NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants.

Abstract

Premature birth is a major public health problem in the United States and internationally. Infants born at or before 32 weeks' gestation (2% of all births in the United States in 2007) are at extremely high risk for death in the neonatal period or for pulmonary, visual, and neurodevelopmental morbidities with lifelong consequences including bronchopulmonary dysplasia, retinopathy of prematurity, and brain injury. Risks for adverse outcomes increase with decreasing gestational age. The economic costs to care for these infants are also substantial (estimated at $26 billion in 2005 in the United States). It is clear that the need for strategies to improve outcomes for this high-risk population is great, and this need has prompted testing of new therapies with the potential to decrease pulmonary and other complications of prematurity. Inhaled nitric oxide (iNO) emerged as one such therapy. To provide health care professionals, families, and the general public with a responsible assessment of currently available data regarding the benefits and risks of iNO in premature infants, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and the Office of Medical Applications of Research of the National Institutes of Health convened a consensus-development conference. Findings from a substantial body of experimental work in developing animals and other model systems suggest that nitric oxide may enhance lung growth and reduce lung inflammation independently of its effects on blood vessel resistance. Although this work demonstrates biological plausibility and the results of randomized controlled trials in term and near-term infants were positive, combined evidence from the 14 randomized controlled trials of iNO treatment in premature infants of ≤ 34 weeks' gestation shows equivocal effects on pulmonary outcomes, survival, and neurodevelopmental outcomes.

Full text

Page 1

Review Copy
Johnston, Michael V; Kennedy Krieger Institute, Neurology
Kramer, Michael; McGill University, Pediatrics and of Epidemiology
and Biostatistics
Mitchell, Christine; Havard medical School, Division of Medical
Ethics
Neu, Josef; University of Florida, Pediatrics
Pursley, Dewayne; Beth Israel Deaconess Medical Center,
Neonatology
Robinson, Walter; Vanderbilt University School of Medicine,
Department of Pediatrics
Rowitch, David; University of California, San Francisco, Neotalogy
Olkkola, Susanne; NIH, OMAR







NATIONAL INSTITUTES OF HEALTH
CONSENSUS DEVELOPMENT CONFERENCE STATEMENT
Inhaled Nitric Oxide Therapy for Premature Infants
October 27–29, 2010


Journal: Pediatrics
Manuscript ID: 2010-3507
Article Type: Special Article
Date Submitted by the
Author:
19-Nov-2010
Complete List of Authors: Cole, F. Sessions; Washington University School of Medicine,
Director, Division of Newborn Medicine
Alleyne, Claudia; Kaiser Permanente Anaheim Medical Center,
Neonatal Intensive Care Unit
Barks, John; University of Michigan Health System, Pediatrics
Boyle, Robert; University of Virginia Medical Center, Pediatrics
Carroll, John; Arkansas Children's Hospital, Pediatric Pulmonary
Dokken, Deborah; Private Practice, Consultant in Family-Centered
Care
Edwards, William; Dartmouth Hitchcock Medical Center, Pediatrics
Georgieff, Michael; University of Minnesota, Pediatrics
Gregory, Katherine; Bpston College, William F. Connell School of
Nursing
Keyword/Category:
Premature infants, Neonatology, Neonatal care, Neonatal
respiratory, Neonatal morbidity



The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation

Page 2

Review Copy

Page 1 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 3

Review Copy
14
DRAFT STATEMENT
November 19, 2010



NATIONAL INSTITUTES OF HEALTH
CONSENSUS DEVELOPMENT CONFERENCE STATEMENT
Inhaled Nitric Oxide Therapy for Premature Infants
October 27–29, 2010

Lead and Corresponding Author:


F. Sessions Cole, M.D.
Panel and Conference Chairperson
Park J. White, M.D. Professor of Pediatrics
Assistant Vice Chancellor for Children’s Health
Vice Chairperson, Department of Pediatrics
Director, Division of Newborn Medicine
Washington University School of Medicine
Chief Medical Officer, St. Louis Children’s Hospital
Campus Box 8116
One Children’s Place
St. Louis, Missouri 63110
(314) 454-6148
Fax (314) 454-4633
cole@kids.wustl.edu


Claudia Alleyne, M.D.
Medical Director, Neonatal Intensive Care
Unit
Kaiser Permanente Anaheim Medical Center
Anaheim, California

