Abstract
Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions.
Abstract
Better measures are needed to predict chronic respiratory morbidity in survivors born prematurely http://ow.ly/1L3n30ihq9C
Introduction
Premature birth is a significant cause of long-term respiratory morbidity, with many infants developing chronic respiratory complications. The most frequently used clinical predictor of long-term respiratory risk is the presence of bronchopulmonary dysplasia (BPD). The definition of BPD has changed considerably since the first histopathological definition of Northway et al. [1] in 1967 based on fibrosis, alveolar inflammation and dysplastic airways. In the post-surfactant and gentle ventilation era, these processes were rarely seen and chronic respiratory morbidity better reflected a disruption of lung growth, resulting in a combination of structural airways damage, failure of alveolarisation and vascular development, with resultant impairment of gas exchange [2]. Following broad international consensus, BPD was redefined to reflect the need for oxygen therapy beyond 28 days after birth [3]. As neonatal respiratory care become more refined, this BPD definition also failed to reflect the physiological consequences of preterm birth. In order to develop more interinstitutional consistency, in 2003 Walsh et al. [4] published a “physiological” definition of BPD standardising the determination of oxygen requirement at 36 weeks. In 2006, Quine et al. [5] tried to quantify the severity of gas exchange impairment, defining BPD as reduced ventilation/perfusion ratio. Despite the evolution of BPD from a histological to physiological clinical entity, common to all these definitions is a single resultant dichotomous diagnosis made near term-corrected gestation.
Over the past 50 years BPD has been used as a surrogate for identifying infants at risk of later respiratory morbidity. Consequently, BPD has become the primary respiratory outcome in the assessment of respiratory strategies adopted in neonatal intensive care units (NICUs). While medical advances, including artificial surfactant, antenatal corticosteroids, lung protective strategies of mechanical ventilation and noninvasive respiratory support techniques improve survival of extremely premature infants, BPD remains a major clinical problem with little change in prevalence over the past 20 years, suggesting that it may lack the precision to delineate the true differences in the long-term implications of modern NICU respiratory therapies [6].
Recently, a high incidence of respiratory morbidity in children born preterm, even in the absence of BPD, has been described [7–9]. Irrespective of BPD diagnosis, children born prematurely have altered lung function with at least partially reversible airflow obstruction (high airways resistance and gas trapping) and increased airway reactivity, but with little evidence of eosinophilic inflammation. Lung parenchymal abnormalities on thoracic imaging, hospital readmissions for respiratory problems and increased respiratory symptoms are common in preterm survivors [10–13]. The high incidence of later pulmonary morbidity among children born preterm, independent of a diagnosis of BPD, highlights the shortcomings of BPD as a surrogate for long-term pulmonary morbidity. The dichotomous nature of modern BPD definitions lacks the ability to describe the evolution of the functional and pathophysiological multifactorial continuous disease processes that increasingly clinicians are aware extend into childhood.
We contend that preterm lung disease represents a pathophysiological continuum requiring repeated evaluation throughout life. As such, BPD, a single time-based dichotomous measure of defining the long-term impact of preterm birth is inadequate. Sensitive and repeatable early-life measures of lung function and structure should inform outcomes of clinical interventions, allow identification of those at risk and follow lung development through childhood.
This review aims to provide a perspective from a literature review of 1) the long-term outcomes of neonatal respiratory therapies; and 2) the current state of neonatal respiratory assessment tools as outcome measures of chronic respiratory morbidity of prematurity.
Search strategy and selection criteria
References for this review were identified through PubMed searches using the terms “bronchopulmonary dysplasia”, “premature”, “prematurity”, “preterm”, “follow up”, “long term”, “respiratory outcomes”, “lung function”, “pulmonary imaging”, “ventilation”, “nasal continuous positive airway pressure” and “high flow nasal cannula”. Articles relating to the specific aims of the review and relevant references cited in those articles were reviewed. All authors repeatedly reviewed the entire manuscript until a consensus was reached. Articles published in English, French and Italian were included.
Long-term outcomes of neonatal respiratory therapies: lessons from literature
There have been many well-designed large clinical trials exploring different aspects of preterm respiratory management in early life. Generally, these studies have used death and/or BPD as the primary outcome measure, which may not inform clinicians accurately about the long-term implications of each therapy. This section summarises some of the major advances and controversies in the respiratory support of the preterm lung and describes whether the trial data allow interpretation of the long-term respiratory implications.
