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Guideline Summary
Guideline Title
NIH Consensus Development Conference statement on inhaled nitric oxide therapy for premature infants.
Bibliographic Source(s)
Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV, Kramer M, Mitchell C, Neu J, Pursley DM, Robinson W, Rowitch DH. NIH consensus development conference: inhaled nitric oxide therapy for premature infants. NIH Consens State Sci Statements. 2010 Oct 29;27(5):1-34. PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)
  • Premature birth
  • Neonatal lung disease
Guideline Category
Management
Risk Assessment
Clinical Specialty
Family Practice
Neurology
Nursing
Pediatrics
Pulmonary Medicine
Intended Users
Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Health Plans
Hospitals
Nurses
Patients
Physician Assistants
Physicians
Respiratory Care Practitioners
Guideline Objective(s)

To provide healthcare providers, patients, and the general public with a responsible assessment of currently available data on the use of inhaled nitric oxide in early routine, early rescue, or later rescue regimens in the care of premature infants <34 weeks gestation who require respiratory support

Target Population

Premature infants born at or before 34 weeks gestation requiring respiratory support

Interventions and Practices Considered

Inhaled nitric oxide for premature infants <34 weeks gestation was considered but not recommended.

Major Outcomes Considered
  • Short term outcomes: bronchopulmonary dysplasia, cardiopulmonary risks, infectious risks, neurological risks, as well as short term survival and death
  • Long term outcomes: pulmonary outcomes, neurodevelopmental outcomes, growth, chronic medical conditions, and survival to childhood

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Note from the National Guideline Clearinghouse (NGC): A systematic review of the literature was prepared by the Johns Hopkins University Evidence-based Practice Center (EPC) for the Agency for Healthcare Research and Quality (AHRQ) for use by the National Institutes of Health (see the "Availability of Companion Documents" field).

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 the EPC staff used controlled vocabulary terms (i.e., MeSH, EMTREE), combined with text words for inhaled nitric oxide (iNO) (see Appendix B, "Detailed Search Strategies" in the Evidence Report; see also the "Availability of Companion Documents" field). They also looked for eligible studies by reviewing the references in pertinent reviews, by scanning conference proceedings, by querying experts, and through knowledge shared at core team meetings.

Sources

The search included electronic and hand searching. On November 9, 2009, searches of MEDLINE® (using PubMed), EMBASE®, the Cochrane Central Register of Controlled Studies (CENTRAL), and PsycInfo databases were run. These searches were run again on June 23, 2010. The references of articles included in this study and those tagged as of interest during the screening process were also searched. As information on long term outcomes for infants treated with iNO is just emerging, the EPC staff 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. The EPC 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

A strategy for MEDLINE, accessed via PubMed was developed, 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 of the Evidence Report).

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). This software was used to store full articles in portable document format (PDF) and to track the results of the abstract screen, article screen, and data abstraction.

Study Selection

Abstract Screen

Each abstract was independently screened by two reviewers. An abstract was excluded at this level if it did not report 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. (See Appendix C, "Abstract Review Form" of the Evidence Report).

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" of the Evidence Report). 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.

Number of Source Documents

A total of 31 articles were included (14 randomized controlled trials, 9 follow-up studies, and 8 cohort studies)

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Not Given)
Rating Scheme for the Strength of the Evidence

Not stated

Methods Used to Analyze the Evidence
Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Note from the National Guideline Clearinghouse (NGC): A systematic review of the literature was prepared by the Johns Hopkins University Evidence-based Practice Center (EPC) for the Agency for Healthcare Research and Quality (AHRQ) for use by the National Institutes of Health (see the "Availability of Companion Documents" field).

Data Abstraction

An independent review process was used 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. 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 follow-up or additional analysis of another study, location, recruitment start and end dates, inclusion and exclusion criteria, description of the study intervention, inhaled nitric oxide (iNO) dose and duration, and length of follow-up (see Appendix C, Study Characteristics Form in the Evidence Report). 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 in the Evidence Report). Case reports were abstracted separately to identify whether they included data relevant to this study (see Appendix C, Case Report Form in the Evidence Report). 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 (RCTs), the Cochrane Collaboration Tool for Assessing Risk of Bias from the Cochrane Handbook for Systematic Reviews of Interventions was used. 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 the Newcastle-Ottawa Scale was adapted in order to determine the risk of bias of the reported data in both cohort and case control studies. 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 follow-up was long enough for outcomes to occur, and (8) incomplete data reported. Similar to the risk of bias forms for RCTs, reviewers used question based forms where they 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 in the Evidence Report.

Grading of the Body of Evidence

At the completion of the review, the quantity, quality and consistency of the body of available evidence was assessed addressing Key Questions 1 through 5. The EPC staff used an evidence grading scheme recommended by the GRADE Working Group and adapted by AHRQ in their Draft Methods Guide (see the "Availability of Companion Documents" field), and recently published in the Journal of Clinical Epidemiology. They considered the strength of the study designs with RCTs as the highest level of evidence, followed by observational studies. If an outcome was evaluated by at least one RCT as well as observational studies the evidence grade was based on the RCTs and followed by the quality of the cohort studies. If an outcome was evaluated by one or no RCTs, the evidence grade was based on the single RCT in addition to the best available observational study.

The investigators 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 as described in the Draft Methods Guide and Owens et al., 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

The investigators created a set of detailed evidence tables containing information extracted from eligible studies. The tables were stratified according to applicable key question. Once evidence tables were created, selected data elements were rechecked 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. The analyses were performed using a Der-Simonian Laird random effects model. In this program, a Woolf-Haldane continuity correction of 0.5 was used when a cell contained zero events. In all analyses, the investigators 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 meta-analyses, the inclusion and exclusion of articles from the meta-analysis, and any sensitivity analyses, are provided in the results section of the Evidence Report.