John D.E. Barks, M.D.
Professor, Department of Pediatrics and
Communicable Diseases
University of Michigan Medical School
Director, Division of Neonatal-Perinatal
Medicine
C.S. Mott Children’s Hospital
University of Michigan Health System
Ann Arbor, Michigan

Robert J. Boyle, M.D., FAAP
Professor of Pediatrics
Associate Faculty, Center for Biomedical
Ethics
Division of Neonatology
University of Virginia Medical Center
Charlottesville, Virginia

John L. Carroll, M.D., FAAP
Professor, Department of Pediatrics
College of Medicine
University of Arkansas for Medical Sciences
Section Chief, Pediatric Pulmonary Division
Arkansas Children’s Hospital
Little Rock, Arkansas

Page 2 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 4

Review Copy
15
Deborah Dokken, M.P.A.
Family Health Care Advocate
Consultant in Family-Centered Care
Chevy Chase, Maryland

William H. Edwards, M.D.
Professor and Vice Chair of Pediatrics
Neonatology Section Chief
Medical Director CHaD Nurseries
Children’s Hospital at Dartmouth
Co-Director, Vermont Oxford Network
Lebanon, New Hampshire

Michael Georgieff, M.D.
Martin Lenz Harrison Professor of
Pediatrics and Child Psychology
Director, Division of Neonatology
Director, Center for Neurobehavioral
Development
University of Minnesota School of
Medicine, Twin Cities
Minneapolis, Minnesota

Katherine Gregory, Ph.D., R.N.
Assistant Professor of Nursing
William F. Connell School of Nursing
Boston College
Nurse Scientist, Brigham and Women’s
Hospital
Chestnut Hill, Massachusetts

Michael V. Johnston, M.D.
Chief Medical Officer and Executive
Vice President
Blum/Moser Professor for Pediatric
Neurology
Kennedy Krieger Institute
Professor of Neurology, Pediatrics, and
Physical Medicine and Rehabilitation
Johns Hopkins University, School of
Medicine
Baltimore, Maryland

Michael Kramer, M.D.
Scientific Director, Institute of Human
Development, Child and Youth Health
Canadian Institutes of Health Research
James McGill Professor, Departments of
Pediatrics and of Epidemiology,
Biostatistics and Occupational Health
McGill University Faculty of Medicine
Montreal Children’s Hospital
Montréal, Québec
CANADA

Christine Mitchell, M.S., M.T.S., R.N.
Associate Director, Clinical Ethics
Division of Medical Ethics
Harvard Medical School
Director
Office of Ethics
Children’s Hospital Boston
Boston, Massachusetts

Josef Neu, M.D.
Professor of Pediatrics, Director
Neonatology Fellowship Training Program
Division of Neonatology, Department of
Pediatrics
College of Medicine
University of Florida, Gainesville
Gainesville, Florida

DeWayne M. Pursley, M.D., M.P.H.
Chair
Section on Perinatal Pediatrics
American Academy of Pediatrics
Assistant Professor of Pediatrics
Harvard Medical School
Chief
Department of Neonatology
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Page 3 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 5

Review Copy
16

Walter Robinson, M.D., M.P.H.
Senior Research Scientist
Center for Applied Ethics
Education Development Center, Inc.
Associate Professor of Pediatrics
Department of Pediatrics
Division of Pediatric Allergy, Immunology,
and Pulmonary Medicine
Center for Biomedical Ethics and Society
Vanderbilt University School of Medicine
Nashville, Tennessee




David H. Rowitch, M.D., Ph.D.
Professor of Pediatrics and
Neurological Surgery Investigator
Howard Hughes Medical Institute
Chief of Neonatology
University of California, San Francisco
San Francisco, California

There are no financial disclosures for any of the authors.

