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Abstract
Objectives Inhaled nitric oxide (iNO) is a known treatment for pulmonary hypertension (PH) associated with bronchopulmonary dysplasia in preterm infants after 7 days of age (postacute phase). However, a consensus regarding the optimal criteria for initiating iNO therapy in this population in the postacute phase is currently lacking. This study, therefore, aimed to identify the criteria for initiating iNO therapy, alongside the associated clinical and echocardiographic findings, in this population.
Design We performed a scoping review using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.
Data sources PubMed, Embase and the Japanese database ‘Ichushi’ were systematically searched for relevant articles published between January 2003 and August 2023.
Eligibility criteria This study included randomised controlled trials, prospective and retrospective cohort studies, case–control studies and case series on iNO therapy in the postacute phase for preterm infants born before 34 gestational weeks, written in English or Japanese.
Data extraction and synthesis Data screening, extraction and charting were performed independently, with the characteristics and findings of the included studies subsequently summarised.
Results We included 10 reports that analysed the data from 10 separate studies. The use of iNO therapy was categorised as prophylactic and rescue purposes. While randomised controlled trials (RCTs) and retrospective analyses indicated the safety of iNO during the postacute phase, the latter highlighted poor prognoses associated with severe cases requiring rescue iNO therapy. Additionally, although echocardiography is currently the primary diagnostic tool for identifying PH in preterm infants, standardised diagnostic criteria are lacking. Further, reports of complications and side effects associated with iNO are rare.
Conclusion Our exploration of the initiation criteria for iNO revealed that definitive guidelines have not been established. Nonetheless, iNO administration during the postacute phase appeared to be safe and devoid of complications.
Trial registration number UMIN000051498.
- NEONATOLOGY
- PAEDIATRICS
- Pulmonary Disease
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.
The protocol has been published to ensure transparency.
We searched the Japanese database ‘Ichushi’, which has documented a long history of active resuscitation of the most vulnerable preterm newborns.
The review did not include a quality assessment of the included studies.
Introduction
Nitric oxide (NO) is a gaseous agent with a targeted effect on pulmonary hypertension (PH), significantly improving outcomes in newborns.1 2 In the USA, medical insurance limitations restrict the use of NO before 34 weeks of postmenstrual age. However, experience with inhaled NO (iNO) treatment has accumulated globally, with reports detailing its effect on both short-term and long-term prognoses in premature newborns.3–5 Bronchopulmonary dysplasia (BPD) significantly impacts pulmonary function and neurodevelopmental outcomes in premature newborns. Moderate-to-severe BPD is recognised as one of the key causes of hypoxic respiratory failure (HRF) or PH in newborns, particularly in the postacute phase, which can be potentially fatal.6 7
Notably, the efficacy of iNO during the postacute phase has been documented for both BPD prevention and rescue from HRF or PH.8–10 However, its effectiveness remains suboptimal. For example, iNO is not covered by medical insurance when initiated after the first week of life in Japan. Hence, it is imperative to establish evidence supporting its efficacy and broaden its indications to include the postacute phase.
Despite the increasing off-label use of iNO, the criteria for its initiation vary across studies. Neonatologists have used diverse parameters to diagnose hypoxia, including oxygen saturation, arterial oxygen partial pressure and the oxygenation index.11–13 Similarly, various echocardiographic findings are used to diagnose PH.7 14 Echocardiography is considered the gold standard for PH diagnosis in newborns; however, logistical challenges may hinder its implementation prior to the initiation of iNO treatment in certain countries. Indeed, iNO is sometimes employed for clinical HRF or PH in the absence of any definitive echocardiographic findings, partly because of the aforementioned reasons. We believe that the current perceived inadequacy of postacute iNO therapy may be partly due to the enrolment of heterogeneous populations without a robust diagnosis of PH in prior studies investigating iNO efficacy.15 In addition, while the mechanism of action of iNO renders it suitable for PH treatment, the optimal initiation criteria, particularly among premature infants in the postacute phase, remain unclear.