Methods Used to Formulate the Recommendations
Expert Consensus (Consensus Development Conference)
Description of Methods Used to Formulate the Recommendations

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.

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 to review available data, to hear scientific summaries from investigators involved in this field, and to solicit input from the general public.

A non-Department of Health and Human Services, nonadvocate 16-member panel included the fields of neonatology, pediatric pulmonology, pediatric neurology, perinatal epidemiology, ethics, neurodevelopmental follow-up, nursing, and family-centered care. In addition, 18 experts from pertinent fields presented data to the panel and conference audience. A Planning Committee developed the following six questions to be addressed by the Consensus Development Panel:

  1. Does inhaled nitric oxide 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 inhaled nitric oxide therapy among premature infants who receive respiratory support?
  3. Are there effects of inhaled nitric oxide therapy on long-term pulmonary and/or neurodevelopmental outcomes among premature infants who receive respiratory support?
  4. Does the effect of inhaled nitric oxide therapy on bronchopulmonary dysplasia and/or death or neurodevelopmental impairment vary across subpopulations of premature infants?
  5. Does the effect of inhaled nitric oxide 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?

The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov External Web Site Policy.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

Guideline developers reviewed published cost analyses.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

External technical experts were recruited from diverse professional backgrounds, including neonatology, pulmonology, cardiology, and neurodevelopment. The technical experts were asked for input regarding key steps of the evidence review 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 National Institutes of Health (NIH) Panel Chair. A draft of the evidence report was sent to the technical experts and peer reviewers, as well as to representatives of the Agency for Healthcare Research and Quality (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, the Evidence-based Practice Center revised the evidence report and submitted a summary of the comments and their disposition.

Recommendations

Major Recommendations
  1. Taken as a whole, the available evidence does not support use of inhaled nitric oxide 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 inhaled nitric oxide 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. Basic research and animal studies have contributed to important understandings of inhaled nitric oxide benefits on lung development and function in infants at high risk of bronchopulmonary dysplasia. These promising results have only partly been realized in clinical trials of inhaled nitric oxide treatment in premature infants. Future research should seek to understand this gap.
  4. Predefined subgroup and post hoc analyses of previous trials showing potential benefit of inhaled nitric oxide have generated hypotheses for future research for clinical trials. Prior strategies shown to be ineffective are discouraged unless new evidence emerges. The positive results of one multicenter trial, which was characterized by later timing, higher dose, and longer duration of treatment, require confirmation. 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.
  5. Based on assessment of currently available data, hospitals, clinicians, and the pharmaceutical industry should avoid marketing inhaled nitric oxide for premature infants <34 weeks gestation.
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is not specifically stated for each recommendation.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Better knowledge of currently available data on the use of inhaled nitric oxide in early routine, early rescue, or later rescue regimens in the care of premature infants <34 weeks gestation who require respiratory support

Potential Harms

Not stated

Qualifying Statements

Qualifying Statements
  • 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, and that the information provided is not a substitute for professional medical care or advice.
  • This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health (NIH) or the Federal Government.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV, Kramer M, Mitchell C, Neu J, Pursley DM, Robinson W, Rowitch DH. NIH consensus development conference: inhaled nitric oxide therapy for premature infants. NIH Consens State Sci Statements. 2010 Oct 29;27(5):1-34. PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2010 Oct
Guideline Developer(s)
National Institutes of Health Consensus Development Conference - Independent Expert Panel
Source(s) of Funding

United States Government

Guideline Committee

Consensus Development Panel

Composition of Group That Authored the Guideline

Panel Members: 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, St. Louis, Missouri; 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, Department of Pediatrics, 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; 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, The 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; 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

Financial Disclosures/Conflicts of Interest

All of the panelists who participated in this conference and contributed to the writing of this statement were identified as having no financial or scientific conflict of interest, and all signed forms attesting to this fact. Unlike the expert speakers who present scientific data at the conference, the individuals invited to participate on National Institutes of Health (NIH) Consensus and State-of-the-Science Panels are reviewed prior to selection to ensure that they are not proponents of an advocacy position with regard to the topic and are not identified with research that could be used to answer the conference questions.

For more information about conference procedures, please see http://consensus.nih.gov/aboutcdp.htm External Web Site Policy.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the National Institutes of Health (NIH) Consensus Development Conference Program Web site External Web Site Policy.

Print copies: NIH Consensus Statements, State-of-the-Science Statements, and related materials are available by visiting http://consensus.nih.gov External Web Site Policy; by calling toll free 888-644-2667; or by emailing consensus@mail.nih.gov. Written requests can be mailed to the NIH Consensus Development Program Information Center, P.O. Box 2577, Kensington, MD 20891. When ordering copies of this statement, please reference item number 2010-00123-STMT.

Availability of Companion Documents

The following are available:

  • Inhaled nitric oxide in preterm infants. Evidence report/technology assessment. AHRQ Publication No. 11-E001. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2010 Oct. 315 p. Electronic copies: Available in Portable Document Format (PDF) from the AHRQ Web site External Web Site Policy.
  • The National Institutes of Health (NIH) Consensus Development Conference: inhaled nitric oxide therapy for premature infants. Webcast. October 27–29, 2010. Bethesda, MD. Available from the NIH Web site External Web Site Policy.
  • Methods guide for comparative effectiveness reviews. AHRQ Publication No. 10(11)-EHC063-EF. Rockville (MD): Agency for Healthcare Research and Quality. 2011 Mar. Available from the AHRQ Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This summary was completed by ECRI Institute on September 14, 2011.

Copyright Statement

No copyright restrictions apply.

Disclaimer

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The National Guideline Clearinghouseâ„¢ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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