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Investigation and management of the long-term ventilated premature infant
Early Human Development xxx (xxxx) xxx–xxx
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Investigation and management of the long-term ventilated premature infant M.F.A. Wright, C. Wallis
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Department of Respiratory Paediatrics, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK
A R T I C LE I N FO
A B S T R A C T
Keywords: Prematurity Chronic lung disease Long-term ventilation Tracheostomy
Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, and despite significant advances in neonatal care over recent decades its incidence has not diminished. Although most affected infants have mild disease requiring a short period of oxygen supplementation or respiratory support, severely affected infants can become dependent on positive pressure support for a prolonged duration. In such cases, investigations should be carried out to ascertain whether there are secondary disease processes exacerbating the child’s respiratory status. In case of established severe BPD, respiratory support with non-invasive or invasive positive pressure ventilation is required. In this paper we discuss the indications for, and practicalities of, the various modalities available. Potential cardiorespiratory sequelae of BPD include recurrent respiratory infections, childhood wheezing illnesses, abnormalities of lung structure and function, and pulmonary hypertension.
1. Introduction A common reason for seeking a respiratory specialist opinion in the neonatal unit is for the ex-preterm infant with bronchopulmonary dysplasia who is unable to wean from respiratory support. This problem can lead to a protracted hospital admission far beyond expected for a preterm infant, who would generally be discharged home without respiratory support by the time they are term corrected gestational age (CGA). This paper reviews the various reasons for long-term ventilatory support (LTV) in premature infants, approach to investigation and management, and the long-term outcomes. 2. Defining BPD When first described in 1967, the name bronchopulmonary dysplasia (BPD) was given to the clinical scenario of premature infants with severe respiratory distress syndrome (RDS) remaining hypoxic and dependent on supplementary oxygen at 28 days of life and demonstrating typical chest radiograph changes [1]. This definition has evolved over time due to increasing survival of extremely preterm and very low birthweight infants, amongst whom an oxygen requirement at 36 weeks postmenstrual age was found to be more predictive of longterm pulmonary outcomes [2]. In 2001, the United States National Institute of Child Health and Human Development (NICHD) modified this definition further to include a BPD severity category and stratification according to the infant's gestational age at birth (Table 1) [3]. These criteria are now widely used by healthcare professionals for the
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diagnosis of BPD. However, it should be noted that although the NICHD definition more accurately predicts pulmonary outcomes, including the need for medications and likelihood of rehospitalisation, at 18–22 months CGA than its predecessors [4], it does not correlate with results of pulmonary function testing at 8–10 years of age [5,6]. 3. Epidemiology BPD is the most common chronic lung disease of infancy, with up to 10,000 new cases seen in the USA each year. Recent studies indicate an incidence of 32–59% amongst infants born at ≤28 weeks gestation, depending on the definition of BPD used [7]. Incidence is inversely proportionate to gestational age and higher amongst infants with intrauterine growth restriction (IUGR), with infants born at < 1250 g accounting for 97% of cases [8]. The incidence of BPD has changed little over recent decades despite advances in neonatal medicine over this period. The continued high prevalence of BPD may be in part to its changing pathogenesis and the improved survival of infants with extremely low gestational age and birth weight. 4. Pathogenesis BPD develops due to a combination of genetic predisposition and environmental factors, and most commonly affects premature infants due to the increased susceptibility of the immature lung to infective and mechanical insults which lead to an inflammatory response. Historically, BPD was attributed to a proinflammatory state
Corresponding author. E-mail addresses: [email protected] (M.F.A. Wright), [email protected] (C. Wallis).
https://doi.org/10.1016/j.earlhumdev.2018.08.015
0378-3782/ © 2018 Elsevier B.V. All rights reserved.
Please cite this article as: Wright, M., Early Human Development, https://doi.org/10.1016/j.earlhumdev.2018.08.015
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Table 1 Bronchopulmonary dysplasia diagnostic criteria. (Adapted from Jobe et al. [3]). Gestational age
< 32 weeks
≥32 weeks
Time point of assessment
36 weeks PMA or discharge home, whichever comes first Treatment with > 21% O2 for at least 28 days, plus: Breathing room air at 36 weeks PMA or discharge, whichever comes first Need for < 30% O2 at 36 weeks PMA or discharge, whichever comes first Need for ≥30% O2 and/or positive pressure (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first
> 28 days but < 56 days postnatal age or discharge home
Mild BPD Moderate BPD Severe BPD
Breathing room air by 56 days postnatal age or discharge, whichever comes first Need for < 30% O2 at 56 days postnatal age or discharge, whichever comes first Need for ≥30% O2 and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge, whichever comes first
Abbreviations: BPD = bronchopulmonary dysplasia; NCPAP = nasal continuous positive airway pressure; PMA = postmenstrual age; PPV = positive pressure ventilation.