Key words: Premature; Inhaled nitric oxide therapy; Bronchopulmonary dysplasia

Abbreviations:
BPD: bronchopulmonary dysplasia
CPAP: continuous positive airway pressure
ECMO: extracorporeal membrane oxygenation
FDA: Food and Drug Administration
iNO: inhaled nitric oxide
IPD: individual patient data
IPH: intraparenchymal hemorrhage
IVH: intraventricular hemorrhage
JHU EPC: Johns Hopkins University Evidence-based Practice Center
MAPPiNO: Meta-Analysis of Preterm Patients on Inhaled Nitric Oxide
NEC: necrotizing enterocolitis
PDA: patent ductus arteriosus
PMA: postmenstrual age
PPM: parts per million
PVL: periventricular leukomalacia
RCT: randomized controlled trial
ROP: retinopathy of prematurity

Abstract:
Premature birth is a major public health problem in the United States and internationally. Infants born at
or before 32 weeks gestation (2 percent of all births in the United States in 2007) are at extremely high
risk for death in the neonatal period or for pulmonary, visual, and neurodevelopmental morbidities with
lifelong consequences, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP),
and brain injury. Risks for adverse outcomes increase with decreasing gestational age. The economic
Page 4 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 6

Review Copy
1
costs to care for these infants are also substantial (estimated at $26 billion in 2005 in the United States).
Clearly, the need for strategies to improve outcomes for this high-risk population is great, and this need
has prompted testing of new therapies with the potential to decrease pulmonary and other complications
of prematurity. Inhaled nitric oxide (iNO) emerged as one such therapy.
To provide healthcare professionals, families, and the general public with a responsible assessment of
currently available data regarding the benefits and risks of iNO in premature infants, the Eunice
Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung,
and Blood Institute, and the Office of Medical Applications of Research of the National Institutes of
Health convened a Consensus Development Conference. Findings from a substantial body of
experimental work in developing animals and other model systems suggest that nitric oxide may
enhance lung growth and reduce lung inflammation independently of its effects on blood vessel
resistance. Although this work demonstrates biologic plausibility and the results of RCTs in term and
near-term infants were positive, combined evidence from the 14 RCTs of iNO treatment in premature
infants <34 weeks gestation have shown equivocal effects on pulmonary outcomes, survival, and
neurodevelopmental outcomes.
Page 5 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 7

Review Copy
1

National Institutes of Health (NIH) consensus and state-of-the-science statements are prepared by
independent panels of health professionals and public representatives on the basis of (1) the results of a
systematic literature review prepared under contract with the Agency for Healthcare Research and
Quality (AHRQ), (2) presentations by investigators working in areas relevant to the conference
questions during a 2-day public session, (3) questions and statements from conference attendees during
open discussion periods that are part of the public session, and (4) closed deliberations by the panel
during the remainder of the second day and morning of the third. This statement is an independent
report of the panel and is not a policy statement of the NIH or the Federal Government.

The statement reflects the panel’s assessment of medical knowledge available at the time the statement
was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic.
When reading the statement, keep in mind that new knowledge is inevitably accumulating through
medical research.

Introduction

Premature birth is a major public health problem in the United States and internationally. Despite
clinical, educational, and scientific efforts, the frequency of preterm birth has risen in the United States
from 10.6 percent in 1990 to 12.7 percent in 2007. Worldwide, approximately 13 million infants are
born prematurely every year. Infants born at or before 32 weeks gestation (2 percent of all births in the
United States in 2007) are at extremely high risk for death in the neonatal period or for pulmonary,
visual, and neurodevelopmental morbidities with lifelong consequences, including bronchopulmonary
dysplasia (BPD), retinopathy of prematurity (ROP), and brain injury. Risks for adverse outcomes
increase with decreasing gestational age. The economic costs to care for these infants are also substantial
(estimated at $26 billion in 2005 in the United States). In addition, the emotional and indirect economic
costs for families are substantial. Unfortunately, however, the multifactorial biological, behavioral, and
environmental causes and the heterogeneity of preterm birth make it extremely unlikely that all
premature births can be prevented.

Many clinical practices integrated into the care of these infants have been inadequately studied for safety
and efficacy, with potentially serious consequences; yet, the smallest and sickest infants are the most
vulnerable to adverse effects of the treatments they receive. The broad boundaries of accepted clinical
practices in neonatal intensive care units lead to practice variations among centers. Large variations
among centers in outcomes of premature infants, including BPD and adverse neurodevelopmental
outcomes, persist after adjusting for risk factors such as gestational age, sex, and disease severity. The
extent to which these differences in outcomes are due to differences in care practices or in patient
characteristics is poorly understood. Clearly, the need for strategies to improve outcomes for this high-
risk population is great, and this need has prompted testing of new therapies with the potential to
decrease pulmonary and other complications of prematurity. Inhaled nitric oxide (iNO) emerged as one
such therapy.