Presently, there is a dearth of comprehensive information regarding the actual usage and initiation criteria for postacute iNO in Japan and other nations. This review, therefore, aimed to provide a comprehensive overview of existing evidence on the administration of iNO after 7 days of life. It covers initiation criteria as well as dosage, duration, discontinuation criteria, concomitant use of other drugs and adverse effects.
Methods and analysis
Protocol and registration
The protocol of this scoping review was registered at UMIN-CTR (registration number: UMIN000051498) and was subsequently published.16 This review was conducted in compliance with the published protocol.
Eligibility criteria
This scoping review followed the Population-Concept-Context (PCC) framework outlined by the Joanna Briggs Institute (table 1, https://doi-org.ezproxy.u-pec.fr/10.46658/JBIMES-20-12). We defined the postacute phase as the late phase of primary hospitalisation, that is, after 7 days of life, based on the definition in previous nationwide surveys by Truog et al10 and Nakanishi et al.4 We employed the seventh day of life as the transition point to exclude premature infants suffering from PH of the newborn. Articles meeting the following eligibility criteria were included: (1) articles enrolling preterm infants born at <34 weeks of gestation and aged >7 days; (2) provision of clinical information on iNO usage; (3) publication between January 2003 and August 2023; (4) conducted in developed countries; (5) written in English or Japanese and (6) encompassing study designs such as RCTs, prospective and retrospective cohort studies, case–control studies and case series. We recruited preterm infants born at <34 weeks of gestation because we have focused on PH in the postacute phase in newborns, a complication primarily observed in extremely preterm infants. To maintain the focus of our review, we narrowed our inclusion criteria by excluding the late preterm infants born between 34 and 36 weeks of gestation, as they rarely develop PH in their postacute phase. The exclusion criteria were as follows: (1) participants with congenital malformation syndrome or chromosomal abnormalities; (2) animal and in vitro studies and (3) conference abstracts, trial registrations and protocol publications.
PCC framework of this scoping review
Information sources
We conducted searches across PubMed and Embase, as well as the Japanese electronic bibliographic database ‘Ichushi’. These searches were carried out by an accomplished librarian, supplemented by manual searches conducted by the authors. Given the paradigm shift in BPD to ‘new BPD’ highlighted by Jobe in 1999,17 alongside the advent of iNO in the clinical neonatology domain around 2000, we limited our search to studies published within the most recent two decades, spanning from January 2003 to August 2023. The search strategies are detailed in online supplemental appendix 1.
Supplemental material
Selection of sources of evidence
Our scoping review approach adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews Checklist (online supplemental appendix 2).18 The search results were deduplicated using EndNote V.20, and imported into Rayyan, a web application,19 to screen eligible studies. The authors (YM, MH, TN and SI) independently evaluated the titles and abstracts of the identified studies using the PCC framework to ascertain potential eligibility based on the inclusion criteria. Subsequently, a thorough full-text review of potentially eligible studies was performed. Any discrepancies regarding study eligibility were resolved through consensus discussion among the authors or adjudicated by another author’s (SK) assessment. The study selection process is illustrated in the PRISMA flow diagram in figure 1.
Supplemental material
Flow diagram showing the study selection process. From: Page et al.24
Data charting and synthesis of results
The characteristics of the included studies, including the study design, settings, populations, information regarding the provision of iNO therapy, efficacy of iNO therapy, complications and other relevant findings, were systematically summarised in a predesigned Excel form (tables 2–4).
Summary of the findings of the included studies
Initiation criteria for iNO in all of the included studies
Summary of the details of postacute iNO administration in preterm infants in the included studies
Critical appraisal of individual sources of evidence
Given the overarching objective of this scoping review to map existing evidence, an assessment of the risk of bias within the included studies was not undertaken.
Patient and public involvement
This study did not involve patients or members of the public, as only existing articles were analysed. However, neonatologists participated in the review process and discussed the results.
Results
Selection and characteristics of sources of evidence
A literature search was conducted on 1 February 2024, yielding 1518 records. Following deduplication, 393 duplicate records were removed. Subsequently, the remaining 1125 records underwent title and abstract screening, resulting in the exclusion of 999 records that did not meet the inclusion criteria. A full-text review of the remaining potentially eligible studies was subsequently performed, leading to the exclusion of an additional 117 citations. Notably, one relevant Japanese study published in 2012 was identified through a manual literature search and included in the review. Ultimately, 10 original records were included in this study. The findings of these included studies are summarised in table 2.
