 

115 13 (11.3) 

7-14 days age at study entry 

112 12 (10.7) 

36 weeks PMA 

Control 15-21 days age at study entry 

173 10 (5.8) 

iNO 15-21 days age at study entry 

182 12 (6.6) 

Banks, 199914 

3-24 months from enrollment 

iNO 16 7 (44) 

Bennett, 200115 

30 months corrected age 

Control 22 7 (32) P-value: 0.13 

RR: 1.65 (0.87–3.3) 

iNO 20 10 (50) 

24.9 +/-7.9 months corrected age 

iNO 105 89 (85) 

E‐130
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Dani, 20062 

NICU Control 20 6 (30) P-value: 0.494 birth 

weight 

iNO 20 4 (20) Nonrespon ders 

6 4 (66) P-value: 

0.078 

Responder s 

14 3 (21) 

Field, 20053 1 year Control 53 34 (64) 

iNO 55 30 (55) 

FrancoBelgium Collabor ative NO Trial Group, 19994 

in NICU Control 45 16 (35) P-value: Not 

significant 

iNO 40 11 (27) 

Hascoet , 200516 7 days of life Control with Hypoxemic 

Respiratory Failure 

84 14 (17) P-value: 0.58 1 

iNO with Hypoxemic Respiratory Failure 

61 8 (13) 

28 days of life 

Control with Hypoxemic Respiratory Failure 

84 26 (31) P-value: Not 

significant 

iNO with Hypoxemic Respiratory Failure 

61 25 (41) 

E‐131
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Hintz SR, 200717 

18-22 months 

Control 210 98 (47) P-value: 0.27 birth 

weight categor y, OI strata 

iNO 210 109 (52) 

Huddy, 200818 4-5 years, median 

4.52 (IQR 0.9) 

Control 19 0 (0) 

4-5 years, median 4.63, IQR 0.84) 

iNO 25 1 (4) 

Kinsella , 20066 

36 wks PMA 

Control 392 98 (25) P-value: 0.08 

RR: 0.79 (0.61-1.03) 

randomi zation strata, study sight 

iNO 394 78 (19.8) 

Kinsella , 19995 Discharge Control 32 17 (53) P-value: 0.65 RR: 1.11(0.7-

iNO 48 23 (48) 1.8)

Mercier, 2010 7

 Control 401 42 (10.5) 

iNO 399 56 (14) 

Schreib er, 20038 

NICU Control 102 23 (22.5) P-value: 0.18 

RR: 0.68 (0.38-1.20)

 RR: 0.68 (0.38-1.20) type of 

ventilati on 

iNO 105 16 (15.2) 

E‐132
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Srisupar p, 200219 

7 days Control 22 2 (11.1) P-value: 1 

iNO 16 2 (12.5) 

Su, 20089 

During Study (9 death within 96 hours) 

Control 33 10 (30.3) 

iNO 32 6 (18.8) 

Subhed ar, 199710 

36 wks PMA 

Control dexametha sone and standard of care 

22 7 (32) 

RR: 1.57(0.76-3.38) 

Groups 1&3; iNO + iNO and dexametha sone 

20 10 (50) 

Dexametha sone alone AND dex + iNO 

21 9 (43) RR: 1.13 

(0.54-2.36) 

iNO AND standard of care 

21 8 (38) 

Van Meurs, 200512 

death before discharge to home or within 365 

Control 208 93 (45) P-value: 0.11 

RR:1.16 (0.96-1.39) 

Birthwei ght, study center, Oxygen ation index 

iNO 210 109 (52) 

E‐133
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Van Meurs, 200711 

Death before discharge to home or within 365 

Control 15 4 (27) P-value: 0.7 

RR: 1.34 (0.45-4.0) 

p-value: 0.65 RR: 1.26 (0.47-3.41)

 OI Stratum 

iNO 14 5 (36) 

Walsh, 201020 2 years Control 288 23 (8) RR: 1.02 (0.59-1.77) 

iNO 294 24 (8.2) 

Watson, 200921 1 year corrected 

age 

Control 384 98 (25.5) P-value: 0.12 iNO 385 80 (20.8) 

Ballard, 20061 

Death or BPD 

36 weeks PMA 

Control 288 182 (63.2) iNO 294 165 (56.1) 

Dani, 20062 

NICU Control 20 18 (90) P-value: 

0.016 OR: 0.111 (0.02-0.610) 

iNO 20 10 (50) 

E‐134
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Nonrespon ders 

6 6 (100) P-value: 

0.035 

Responder s 

14 10 (71) 

Field, 20053 

36 weeks PMA 

Control 53 48 (91) 

iNO 55 49 (89) 

36 weeks PMA 

Control trial entry <= 3 days 

37 32 (86) RR: 0.98(0.87-

1.11) 

iNO trial entry <= 3 days) 