Nitric oxide is a gas that is ubiquitously produced in the human body. It serves as a signaling molecule
with numerous regulatory effects on multiple human organ systems, including blood vessels, the lung,
the heart, the nervous system, the immune system, and stem cells, and on the development of cancer.
Over the past decade, the efficacy of nitric oxide in reducing blood vessel resistance and its easy
Page 6 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 8

Review Copy
4
administration via endotracheal tube to infants with respiratory distress led to trials in term and near-
term newborns suffering from persistent pulmonary hypertension, a condition that results from failure of
normal fetal lung blood vessel relaxation immediately following birth. Large, placebo-controlled trials
showed that nitric oxide decreases death or the need for extracorporeal membrane oxygenation (ECMO)
in term and near-term infants with persistent pulmonary hypertension and led the Food and Drug
Administration (FDA) to approve iNO as a therapy for that disease.

Findings from a substantial body of experimental work in developing animals and other model systems
suggest that nitric oxide may enhance lung growth and reduce lung inflammation independently of its
effects on blood vessel resistance. Although this work demonstrates biologic plausibility and the results
of RCTs in term and near-term infants were positive, combined evidence from the 14 RCTs of iNO
treatment in premature infants <34 weeks gestation have shown equivocal effects on pulmonary
outcomes, survival, and neurodevelopmental outcomes. Despite these equivocal results, the off-label use
of iNO has increased substantially. Controversy about its use in premature infants has been fueled by the
refusal of some third-party payers to cover the substantial costs for iNO administration (up to $3,000 a
day).

To provide healthcare professionals, families, and the general public with a responsible assessment of
currently available data regarding the benefits and risks of iNO in premature infants, the Eunice
Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung,
and Blood Institute, and the Office of Medical Applications of Research of the National Institutes of
Health convened a Consensus Development Panel that included experts in the fields of neonatology,
pediatric pulmonology, pediatric neurology, perinatal epidemiology, ethics, neurodevelopmental follow-
up, nursing, and family-centered care to review available data, to hear scientific summaries from
investigators involved in this field, and to solicit input from the general public. A Planning Committee
developed six questions to be addressed by the Consensus Development Panel.

As part of a comprehensive data review, an independent group, the Johns Hopkins University Evidence-
based Practice Center (JHU EPC), generated a systematic review of all available human studies
concerning use of iNO in premature infants. This review, along with an as yet unpublished, updated
Cochrane review and an unpublished individual patient data meta-analysis (the Meta-Analysis of
Preterm Patients on Inhaled Nitric Oxide [MAPPiNO] IPD meta-analysis), provided the Panel with
summaries of the available evidence from these trials. One of the published trials, and therefore the JHU
EPC systematic review, included infants of 34 weeks gestation. The Panel’s review of the published
evidence is therefore based on infants ≤34 weeks gestation. Its recommendations for clinical use of iNO,
however, are limited to infants <34 weeks to avoid contradiction and confusion with the FDA’s labeled
indications for iNO use. Where applicable, the Panel chose to follow the Cochrane review approach of
subdividing the 14 trials into 3 clinically relevant groups based on characteristics of the participating
infants and specific treatment strategies: early routine (initiation at <3 days, routine use in intubated
infants), early rescue (initiation at <3 days based on oxygenation status), and later rescue (initiation at
>3 days based on BPD risk).

Many of the trials and meta-analyses examined results in clinical or demographic subgroups. When
treatment effects differ across subgroups, however, as they did in some of the iNO studies, it is unwise
to make firm inferences about subgroup differences when those differences are observed post hoc. Post
hoc analysis of treatment effects in specific subgroups (e.g., dose of iNO, gestational age, early versus
Page 7 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 9

Review Copy
5
late initiation of treatment), whether within or across trials, is prone to false-positive results. The
Consensus Development Panel therefore considered the subgroup results of these analyses as
hypothesis-generating, rather than hypothesis-testing, and used them as a basis for recommending future
research directions.

The six questions considered by the Consensus Development Panel are listed below and addressed in the
following sections.