Synthesis of results
Initiation criteria for postacute iNO
The initiation criteria for postacute iNO are poorly described in the literature; one of the most critical initiation criteria is echocardiographic diagnosis of PH since NO acts specifically on pulmonary smooth muscle cells to decrease their tone, thus reducing pulmonary blood pressure. While the diagnostic criteria for PH are often poorly described in the literature, they are essential for the effective and safe administration of iNO in the postacute phase. Among three studies focusing on iNO prophylaxis for BPD, none reported the diagnostic criteria for PH due to the nature of the studies.8 9 11 However, in five studies examining the use of echocardiography to diagnose PH before iNO initiation, various criteria were reported.12–14 20 21 Specifically, four studies identified ventricular septal wall flattening or bowing in the end-systole or pulmonary artery (PA) pressure elevation as indicators of PH.12–14 21 Fraga et al further provided additional detailed echocardiographic findings for PH diagnosis, such as right-to-left shunting at the patent foramen ovale (PFO) or patent ductus arteriosus (PDA) level and the tricuspid peak velocity:right ventricular ejection time ratio, as markers for PA pressure elevation.14 Accurate diagnosis of nitric-responsive PH, excluding conditions including left ventricular dysfunction, is critical. Echocardiography performed by a neonatologist before iNO initiation, as well as other multiple diagnostic criteria, should be considered crucial for the accurate and effective diagnosis of PH.
To measure the severity of respiratory compromise, various measures have been used. Three studies employed the respiratory severity index (mean airway pressure×fraction of inspired oxygen),8 11 12 one used the OSI13 and two employed the oxygenation index.12 22 In out-of-concept studies, Hussain et al reported the use of echocardiography for PH diagnosis and noted echocardiographic findings, including flattened ventricular septum, tricuspid regurgitation (TR) and right-to-left shunt at the PFO/PDA level.12 They also reported a 60% reduction in iNO use following the implementation of a weaning protocol.
A summary of these findings is presented in table 3.
Details of postacute iNO administration
This section summarises details of the postacute iNO administration as outlined in the PCC framework, such as postnatal day of iNO initiation, dosage of iNO, duration of iNO therapy, discontinuation criteria of iNO therapy, concomitant use of other drugs and adverse effects.
The initiation day and duration of iNO administration varied widely, ranging from 2 to 314 days. The extended duration of iNO treatment may be attributed to its utilisation as a rescue therapy in postacute cases. Notably, three RCTs included a 24-day preprotocol dosing period.8 9 11 The criteria for discontinuation are not well described. Regarding RCTs,8 9 11 they were designated as protocol treatment. However, for rescue treatment, they probably could not be stopped.13 14 20–22 Additionally, for retrospective studies,4 10 it may not be possible to retrieve these data. Hussain et al implemented a weaning protocol at their institution and successfully reduced the total iNO hours from 149 hours to 59 hours; however, the study was excluded from our review because it did not align with the study concept.12
The starting dose of iNO ranged from 3 to 20 ppm, with four studies starting at 20 ppm8 9 11 20 and one study reporting a maximum dose of 80 ppm.20 Regarding adjunctive medications, reports involving the use of surfactants,11 13 20 inotropes,12 20 corticosteroids,13 bronchodilators14 and diuretics14 were included. RCTs did not report significant differences in adverse events or increases in complications related to preterm birth,8 9 11 which aligns with the findings of retrospective studies.4 12 13 21 22 However, one case of pulmonary oedema was reported after 48–168 hours of iNO administration, without evidence of left ventricle dysfunction based on echocardiography.14 A summary of these data is presented in table 4.