Oxygen and mechanical ventilation: predictors of long-term respiratory impairment?
It is well known that higher oxygen needs are associated with ventilator-induced lung injury, as well as directly inducing acute lung injury [2, 3]. Prolonged neonatal oxygen exposure has been identified as a prognostic indicator for subsequent long-term airway obstruction [14–16]. Duration of oxygen supplementation, especially if lasting >1 month, was associated with impairment of forced expiratory volume in 1 s (FEV1) in 10–18-year-old children and with respiratory resistance and reactance assessed using the forced oscillatory technique (FOT) in preschool children who had BPD [17]. Duration of oxygen exposure in neonatal life was found to be predictive of later pulmonary abnormalities on high-resolution computed tomography (HRCT) imaging [18].
Oxygen exposure requires consideration of dose as well as duration. Stevens et al. [19], using an area under the curve analysis of cumulative oxygen exposure, identified that the accumulated oxygen exposure at 72 h of life predicted respiratory symptoms and respiratory-related health service and medication use during infancy in a dose-dependent manner. This suggests that the dose of early-life oxygen supplementation, rather than its duration, may be a stronger and earlier prognostic respiratory predictor. A reproducible and simple to use oxygen cumulative score to indicate magnitude of injury, correlated to later respiratory function is needed.
Mechanical ventilation has an important role in early lung injury. Duration of mechanical ventilation, but not duration of oxygen supplementation, correlates with increased ventilation/perfusion mismatch (single photon emission computed tomography) at 37 weeks postmenstrual age in infants with BPD [20]. In later childhood, duration of mechanical ventilation is associated with reduced forced vital capacity, increased functional residual capacity and bronchial hyperresponsiveness [20–24].
Both oxygen supplementation and ventilator support have a strong link to long-term respiratory outcomes. However, current BPD definitions are limited to the duration of oxygen supplementation and mechanical ventilation, rather than oxygen dose or type mechanical ventilation.
High-frequency oscillatory ventilation: time for a well-designed study of long-term outcomes?
High-frequency oscillatory ventilation (HFOV) aims to correct atelectasis while minimising exposure to barotrauma/volutrauma, using subanatomical dead space tidal volumes, and thus was originally proposed as an effective method of reducing BPD. Despite 19 randomised controlled trials (RCTs) of first-intention HFOV in preterm infants and extensive meta-analyses, the theoretical lung protective potential of HFOV over conventional mechanical ventilation (CMV) has not been demonstrated [25, 26]. In many NICUs, HFOV is used as a rescue therapy rather than first-intention treatment. Rescue HFOV has only been evaluated in a single RCT [27]. The investigation of first-intention HFOV serves as an example of the complexity of neonatal respiratory trial interpretation. With >15 years between the early and later trials of HFOV, NICU care has changed considerably. Throughout this period CMV strategies, such as the availability of synchronisation and volume targeting, have improved, and it has become evident that mode of support is of lesser importance than how clinicians apply it. Favourable BPD outcomes from HFOV were only observed when HFOV was applied using a high lung volume approach, and only if CMV was not applied optimally [26].
Long-term respiratory outcomes have been reported from some trials (table 1). The HIFI (High-Frequency Ventilation in Premature Infants) trial, the first large RCT to compare CMV with HFOV in an era without antenatal steroids or surfactant, found no difference in BPD and mortality, but higher rates of air leak and intraventricular haemorrhage attributed to the low lung volume HFOV strategy [28]. There was no subsequent difference in respiratory morbidity and function or morbidity at 9 months, 2 years and 8–9 years in survivors [29–31]. A similar longitudinal finding was reported by Lista and colleagues [7, 32] in a more recent small cohort of infants followed-up to 7 years, in whom antenatal steroid exposure, prophylactic surfactant therapy and high lung volume HFOV were used.