1. Does iNO therapy increase survival and/or reduce the occurrence or severity of
bronchopulmonary dysplasia 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 bronchopulmonary dysplasia and/or death or
neurodevelopmental impairment vary across subpopulations of premature infants?

5. Does the effect of iNO therapy on bronchopulmonary dysplasia and/or death or
neurodevelopmental impairment vary by timing of initiation, mode of delivery, dose and
duration, or concurrent therapies?

6. What are the future research directions needed to better understand the risks, benefits, and
alternatives to nitric oxide therapy for premature infants who receive respiratory support?


1. Does iNO therapy increase survival and/or reduce the occurrence or severity of BPD among
premature infants who receive respiratory support?

The Panel addressed this question by including all of the trials that enrolled premature infants <34 weeks
gestation irrespective of the timing, dosing regimen, duration of iNO therapy, or subcategorization of the
subjects. None of the individual trials included in the systematic reviews showed a statistically
significant effect of iNO on survival in this population. Meta-analysis by the JHU EPC of 11 RCTs
revealed that treatment with iNO did not increase survival. The individual patient data approach used in
the MAPPiNO study of pooled data from 11 RCTs demonstrated no statistically significant effect of
iNO on death at any time, death by 36 weeks postmenstrual age (PMA), or death before discharge.
Inclusion or exclusion of the one trial with enrollment exclusively after 1 week did not affect the results
of the meta-analysis. Thus overall, in premature infants <34 weeks gestation requiring respiratory
support, current evidence shows that treatment with iNO in the neonatal period does not increase
survival.

Interpretation of results from RCTs was complicated by different studies calculating BPD rates using
survivors versus the total group as the denominator, and by the competing risks of death and BPD. In
other words, an infant who dies in the first weeks of life is not at risk for developing BPD, which is
Page 8 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 10

Review Copy
6
usually based on criteria at 28 days. Since most of the trials and the JHU EPC systematic review
included analyses of BPD alone, however, the Panel also examined that evidence. None of the individual
trials included in the systematic reviews showed statistically significant differences in BPD at 36 weeks
PMA in those who received iNO compared with controls. The JHU EPC meta-analysis (8 RCTs) of
BPD among surviving infants at 36 weeks PMA found no statistically significant differences in rates of
BPD between iNO and control groups. The approach utilized in the MAPPiNO IPD meta-analysis did
not report on BPD as a sole outcome variable. Thus, among premature infants who required respiratory
support and were surviving at 36 weeks PMA, current evidence does not support the hypothesis that
treatment with iNO in the neonatal period reduces the occurrence of BPD.

The composite outcome of “death or BPD at 36 weeks PMA” was reported, although not always as a
primary outcome, in 11 iNO RCTs. Two individual trials found statistically significant reductions in the
composite outcome of death or BPD in the iNO treated group. The JHU EPC meta-analysis of 11 RCTs
showed a small, statistically significant reduction in the composite variable death or BPD at 36 weeks
PMA. Exclusion of the one trial with enrollment after 1 week of age did not change the results of the
meta-analysis. The MAPPiNO IPD meta-analysis of pooled data from 10 trials showed a similarly small
effect size for BPD or death as the JHU EPC analysis, but did not achieve statistical significance. The
small effect on this composite outcome should be interpreted cautiously.

The JHU EPC systematic review of the effect of iNO on the severity of BPD in the RCTs was
compromised by the wide variation in BPD definitions and other study parameters. The JHU analysis
concluded that insufficient data are available to perform a meta-analysis for any measure of severity due
to the lack of uniformity in definitions and study measures used. There is insufficient evidence to
support the hypothesis that treatment with iNO in the neonatal period reduces the severity of BPD. Two
individual trials reported a statistically significant favorable effect of iNO on pulmonary outcomes
reflecting severity of BPD; rates of hospitalization and respiratory support at 40 and 44 weeks PMA; and
a statistically significant reduction in the average duration of supplemental oxygen. Although these trials
raise intriguing questions, the effects of iNO on the severity of BPD have not been adequately studied in
subpopulations.

The available evidence therefore is insufficient to recommend the routine use of iNO in clinical care of
premature infants <34 weeks gestation requiring respiratory support.