Studies investigating prophylactic iNO use for BPD
Three RCTs investigated the use of iNO administration to prevent the development of BPD.8 9 11 All of these studies were multicentre and involved a relatively large number of patients, ranging from 451 to 582. The findings of these included studies are summarised in table 2. All studies included in the analysis investigated survival without BPD as the primary outcome. Among them, only one study showed the efficacy of iNO within the treated group (relative benefit 1.23, 95% CI 1.01 to 1.51, p=0.042),8 while the remaining studies did not demonstrate improvement.9 11 None of the studies reported an increase in short-term outcomes or prematurity-associated comorbidities. Additionally, it is worth mentioning that although the study by Hasan et al enrolled newborns between 5 and 14 days of age, it did not specify when iNO therapy was initiated. Nevertheless, we included this study as it yielded significant findings, demonstrating no difference in respiratory or neurodevelopmental outcomes at 18–24 months postmenstrual age.20
Studies investigating rescue iNO use for HRF and PH
Seven studies focused on the use of iNO for rescue purposes. These studies comprised two database analyses,4 10 four retrospective cohort studies conducted in single tertiary centres,13 14 20 22 and one multicentre retrospective cohort study.21 Additionally, we included two retrospective reports in Japanese and summarised their results by extracting patient information that matched the study concept provided by the authors.21 22 The number of participants ranged from 12 to 462. A summary of these studies is presented in table 2. Among these studies, four reported worse respiratory outcomes, and four reported death before discharge. Oka et al13 noted a positive response to post-acute iNO, defined as a >20% reduction in the oxygen saturation index (OSI), when introduced earlier. They also found no difference in the incidence of in-hospital outcomes between responders and non-responders. Despite finding that two newborns received iNO treatment on day 6 of life and another on day 5, we included this study as the majority of the included newborns matched the inclusion criteria. Nakanishi et al4 reported in their retrospective cohort study using the Neonatal Research Network of Japan database that there was no increase in developmental outcome at 3 years of age following postacute iNO treatment. Fraga et al14 emphasised the importance of echocardiographic assessment of PH in infants with severe BPD before initiating iNO.
Discussion
Summary of evidence
In this scoping review, a comprehensive screening of the English and Japanese literature from three databases published over two decades yielded 1518 reports. These studies were meticulously screened by at least two independent reviewers, focusing on the use of postacute iNO for PH associated with BPD (BPD-PH) in preterm infants. Using the PCC framework, two distinct groups of reports were identified: one where iNO was used prophylactically to prevent the development of BPD later and another where iNO was used as a rescue therapy for preterm infants with BPD-PH.
Studies investigating prophylactic iNO use for BPD
In this subset of studies, patients were enrolled according to predefined protocols, with iNO administered as planned in terms of duration and dosage. While RCTs allowed for quantitative assessment, gathering clinical information on iNO use and associated complications or adverse events in preterm infants with BPD-PH posed challenges. One RCT published by Ballard et al8 demonstrated the effectiveness of postacute iNO in promoting survival without BPD, while two other studies did not show significant efficacy.9 11 Importantly, large prospective studies reported no adverse events with consistent iNO use.
Studies investigating rescue iNO use for PH
The seven reports in this category constituted the focal point of our review. These studies were retrospective in nature, primarily due to ethical constraints in conducting RCTs in patients with severe clinical courses, necessitating rescue treatment with iNO, especially given the lack of effective alternative therapies.
Among these studies, only a few have clearly described the indications for post-acute iNO use,12 14 with only three reports using echocardiography as a criterion for diagnosis of PH.13 14 21 However, the use of echocardiography as the gold standard for diagnosing PH varies among countries due to differences in available resources at the bedside.7 23 Nevertheless, to enhance the reliability of accumulated studies, quantitative evaluation using echocardiography is imperative and should be incorporated into the diagnostic criteria for BPD-PH developed in the postacute phase.
Employing large-scale multicentre studies or national data analyses, as demonstrated by Nakanishi et al,4 may help to overcome the challenges posed by the rarity of the study population and facilitate the acquisition of high-quality data.
Other findings
Among the studies mentioned above, we obtained valuable insights into clinical settings regarding the use of echocardiography as a diagnostic criterion for PH in the postacute phase, information on the parameters used in the diagnostic procedure, and the practical utilisation of iNO. Furthermore, we identified respiratory severity scores and OSI as potential surrogate parameters for assessing dyspnoea. Considering the rare reporting of complications and comorbidities associated with iNO use, the implementation of postacute iNO appears to be safe.