Studies assessing short- and long-term respiratory outcomes of high-frequency oscillatory ventilation (HFOV) compared to conventional ventilation (CV) for acute pulmonary dysfunction in preterm infants
In contrast, the Provo multicentre high lung volume HFOV trial reported significantly less obstructive lung function and maldistribution of ventilation in 6-year-old children ventilated with HFOV during the neonatal period [33, 34]. It is possible that HFOV preserves small airway function better than CMV once long-term injury is established, with higher maximal flow at functional residual capacity observed at 12 months in a small series of infants with BPD [35]. More recently, the UKOS (United Kingdom Oscillatory Study) trial reported better small airway function and less airway obstruction in a cohort of 319 adolescent survivors randomised to a high lung volume HFOV strategy than those managed with CMV, although no difference in BPD was reported [36–39]. Prophylactic surfactant and antenatal steroids were well established in NICU practice when the UKOS trial was performed [40]. The trial was criticised for its pragmatic trial design, short duration (72 h) of HFOV use and lack of aggressive lung recruitment during HFOV [41]. A second, large HFOV trial with stricter ventilation strategies, high study compliance and longer durations of HFOV use showed a greater benefit of HFOV in reducing BPD, but did not report long-term outcomes [42]. Irrespective of this, the data from the PROVO and UKOS trials suggest that HFOV may confer long-term respiratory benefits that are not being realised with current reliance on BPD as an outcome.
Volume-targeted ventilation: still few data regarding long-term outcomes
Volume-targeted ventilation (VTV) is now widely used during CMV support of premature infants. There is a strong physiological rationale to limit excessive tidal volume exposure, and VTV achieves this by dynamically adapting to changing disease state [43]. Meta-analysis has shown that VTV reduces BPD, as well as survival without BPD, compared to support without VTV in preterm newborns [44–46]. Whether this benefit is a result of shorter duration of mechanical ventilation or a reduction in volutrauma exposure is unclear. Singh and co-workers [47, 48] reported that significantly fewer children required administration of inhaled steroids and/or bronchodilators at 2 years old if supported with VTV (table 2). Further studies are needed to confirm whether the physiological rationale of VTV in early life confers long-term respiratory benefits.
Study assessing long-term respiratory outcomes of volume-targeted ventilation versus pressure-controlled mechanical ventilation in preterm infants
Can BPD capture the respiratory consequences of early noninvasive ventilation?
Recent large longitudinal cohort data from Doyle et al. [8] found the same or worse lung function in 8-year-old ex-preterm children born in 2005 compared with those born in 1991 and 1997. Importantly, children in the more recent cohort were managed in an era of greater noninvasive ventilation (NIV). This raises the fascinating hypothesis that the early lung-protective effects of NIV may not confer protection from long-term respiratory impairment. Although early stabilisation with continuous positive airway pressure (CPAP) has demonstrated beneficial short-term outcomes, with reductions in death, BPD and important secondary respiratory outcomes [49, 50], its long-term efficacy has only been investigated in two follow-up studies of the large the COIN (Continuous Positive Airway Pressure or Intubation at Birth) and SUPPORT (Surfactant, Positive Pressure, and Oxygenation Randomized Trial) trials (table 3) [9, 50–52].
Studies assessing long-term respiratory outcomes of early noninvasive ventilation strategies in preterm infants
Both COIN and SUPPORT trials found that early CPAP did not significantly reduce the rate of death or BPD [50, 51]. In a single-centre subcohort study of the COIN trial, improved lung mechanics and decreased work of breathing at 8 weeks corrected age were found in the CPAP group [52]. In the Breathing Outcomes Study, a secondary study to SUPPORT, patients in the CPAP group had lower rates of several important respiratory morbidities at 18–22 months, including respiratory illnesses, treatment with oxygen or diuretics at home and overnight hospitalisation for breathing problems [9]. Despite observing no difference in the incidence of BPD, both COIN and SUPPORT follow-up studies found better long-term respiratory outcomes using early CPAP [9, 52]. In addition, Doyle et al. [8] reported a longer duration of oxygen therapy in the 2005 cohort, attributing this to a combination of NIV use and greater availability of oximetry monitoring. This may account for the differences of the protocolised NIV strategies in COIN and SUPPORT trials.
Surfactant: long-term efficacy beyond the NICU?