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

Premature infants are at risk for short-term complications, including patent ductus arteriosus (PDA),
late-onset (>7 days) sepsis, necrotizing enterocolitis (NEC), ROP, pulmonary complications (e.g., air
leak, pulmonary hemorrhage), and brain injury (e.g., intraventricular hemorrhage [IVH],
intraparenchymal hemorrhage [IPH], and periventricular leukomalacia [PVL]). In addition, iNO may
lead to accumulation of methemoglobin formed by the reaction of nitric oxide with hemoglobin.

Although different trials monitored different combinations of these complications and used differing
study designs (e.g., timing dose of iNO), the JHU EPC (examining PDA, late-onset sepsis, NEC, ROP,
pulmonary complications, IVH, PVL, IPH, or toxic levels of methemoglobin), the updated Cochrane
meta-analysis (examining severe IVH, combined outcomes of severe IVH or PVL), and the MAPPiNO
Page 9 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 11

Review Copy
7
IPD meta-analysis analyses (examining air leak, pulmonary hemorrhage, or severe ROP) showed no
evidence for an increased risk of any of these complications or methemoglobin levels considered toxic
in term infants and adults at doses up to 20 ppm.

The updated Cochrane meta-analysis did show that early rescue administration of iNO was associated
with a nonsignficant trend toward increased severe IVH, and the MAPPiNO IPD meta-analysis showed
a nonsignificant trend toward increased severe neurological events (e.g., IVH, IPH, cystic PVL) with
iNO treatment.

Although these morbidities might be exacerbated by iNO, there may be other important indicators
specific to premature infants that have not been examined.

In summary, there is no evidence that treatment with iNO either increases or decreases the risk of
several short-term complications of prematurity, including PDA, late-onset sepsis, severe ROP, and
pulmonary complications (e.g., air leaks, pulmonary hemorrhage).

3. Are there effects of iNO therapy on long-term pulmonary and/or neurodevelopmental
outcomes among premature infants who receive respiratory support?

Long-Term Pulmonary Outcomes

The JHU EPC reported two RCTs examining long-term pulmonary outcomes. One large study
demonstrated a statistically significant decrease in use of lung-related medications and fewer parental
reports of respiratory symptoms at 12 months in children receiving iNO compared with controls; a
smaller study found no statistically significant difference in reported use of lung medications or reports
of symptoms at 12 months. Neither study found a statistically significant difference in rates of
hospitalization for lung problems or wheezing at 12 months. The lack of a difference in hospitalization
or wheezing casts doubt on the clinical importance of a difference in medication use between those who
received iNO and the controls.


The Panel concludes, as did the JHU EPC, that there is evidence in one trial of an advantage in long-
term pulmonary outcome for the use of iNO, but that this evidence is not strong enough to justify the
widespread use of iNO to prevent long-term pulmonary disease.

Long-Term Neurodevelopmental Outcomes

None of the trials examining long-term neurodevelopmental outcomes in children have convincingly
demonstrated a long-term neurodevelopmental effect of iNO. Individually, none of the trials found a
statistically significant difference in the incidence of motor delay between those who had received iNO
and controls. For cerebral palsy, the two trials that did show associations conflicted in the direction of
association. There is insufficient evidence to determine whether there is an effect of iNO on motor
impairment or if it differs by the birth weight of the treated infants. There also were no significant
differences between the iNO and control groups in the proportion of children with visual or hearing
impairment. Few individual trials and none of the meta-analyses revealed a statistically significant
association between neonatal iNO treatment and any neurodevelopmental outcome up to 5 years of age.
Page 10 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 12

Review Copy
8

Studies of long-term neurodevelopment in preterm infants <34 weeks gestation treated with iNO have
been hampered by variation in measures used to assess neurodevelopmental status and the ages at which
outcomes are measured, and by the lack of physiologic, radiologic, functional, or quality-of-life
measures used as outcomes. Most studies of long-term effects typically have used overly broad
measures of development in the absence of physiologic or anatomic examinations; many also have used
the measure at too young an age. While 18 to 24 months is appropriate for detecting cerebral palsy,
testing at school age is more appropriate for diagnosing intellectual disability. Newer methods of
assessment, including correlated neuroimaging and standardized behavioral testing, should be included
in any future assessments of the long-term neurodevelopmental consequences of iNO.

4. Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary
across subpopulations of premature infants?

