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Abstract
Introduction Inhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue for hypoxic respiratory failure and pulmonary hypertension secondary to BPD has increasingly been used in preterm infants after 7 days of postnatal age (in the postacute phase), despite its off-label use. However, the initiation criteria of iNO therapy for preterm infants in the postacute phase are varied. The aim of this scoping review is to identify the clinical and/or echo findings at the initiation of iNO therapy in preterm infants in the postacute phase.
Methods and analysis We will search PubMed, Embase and the Japanese database ‘Ichushi.’ The following studies will be included in the review: randomised controlled trials, prospective/retrospective cohort studies, case–control studies and case series on iNO therapy for preterm infants in the postacute phase; studies published between January 2003 and August 2023; studies conducted in developed countries and studies written in English or Japanese. We will independently screen, extract and chart data using the population–concept–context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We will summarise the characteristics and findings of the included studies.
Ethics and dissemination Obtaining an institutional review board approval is not required because of the nature of this review. A final report of review findings will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences.
Trial registration number UMIN000051498.
- NEONATOLOGY
- Paediatric thoracic medicine
- Neonatal intensive & critical care
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This will be the first scoping review that will map the inhaled nitric oxide therapy for preterm infants in the postacute phase.
This review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews to ensure a transparent process.
We will not perform any quality assessment of the included studies in this review, as it is outside of the framework of this scoping review.
Introduction
Rationale
Nitric oxide (NO) is a signalling substance that acts as a vasodilator. Inhaled NO (iNO) has pulmonary vasodilating effects and is recommended for early-onset neonatal hypoxic respiratory failure (HRF) and pulmonary hypertension (PH), also known as persistent PH of the newborn, in term and late preterm infants.1 2 The use of iNO therapy in preterm infants, especially in extremely preterm infants born at <28 weeks gestation, has recently been increasing.3 4 However, the effectiveness of iNO therapy in preterm infants after 7 days of postnatal age (in the postacute phase) remains controversial.
Bronchopulmonary dysplasia (BPD) is a major neonatal respiratory complication caused by prematurity and associated with adverse effects in terms for long-term respiratory and neurodevelopmental outcomes. Some patients with moderate and severe BPD develop HRF and PH, which could lead to life-threatening respiratory conditions.5 6 Current studies have demonstrated the effects of the off-label use of iNO in preventing BPD or rescuing for HRF and/or PH among preterm infants in the postacute phase.7–9 As a prophylactic intervention for BPD, a randomised controlled trial demonstrated that iNO therapy in infants at 7–21 days of age improved their BPD-free survival at 36 weeks of postmenstrual age.7 In a most recent Cochrane review article, although the later use of iNO tends to be beneficial in preventing BPD, the 95% CIs indicated no effect, and the effect size was estimated to be small (risk ratio 0.92, 95% CI 0.85 to 1.01).10 As a rescue therapy for HRF and/or PH secondary to BPD, several retrospective observational studies have reported that the off-label use of iNO for preterm infants in the postacute phase improves oxygenation in the short-term assessment.8 9
Although the off-label use of iNO has increased, the initiation criteria of iNO vary in each study. Neonatologists diagnose hypoxaemia using various parameters, including oxygen saturation, partial pressure of arterial oxygen and oxygenation index. Similarly, many different echocardiographic findings are used for the diagnosis of PH, which are as follows: the septum flattened or bowed into the left ventricle at end systole; pulmonary artery pressure estimated by measuring the peak velocity of tricuspid regurgitation and right-to-left shunting in the ductus arteriosus or foramen ovale. A retrospective study also used iNO therapy according to the presence of refractory hypoxaemia or echocardiographic findings.8 Furthermore, the iNO dosage also varied from 5 to 20 ppm in each study.
Therefore, previous studies investigating the effects of iNO might include a heterogeneous population. Although iNO is originally indicated for the treatment of PH, iNO for preterm infants in the postacute phase is currently initiated according to various parameters, even for HRF without sufficient clinical or echocardiographic evidence of PH, due to the lack of optimised initiation criteria. Hence, this scoping review aims to map the detailed clinical and/or echocardiographic findings at the initiation of iNO therapy for preterm infants in the postacute phase.