Exogenous surfactant replacement therapy has revolutionised the management of hyaline membrane disease [53]. While short-term effectiveness of surfactant treatment is well established, data on respiratory long-term outcomes remain evidence-poor (table 4). Initial long-term follow-up studies of surfactant therapy against placebo produced contradictory results, illustrating the limitation of small sample sizes [54–59]. Historical cohort comparisons of infants managed before (1980s) and after (1990s) the introduction of surfactant reported similar respiratory morbidity and function (airway obstruction, hyperresponsiveness and pulmonary hyperinflation) in childhood and early adulthood [60–63]. However, these trials studied children born when the surfactant replacement had just been introduced and other potentially beneficial therapies (VTV, HFOV and NIV) were not in routine use [60, 63]. Two large cohort follow-up programmes, the Victorian Infant Collaborative Study and that of Vollsæter et al. [64, 65], reported similar lung function in children who were born prematurely in 1991–1992 and 1997–2000. It is important to note that many of the infants born in 1997–2000 would not have survived if born in 1991–1992, suggesting that the combination of more protective ventilation approaches with near universal surfactant use had a positive effect. A recent meta-analysis of the neonatal respiratory outcomes between the pre- and the post-surfactant era found better FEV1 at school age and early adulthood of subjects born prematurely in the post-surfactant era, especially those with BPD [11, 66]. Furthermore, neonatal exogenous surfactant administration reduced respiratory hospitalisation within the first 3 years post-discharge [67].
Studies assessing long-term respiratory outcomes of surfactant treatment in preterm infants
Although it is likely that surfactant is beneficial to the preterm lung in the long term, it is unfortunate that longitudinal pulmonary function evaluation was not a feature of many surfactant trials. This would have allowed exploration of the mechanistic role of exogenous surfactant, specifically whether these benefits were due to alterations in lung growth or simply prevention of injury due to reduction in mechanical ventilation duration and need. This is especially important as less invasive surfactant therapy during NIV becomes more popular. Long-term pulmonary follow-up of less-invasive surfactant methods may provide valuable insight into whether surfactant function is altered during NIV.
The current state of neonatal respiratory assessment tools as outcome measures of chronic respiratory morbidity of prematurity
Despite the rationale for the use of childhood functional respiratory status, rather than BPD (by any diagnostic criteria), as the principal method of assessing the efficacy of neonatal respiratory therapies, traditional pulmonary function tests are impractical in neonates. Thus, new functional measures that can be performed in early life and then repeated during childhood, are urgently needed. Ideally such measurements would provide a standardised functional definition of pathological lung state that correlates with later respiratory morbidity, and at a resolution that would allow interrogation of the hypothesised differences between current respiratory therapies. Very early measures of the immature and developing airways of preterm infants need to delineate specific developmental lung states. The availability of such measures would benefit clinical trial design and offer potential to address the role of later life childhood respiratory events, such as respiratory infections and environmental factors, on lung growth and development.
A variety of clinical sequelae, functional tests and thoracic imaging methods have been proposed to assess later pulmonary outcomes in infants born prematurely. Many of these are based on techniques developed to capture and track early lung disease in other chronic paediatric pulmonary diseases, particularly cystic fibrosis and recurrent wheezing. Although the ability of specific tests to detect abnormalities varies according to the underlying disease pathophysiology, this common interest has led to furthering our understanding of respiratory outcome measures in preschool children generally [68].
Dynamic lung function tests
Objective dynamic physiological measures may have a key role in the early diagnosis of chronic respiratory morbidity in preterm patients, but measuring lung function in early life is challenging. The American Thoracic Society reviewed safe, feasible and potentially clinically useful lung function tests in preschool children in 2009–2010 [68]. The application to the clinical management of six lung function tests (infant raised-volume rapid thoracic compression and plethysmography, spirometry, specific airway resistance, FOT, the interrupter technique and multiple-breath washout) was reviewed in children aged <6 years with cystic fibrosis, BPD and recurrent wheeze. Spirometry, specific airway resistance and the interrupter resistance technique were identified as potentially useful methods for identifying obstructive lung disease, a feature of BPD. Plethysmography and raised-volume rapid thoracic compression may prove more insightful given the potential to measure trapped gas. FOT, which measures dynamic respiratory mechanics directly, offers a sensitive method of identifying disturbances of the more peripheral airways, but commercial infant systems are lacking. The utility of using multiple-breath washout techniques to quantify ventilation homogeneity in infants remains controversial [17, 68, 69]. Although insufficient evidence was found to recommend the incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of children affected with these diseases, the potential to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as research tools was recognised [68]. However, published evaluation of all these techniques in preterm preschoolers is very limited and further studies are needed to identify whether these methods are able to reliably identify the early prodromal features of chronic respiratory morbidity following preterm birth. The multimodal nature of preterm lung disease suggests that no single dynamic measure will be useful. A more appropriate approach may be to develop and evaluate a composite suite of measures.