The Panel elected to review common clinical variables that may interact with iNO treatment apart from
timing or duration of treatment (see response to Question 5). Analysis of subpopulations is limited by
the fact that few trials have identified subgroups, subgrouping results in small sample sizes in each
subcategory, and trials are often not powered to detect subgroup differences. In addition, when trials did
define subgroups, definitions varied across trials and were usually post hoc.

Based on the JHU EPC systematic review, there is insufficient evidence to evaluate whether factors such
as sex, gestational age, ethnic group/race, and socioeconomic status were associated with increased
benefit or risk from iNO therapy. There is no information regarding effects of growth restriction,
antenatal steroid use, multiple gestation, chorioamnionitis, or other antenatal factors.

The JHU EPC systematic review reveals insufficient evidence of decreased incidence of death or BPD
particular to any subgroup of premature infants treated with iNO. Five studies (representing three
independent clinical trials) reported outcomes by birth weight. Two of the three trials demonstrated a
significant reduction in the composite outcome of death or BPD when iNO was administered to
premature infants >1,000 grams, but not in those <1,000 grams.

This review raises a concern for safety of iNO in premature infants <1,000 grams. Three studies of
infants of this birth weight treated within 48 hours of delivery reported an increased risk of death, severe
IVH and PVL, neurodevelopmental impairment, BPD, and/or oxygen dependence at 1 year of age.
However, in another large study that initiated iNO at 7 days of life, no such safety concerns were noted
in this birth-weight category.

Based on the JHU EPC systematic review of published studies, there is insufficient evidence of
improvement in neurodevelopmental outcomes in any subgroup of premature infants treated with iNO.

Published trials have shown insufficient evidence of benefit to premature infants with pulmonary
hypoplasia or hypertension, likely due to small numbers of such patients and severity of illness.
Additional studies in this population will be difficult to accomplish. Therefore, clinical use in this
population should be left to clinical discretion.

Page 11 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 13

Review Copy
9
Based on published data, the Panel recommends special caution in studies of early rescue use of iNO in
premature infants <34 weeks gestation weighing <1,000 grams.

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?

Infants treated with early routine and early rescue iNO (see Introduction for definitions of these groups)
had no significant reduction in death, BPD, or the composite outcome of death or BPD. However,
infants treated in the later rescue group, predominantly represented by one, large multicenter trial in
which the treatment protocol was unique not only in the timing of initiation, but also in dosing and
duration, revealed an overall reduction in the composite outcome of death or BPD and a post hoc finding
of greater efficacy when treatment was initiated during the second postnatal week, as compared with the
third postnatal week. The method of treatment allocation and statistical analysis of multiples enrolled in
the trial made it difficult to integrate this trial’s findings in a conventional meta-analysis. Nevertheless,
different statistical approaches to the analysis of multiples did not substantially change the estimate of
the effect of iNO.

The effect of mode of ventilation (conventional versus high frequency) on efficacy and safety of iNO
was evaluated in two trials, in one by prospective randomization and in the other by post hoc analysis.
No studies have directly compared delivery by continuous positive airway pressure (CPAP) or nasal
cannula versus endotracheal positive pressure ventilation. There is insufficient evidence to determine
whether mode of ventilation impacts outcome from iNO treatment.

None of the trials published to date randomized subjects by dose or treatment duration of iNO. Despite
this limitation, these trials can be subdivided into three broad dosage groups: 5 parts per million (ppm),
10 ppm, and 20 ppm. In a dose-stratified meta-analysis by the JHU EPC, which combined all three
treatment initiation subgroups, iNO therapy in the group that received a maximum dose of 10 ppm was
associated with a statistically significant reduction in the risk of BPD, but not death, or the composite
outcome of death or BPD. These results do not form a basis for deciding that one dosing regimen was
superior, because they were based on post hoc comparisons and there was too much variability among
the study designs within each dose group. A more focused examination of dosing and treatment duration
within clinically meaningful subgroups is needed.

Little is known about the effect of concurrent therapies on the efficacy and safety of iNO. Only one trial
directly addressed the effect of iNO with a concurrent therapy, glucocorticoids. Further research is
needed to determine the effect of concurrent therapies—such as antenatal and postnatal glucocorticoids,
surfactant, vitamin A, indomethacin, and caffeine—on the efficacy and safety of iNO.