Methods and analysis
Eligibility criteria
The population–concept–context (PCC) framework for the scoping review by the Joanna Briggs Institute11 will be used in the present scoping review (table 1). We will include articles that meet the following eligibility criteria: (1) participants are preterm infants born at <34 weeks gestation and aged >7 days; (2) with clinical and/or echocardiographic findings at iNO initiation; (3) published between January 2003 and August 2023; (4) conducted in developed countries; (5) written in English or Japanese and (6) with the following study design: randomised controlled trials, prospective/retrospective cohort studies, case–control studies and case series. The exclusion criteria will be as follows: (1) participants had congenital malformation syndrome or chromosomal abnormality; (2) animal and in vitro studies and (3) protocols (a type of publication).
PCC framework of the present scoping review
Information sources
We will search PubMed, Embase and the Japanese electronic bibliographic database “Ichushi”. The searches will be conducted by an expert librarian and the supplemental hand searches will be conducted by reviewers. The keywords were collected through experts’ opinions, literature review, controlled vocabulary (Medical Subject Headings) and reviewing the primary search results, including terms relating to population, concept and contexts, including ‘inhaled nitric oxide,’ ‘iNO,’ ‘preterm infants,’ ‘bronchopulmonary dysplasia,’ ‘hypoxic respiratory failure,’ and ‘pulmonary hypertension.’ We will search studies published between January 2003 and August 2023. Jobe reported that the clinical and pathological characteristics of BPD have changed because more premature infants have survived due to progress in neonatal care that includes antenatal glucocorticoids, surfactant treatments and gentler ventilation strategies.12 Additionally, from around 2000, the use of iNO therapy for neonates was approved in some countries, and the studies on iNO use in preterm infants have been increasingly conducted. Therefore, we defined the search period as the last two decades. The search strategies are shown in online supplemental appendix.
Supplemental material
Selection of sources of evidence
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA)13 and Rayyan, a web application,14 will be used to screen the eligible studies. The titles and abstracts of the studies identified in the initial electronic searches will be screened independently by the authors to assess their potential eligibility of meeting the inclusion criteria using PCC framework. Subsequently, a full-text review of these potentially eligible studies will be performed by two or more authors independently. Any disagreement between them over the eligibility of studies will be resolved through a discussion and decided by consensus or resolved with other author’s assessment. The study selection process will be shown using the PRISMA flow diagram.
Data charting
The following data will be extracted from all included studies and charted into the prepiloted Excel form (tables 2 and 3).
Dummy Excel table for extracting the characteristics of the included studies
Dummy Excel table for extracting the data of iNO therapy
Data items
The characteristics of included studies
Study title.
Author name.
Year of publication.
Study design.
Country.
Sample size.
Population.
Information involving iNO therapy
Initiation criteria of iNO (such as supplemental O2 level, PH, echocardiographic parameter, surrogate marker of hypoxia, adjunctive therapy).
Postnatal day of the iNO therapy initiation.
Dosage of iNO concentration (ppm).
Duration of iNO therapy.
Discontinuation criteria of iNO.
Other drugs used in combination with iNO therapy.
Adverse effects.
Critical appraisal of individual sources of evidence
The objective of this scoping review is to map the existing evidence. Therefore, we will not assess the risk of bias for the included individual studies.
Synthesis of results
We will summarise the characteristics of the included studies and detailed findings of iNO therapy. The results will be expressed on the table and described narratively.
Ethics and dissemination
Obtaining an institutional review board approval is not required because of the nature of the methodology used in the analysis. The University hospital Medical Information Network-Clinical Trial Registry was satisfied with the International Committee of Medical Journal Editors (ICMJE) criteria and registered the review protocol for clinical trial registration (registration number: UMIN000051498). A final report will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences.
Patient and public involvement
This study will not involve patients and the public as only existing articles were analysed. However, neonatologists will participate in the review process and discuss the results. We will consult stakeholders and experts throughout the review process.
Acknowledgments
We wish to thank Kuniko Sato, who is a librarian, for considering the search strategy.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors SK and HN conceptualised and designed this study. All authors contributed to the scope and design of this review. DS and EO developed our search strategy with consultation to a medical librarian at St. Luke’s International University. YM, MH, TN and SI will perform screening and extraction data. AN, DS and EO supervised the study design and edited the manuscript. YM drafted the first version of the manuscript. All authors have read and revised the draft. All authors have approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.