38 32 (84) 

36 weeks PMA 

Control trial entry > 3 days 

16 16 (100) 

iNO trial entry > 3 days 

17 17 (100) 

FrancoBelgium Collabor ative NO Trial Group, 19994 

in NICU Control 45 24 (53) 

iNO 40 18 (45) 

Kinsella , 19995 Discharge Control 32 29 (91) P-value: 0.14 RR: 0.85(0.7-

1.03) 

iNO 48 37 (77) 

E‐135
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Kinsella , 20066 

36 wks PMA 

Control 392 295 (75.3) 

P-value: 0.24 RR: 0.95 (0.87-1.03) 

Study sight, randomi zation strata 

iNO 394 282 (71.6) 

Schreib er, 20038 

NICU Control 102 65 (63.7) P-value: 0.03 

RR: 0.76 (0.60-0.97) 

RR: 0.77 (0.60-0.98) 

type of ventilati on 

iNO 105 51 (48.6) 

Subhed ar, 199710 

36 weeks PMA 

Control dexametha sone and standard of care 

22 21 (95) 

RR: 1.05 (0.84-1.25) 

Groups 1&3; iNO + iNO and dexametha sone 

20 20 (100) 

Dexametha sone alone AND dex + iNO 

21 20 (95) RR: 0.95 

(0.79-1.18) 

iNO AND standard of care 

21 21 (100) 

Van Meurs, 200711 

Death before discharge to home or 

Control 15 9 (60) P-value: 0.87 

RR: 0.83 (0.43-1.62) 

p-value: 0.5 RR: 0.80 (0.43-1.48) 

OI Stratum 

E‐136
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure within 365 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

iNO 14 7 (50) 

Van Meurs, 200512 

before discharge to home or within 365 days among hospitalize d infants 

Control 208 170 (82) P-value: 0.52 

RR: 0.97 (0.86-1.06) 

birth weight, study site, Oxygen ation index 

iNO 210 167 (80) 

Watson, 200921 

1 Year corrected 

Control 385 110 (28.7) P-value: 0.29 iNO 384 97 (25.3) 

Hintz SR, 200717 

Death or NDI, Death or moderate to severe CP 

18-22 months 

Control 200 109 (54) P-value: 0.07 

RR:1.17 (0.99-1.38) 

P-value: 0.07 RR: Model #1: 1.15 (0.99-1.34) 

Model #1: BWt, center, OI entry criterion strata, sex 

iNO FollowUp group 199 127 (64) 

E‐137
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Hintz SR, 200717 

Death or NDI, Death or NDI:any of the following: modsevere CP, blind, deaf, MDI<70 or PDI<70 

18-22 months 

Control 200 146 (73) P-value: 0.32 

RR:1.07 (0.95-1.19) 

P-value: 0.3 RR: Model #1: 1.06 (0.95-1.17) 

Model #1: BWt, center, OI entry criterion strata, sex 

iNO FollowUp group 198 154 (78) 

18-22 months 

Control HFV, F/U cohort 

119 93 (78) P-value: 0.91 RR: 1.01 (0.88-

1.15) 

OI criterion , center, and sex Birth weight, center, OI entry criterion strata, sex 

iNO tx, HFV 

115 90 (78) 

18-22 months 

Control Convention al vent, F/U cohort 

81 53 (65) P-value: 0.12 RR: 1.15(0.97-

1.36) 

OI criterion , center, and sex Birth weight, center, OI entry criterion 

E‐138
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

strata, sex 

iNO tx, Convention al Vent 

83 64 (77) 

Field, 20053 

Death or Severe Disability 

1 year corrected 

Control trial entry <= 3 days 

37 24 (65) RR: 0.99(0.76-

1.28) 

diagnosi s, OI severity 

iNO trial entry <= 3 days 

38 25 (66) 

1 year corrected 

Control trial entry > 3 days 

16 12 (75) diagnosi 

s, OI severity 

iNO trial entry > 3 days 

17 12 (71) 

Bennett, 200115 

Survival 30 months 

corrected age 

Control 22 14 (63.6) P-value: 0.13 

RR:1.65(0.87-3.3) iNO 20 8 (40) 

Hamon, 200513 28 days Control Hypoxemic 

Respiratory Failure, no iNO 

39 27 (69.3) 

iNO treated Hypoxemic Respiratory Failure 

37 22 (59.5) 

Mestan, 200522 

25.2+/-8.4 months 

Control 102 79 (78) 

E‐139
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

corrected age 

Schreib er, 20038 

Survived NICU 

Control 102 79 (77.5) 

iNO 105 89 (84.8) 

Ballard, 20061 

Survival without BPD 

36 weeks PMA 

Control 288 105 (36.5) p-value:0.04 

RR: 1.26 (1.02-1.55)