Gaps
This scoping review underscores that the utilisation of iNO to treat PH in the postacute phase primarily occurs for rescue purposes. However, reports focusing on rescue purposes were predominantly retrospective, potentially biasing the inclusion of severe cases that led to adverse outcomes following iNO therapy. Additionally, due to the severity of oxygen desaturation in BPD-PH or HRF stemming from various causes, iNO may be initiated prior to a detailed evaluation of the PH status. Alternatively, although neonatologists in Japan implement bedside diagnostic echocardiography prior to administering iNO, this protocol may not be universally adhered to in other developed countries due to logistical issues, even though it is critical for PH diagnosis. Moreover, the clinical settings were not explicitly identified in this review due to insufficient data collection in each report. Another critical issue is the inter-rater variability associated with echocardiography, which needs to be addressed before its widespread adoption as a standard test. It is essential to promote the use of comprehensive echocardiographic evaluation for PH before administering iNO. While identifying a simple and robust parameter may help streamline the process, it is crucial to consider a holistic approach that encompasses multiple diagnostic criteria to ensure an accurate and effective diagnosis.
Strengths and limitations
To our knowledge, this is the first scoping review to explore the use of iNOs in postacute settings. However, despite including some reports that did not fully align with our prespecified study concept, the information gathered on the diagnosis of PH was insufficient, leading to unsatisfactory results. The severity of PH associated with BPD alongside the heterogeneity within the population, such as gestational age or the timing of iNO introduction, even in large-scale studies, further complicates efforts to enhance the quality of evidence regarding postacute iNO administration. The failure to select patients with PH using echocardiography may be a key reason why the efficacy of postacute iNO administration has not been convincingly demonstrated, which is a critical issue, given that iNO is a selective vasodilator.
Furthermore, ethical challenges hinder patient recruitment for RCTs examining the efficacy of postacute iNO administration in patients with BPD-PH. Additionally, collecting comprehensive data, including diagnostic criteria for PH before iNO introduction in the postacute phase, poses significant challenges in retrospective studies, especially when conducted on a large scale. To address these challenges, it is crucial to conduct prospectively registered cohort studies at the national level or report valuable information from large-scale single-centre or multicentre studies. Notably, the low incidence of adverse events or complications associated with iNO use allows for a positive view regarding the introduction of postacute iNO in preterm infants.
Conclusion
This scoping review sheds light on the clinical settings and current utilisation of postacute iNO therapy. Our results showed that the available evidence is insufficient to firmly support the use of postacute iNO in treating infants with PH associated with BPD. Prospective studies with high-quality evidence are essential to address this knowledge gap. Additionally, given the severity and rarity of this disease, detailed retrospective studies are also warranted. We believe that accumulating evidence regarding the efficacy and safety of postacute iNO in preterm infants will pave the way for its appropriate utilisation as a promising gaseous agent in this population.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Acknowledgments
We wish to express our sincere gratitude to Kuniko Sato, a librarian at St. Luke's International University, for her invaluable assistance in establishing the search strategy. The authors are members of the Japan Society for Neonatal Health and Development and conducted this study as its representatives.
References
Footnotes
Collaborators Japan Society for Neonatal Health and Development.
Contributors SK and HN conceptualised this study. All authors (SK, YM, MH, TN, SI, KH, AO, TH, MM, FN, MO, AN, SY, DS, EO and HN) contributed to the scope and design of this review. DS and EO developed the search strategy through consultation with the medical librarian at St. Luke’s International University, KS. SK, YM, MH, TN and SI performed the screening, data charting and data synthesis. SK prepared the first draft, and all other authors provided substantial input for the development of the final version. DS and HN provided feedback on the methodology. All authors (SK, YM, MH, TN, SI, KH, AO, TH, MM, FN, MO, AN, SY, DS, EO and HN) have read and revised the draft and have approved the final version of the manuscript. SK is responsible for the overall content as guarantor.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. However, this study was supported by the Japan Society for Neonatal Health and Development.
Disclaimer The supporting society had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Competing interests None declared.
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.