Uncalibrated plethysmography techniques, such as respiratory inductance plethysmography [70], electromagnetic impedance plethysmography [71] and electrical impedance tomography (EIT) [72], have been used widely as research tools to evaluate the neonatal ventilator–lung interaction, and potentially guide respiratory care. Of these, EIT is the most established, and dedicated infant EIT systems have been developed recently [72, 73]. EIT is a noninvasive, radiation free and, importantly, continuous measure of multiple regional measures of tidal ventilation, end-expiratory and breathing pattern homogeneity [72]. EIT has been used widely to define short-term respiratory status of specific neonatal therapies, including NIV, HFOV, VTV and surfactant administration [74–79]. Recent international consensus guidelines [72], including standardised methodology, terminology and recommendations for use in infants and children during NICU and ambulatory care, offer the potential for EIT to be a powerful dynamic function tool, especially if combined with other methods of assessing ventilation homogeneity (multiple breath washout) and lung mechanics (FOT). As EIT can be performed independent of age, clinical care and without instrumentation of the respiratory system we would suggest that future studies using EIT in the NICU include longitudinal measurements.
Structural lung imaging
Structural lung abnormalities have been explored as long-term outcome measures in patients born prematurely. Chest HRCT is the most sensitive tool for assessing early structural lung abnormalities in infants with cystic fibrosis, and may predict risk of later symptomatic lung disease in preterm infants [80]. The association between abnormality on HRCT scans and the severity of lung function impairment has been demonstrated in preterm survivors. However, it is important to note important limitations of HRCT scanning in clinical practice, specifically radiation exposure and need for general anaesthesia in younger children [18, 80].
Magnetic resonance-based imaging (MRI), although traditionally considered not suitable to quantify lung disease, has been shown to detect abnormal lung structure and perfusion in young children with cystic fibrosis, without the need for a general anaesthetic. These results suggest that MRI may be suitable for non-ionising long-term respiratory monitoring from early childhood in preterm infants. Pulmonary MRI has been shown to reveal quantifiable abnormalities in premature patients; however, further validation studies are needed [81]. The alveolar structure itself can be observed by hyperpolarised helium MRI, which has demonstrated catch-up of alveolar structural growth following preterm birth [82].
Despite limited information, and often a lack of standardisation, chest imaging is already providing new insight into the nature and development of long-term respiratory function in children born prematurely. As our knowledge increases regarding the significance of structural lung imaging at different ages, there may be a role for routine scanning to determine prognosis and appropriate follow-up. Ideally structural assessment should be paired with functional measures.
Conclusion
Future trials of neonatal respiratory therapies should include long-term respiratory outcomes. However, both the techniques and the outcomes need to be standardised. Dynamic lung function tests offer the most potential for capturing the respiratory consequences of prematurity. It is unlikely that any one test will be robust or practical enough to serve all ages. A combination of methods, combined with intermittent imaging of structural lung growth and disease, would allow for meaningful assessment of neonatal novel therapies or prevention strategies, and offer the potential to titrate neonatal respiratory care individually for the best respiratory health outcomes.
Footnotes
Author contributions: F. Ciuffini developed the concept and wrote the first draft under guidance from C.F. Robertson and D.G. Tingay. All authors contributed to redrafting the manuscript including tables.
Conflict of interest: None declared.
Support statement: This study is supported by the Victorian Government Operational Infrastructure Support Program (Melbourne, Australia). D.G. Tingay is supported by a National Health and Medical Research Council Clinical Career Development Fellowship (Grant ID 11123859). Funding information for this article has been deposited with the Crossref Funder Registry.
Provenance: Submitted article, peer reviewed.
- Received September 20, 2017.
- Accepted January 31, 2018.
- Copyright ©ERS 2018.
ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
References