 RR: 1.45 (1.03-2.04) 

cluster (multiple s) using GEE; from the letter to the editor correcti on 

iNO 294 129 (43.9) 

Control 7-14 days age at study entry 

115 31 (27) RR: 1.91 

(1.31-2.78) 

iNO 7-14 days age at study entry 

112 55 (49.1) 

Control 15-21 days age at study entry 

173 74 (42.8) RR: 0.99 

(0.77-1.28) 

iNO 15-21 days age at study entry 

182 74 (40.7) 

Hamon, 2005 13 28 days Control 39 12 (31) iNO 37 14 (38) 

E‐140
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Bennett, 200115 

Severe neurodisa bility - one or more of: 

30 months corrected age 

Control 14 5 (36) P-value: 0.12 

moderate or severe developm ental delay; CP; sensorine ural impairmen t (hearing loss requiring hearing aids and blindness) 

iNO 7 0 (0) 

Field, 20053 

Severe disability defined as no /little 

1 year corrected age 

Control 18 2 (11) 

iNO 25 7 (28) 

head control or inability to sit unsupport ed or no/minima l response to visual stim (equivalen t to DQ <50 age 

E‐141
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcomeadjusted) 

 Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Hintz SR, 200717 

NDI: any of the following: modsevere CP, blind, deaf, MDI<70 or PDI<70 

18-22 months 

Control 102 48 (47) P-value:0.74 

RR: 1.07 (0.80 - 1.44) 

iNO 89 45 (51) 

Huddy, 200818 

Moderate or severe cognitive disability (GCAS<7 0) 

4-5 yrs, median 4.52 (IQR 0.9) 

Control 16 6 (37.5) 

4-5 yrs, median 4.63, IQR 0.84) 

iNO 22 6 (27.3) 

Moderate / Severe CP 

4-5 years Control 16 2 (12.5) 

iNO 22 3 (13.6) 

Mestan, 200522 

Abnormal neurodeve lopmental outcome (any disability or any BSID II score <70) 

25.2+/-8.4 months corrected age 24.9 +/-7.9 months corrected age 

Control 68 31 (46) P-value:0.01 

RR: 0.53 (0.33-0.87) 

iNO 70 17 (24) 

Van Meurs, 200711 

NDI = any one of the following: moderate to severe CP, blind, 

18 to 22 months 

Control 8 2 (25) 

iNO 9 1 (11) 

E‐142
Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcomedeaf, MDI <70, or PDI <70 

 Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

Walsh, 201020 

NDI in subset with complete evaluation s 

2 years Control 212 (51) RR:0.93 

(0.76-1.14) 

iNO 207 (48) 

Neurodev elopmenta l Impairmen t (NDI = MDI<70, PDI<70, unable to crawl or walk (GMFCS> =2), bilateral blindness, or bilateral deafness requiring amplificati on). 

2 years Control 234 114 (49) RR: 0.92 

iNO 243 109 (44.8) (0.75-1.12) 

Moderate / Severe CP 

2 years Control 234 12 (5.1) RR: 1.23 

(0.59-2.55) 

iNO 243 12 (4.9) 

Watson, 200921 NDI (CP, severe 

hearing loss, MDI 

1 year corrected age 

Control 218 73 (33.5) P-value: 0.66 iNO 237 84 (35.4) 

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Evidence Table : Cerebral Palsy for KQ3 continued 

Evidence Table 17. All outcomes addressed in the KQ5 subgroups including death, BPD, and NDI (continued) Author, Year 

Outcome Time of 

outcome measure 

Study Arm N 

(number of participants measured) 

Participants with Outcome— n (%) 

Relative Effect (95% CI) 

Adjusted Relative Effect (95% CI) 

Adjust 

ments 

Dur

or PDI< 70,or blindness) 

Van Meurs, 200711 

Moderate / Severe CP 

18 to 22 months 

Control 8 0 (0) iNO 9 0 (0) 

BPD: Bronchopulmonary Dysplasia; BSID: Bayley scale of infant devleopment; BW: Birth weight; CI: Confidence Interval; CP: Cerebral palsy; DQ: 

EDC: Estimated date of confinement; F/U: Follow: up; HFOV: High-frequency oscillatory ventilation; HFV: High-frequency ventilation; HRF: Hypo

iNO: Inhaled nitric oxide; IQR: Inter-quartile range; IVH: Intraventricular hemorrhage ; MDI: Mental developmental scale; NDI: NeurodevelopmentaNeonatal intensive care unit; NS: Not significant; OI: Oxygenation index; OR: Odds ratio; PDI: Psychomotor Development Index; PMA: Post-menstrleukomalacia; RR: Relative risk; SD: Standard Deviation; tx: Treatment; 

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