There is no evidence to suggest that variations in these treatment regimen factors (e.g., dose, timing,
mode of administration) are harmful in terms of BPD, death, or neurodevelopmental outcome. The
design of future trials comparing treatment regimens should include a longer duration of follow-up to
ensure long-term safety.

There is insufficient evidence to conclude that the efficacy of iNO therapy with respect to BPD and/or
death, or neurodevelopmental impairment, varies by timing of initiation, mode of delivery, dose and
duration of therapy, or concurrent therapies. Although the evidence suggests that some treatment
Page 12 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 14

Review Copy
pulmonology, pediatric neurology, neurodevelopmental follow-up, neonatal pharmacology,
lung development, brain development, nitric oxide physiology, biostatistics, and clinical trial
design, as well as ethicists, nurses, respiratory therapists, and families.
10
regimens may provide greater benefit, further RCTs designed to address these specific hypotheses must
be undertaken.

6. What are the future research directions needed to better understand the risks, benefits, and
alternatives to nitric oxide therapy for premature infants who receive respiratory support?

1.
Understanding risks, benefits, and alternatives to iNO therapy for premature infants
requires investigation of iNO’s mechanisms of action through additional basic research in
developmentally relevant experimental models, especially understanding the respective roles
of dosing, delivery, and timing of therapy and of accompanying ventilation strategies,
oxygen management, and concurrent therapies in optimizing the benefits of iNO, on
understanding the pharmacology and toxicology of iNO specifically in premature infants, and
on increasing tissue-specific production of endogenous nitric oxide.

2.
Future trials for evaluation of safety and efficacy of iNO for premature infants should be
informed by prior trials and future studies in premature animals or other model systems,
examine both short- and long-term pulmonary and neurodevelopmental outcomes, and
investigate effect-modifying factors (e.g., pharmacokinetic, genetic, racial/ethnic, and disease
risk factors).

3.
Future randomized trials should be designed to assess variations in the timing, dose, and
duration of treatment by randomizing them separately, to include a placebo control, to ensure
a sample size sufficient to detect a significant interaction between gestational age category
and treatment arm, and to consider an appropriate developmental window for efficacy and
safety.

4.
Future trials should assess the long-term safety and efficacy of iNO treatment by
following study subjects to a minimum of school age with standardized assessments of
behavior, cognitive ability, neuroanatomy, and neurophysiology.

5.
Design of future efficacy and safety trials of iNO for premature infants should include
interdisciplinary teams of experts in high-risk obstetrics, neonatology, pediatric

6.
Given the large differences in outcomes of death and BPD among neonatal intensive care
units, comparative effectiveness research strategies should be considered to identify
components of care which may have greater impact on improving outcomes than iNO.

7.
In addition to the Panel’s iNO research recommendations, future research should pursue
promising strategies other than iNO.

8.
Biomarker, neuroimaging, pulmonary function testing, pulmonary imaging, and other
techniques with potentially better predictive accuracy should be developed and tested.

Page 13 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

Page 15

Review Copy
11

Conclusions

1. Taken as a whole, the available evidence does not support use of iNO in early routine, early
rescue, or later rescue regimens in the care of premature infants <34 weeks gestation who
require respiratory support.

2.
There are rare clinical situations, including pulmonary hypertension or hypoplasia, that
have been inadequately studied in which iNO may have benefit in infants <34 weeks
gestation. In such situations, clinicians should communicate with families regarding the
current evidence on its risks and benefits as well as remaining uncertainties.

3.
Future research should seek to understand the gap between benefits on lung development
and function in infants at high risk of BPD suggested by basic research and animal studies
and the results of clinical trials to date.

Predefined subgroup and post hoc analyses of previous trials showing potential benefit of
iNO have generated hypotheses for future research for clinical trials. Prior strategies shown
to be ineffective are discouraged unless new evidence emerges. Future trials should attempt
to quantify the individual effects of each of these treatment-related variables (timing, dose,
and duration), ideally by randomizing them separately.
4.

5.
Based on assessment of currently available data, hospitals, clinicians, and the
pharmaceutical industry should avoid marketing iNO for premature infants <34 weeks
gestation.


Page 14 of 13
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
Confidential - Not for Circulation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60