In each case, an investigation pathway should be developed that targets the most likely diagnosis based on the child's history and clinical features. However, it should be noted that whilst most of the conditions that may mimic BPD are rare and the presence of a second unrelated disease process is relatively unusual, the conditions we describe as potential exacerbating factors in Table 2(a) are collectively very common in preterm infants and should generally be the initial focus of further investigation (Fig. 1). Prevention of BPD development is the subject of extensive research and beyond the scope of this article. Areas of interest include: (a) antenatal management, (b) use of endotracheal surfactant, (c) non-invasive respiratory support in the early neonatal period, (d) the role of medications such as vitamin A and corticosteroids.
resulting from oxygen toxicity, ventilator-induced lung injury, and shearing injury to alveoli resulting from surfactant deficiency. The resulting high levels of proinflammatory cytokines and growth factors (e.g. IL-1, IL-6, ICAM-1, TNF-α and TGF-β) ultimately lead to fibrosis of lung parenchyma and small airways. Cases resulting from these insults are now regarded as ‘old BPD’. Over recent years there has been an apparent change in the pathogenesis of BPD due to advances in the early management of preterm infants, including the introduction of antenatal steroids and endotracheal surfactant, increased use of noninvasive ventilation (NIV) in the delivery room, and a less aggressive approach to mechanical ventilation. A different clinical picture described as ‘new BPD’ has now emerged, in which the main aetiological factor is a developmental disorder of lung growth resulting from extreme prematurity. Lung growth abnormalities are typified by fewer numbers of large, oversimplified alveoli and a smaller total surface area for gas exchange. Compared to ‘old BPD’ the airways are relatively spared with less smooth muscle hypertrophy and fibrosis. As development of the pulmonary vasculature is also affected, pulmonary hypertension frequently coexists with ‘new BPD’.
6. Management of LTV-dependent BPD Management of LTV-dependent BPD can be considered as having 3 separate components: 1. Provision of long-term ventilatory support to infants with BPD 2. Management of exacerbating comorbidities 3. Potential medical therapies
5. Diagnosis and investigation The diagnosis of BPD is made clinically, usually based on the definition proposed by the NICHD (Table 1). As well as a persistent requirement for respiratory support, affected infants typically have a history of significant prematurity or IUGR with examination findings including tachypnoea and the use of accessory muscles of respiration. Bilateral reticulo-nodular opacifications and hyperinflation are common chest radiograph features. No biomarkers have yet been identified that can reliably predict which preterm infants will be affected. Proposals that BPD diagnosis should be based on physiological tests such as a 60-min room air challenge have not been widely adopted [9,10]. In typical cases of mild to moderate BPD, additional investigations are not necessary and weaning of respiratory support and oxygen supplementation is achieved as the child grows. In infants with an atypical presentation or clinical course, further investigation may be required to identify any factors that might be exacerbating their lung disease (Table 2(a)) and to rule out other conditions that might be masquerading as, or coexisting with, BPD (Table 2(b)). Our institutional practice is to investigate children who meet any of the following criteria:
6.1. Long-term ventilatory support of infants with BPD In each case of BPD, the goals of the clinician should be to stabilise the child on the least invasive mode of respiratory support that will achieve acceptable gas exchange, to prevent the development of treatment related side effects, and to wean the child from respiratory support as soon as this can be safely achieved. Various methods of respiratory support exist, and their individual frequency of use varies considerably between treatment centres [11]. Our suggested approach to respiratory management is summarised in Fig. 2. 6.1.1. Non-invasive positive pressure In recent years, NIV has become widely used to facilitate weaning of infants with BPD from mechanical ventilation and prevent the recurrence of respiratory failure necessitating reintubation. Continuous positive airway pressure (CPAP) involves the delivery of a constant distending pressure to the airways to maintain alveolar inflation and prevent atelectasis. Intermittent positive pressure ventilation (IPPV) superimposes an intermittent peak pressure on CPAP at a set respiratory rate which, depending on the ventilator used, can be synchronised with the infant's spontaneous breaths. In neonates and small infants, NIV is delivered via a nasal mask or prongs, whereas in the larger infant a fullface mask can also be used. Studies of NIV in preterm infants consistently show advantages of IPPV over CPAP, including reduced rates of respiratory failure, reduced need for intubation or surfactant administration, and earlier hospital discharge [12,13]. However, there are no apparent differences in rates
1. Infants who remain dependent on positive pressure support at term CGA. 2. Infants who have a persistently high supplementary oxygen requirement over time. 3. Infants with atypical clinical features (Table 3). 4. Infants with respiratory compromise disproportionate to their degree of prematurity and postnatal age.
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Table 2 Conditions that can exacerbate underlying BPD. a. Conditions more common in the premature infant • • • • • •
Gastro-oesophageal reflux with aspiration lung disease Incoordinate swallow with aspiration lung disease Airway malacia Subglottic stenosis following intubation Congenital heart disease e.g. patent ductus arteriosus, pulmonary vein stenosis Pulmonary hypertension
b. Dual pathologies that may coexist with and exacerbate BPD Lung parenchyma
Interstitial lung disease (ILD) e.g. surfactant dysfunction disorders Lung growth abnormality e.g. pulmonary hypoplasia, Trisomy 21 Primary ciliary dyskinesia Cystic fibrosis Upper airway lesions e.g. laryngeal web or cleft, complete tracheal rings Compressive vascular lesions e.g. vascular ring or sling Immunodeficiency Neuromuscular weakness e.g. congenital myopathy, metabolic or mitochondrial diseases Congenital heart disease e.g. atrial septal defect (ASD), transposition
Airways Non-respiratory
young infants is 6–8 L/min. Its main perceived advantages over NIV are that the interface is simpler to apply, less likely to cause skin trauma, and better tolerated [15]. A 2016 Cochrane review found HFNC to be comparable to other forms of non-invasive support for initial management of preterm infants with RDS, with no differences in rates of treatment failure, reintubation or BPD, and reduced rates of nasal trauma and pneumothorax. Two studies reported reduced duration of hospital admission when weaning off HFNC compared to CPAP [16]. Although HFNC is becoming more readily available in the home setting, it must be delivered from a fixed source and no portable device is currently available. As such, it is appropriate for nocturnal use only, and eligible infants should be stable on supplementary oxygen or without any respiratory support during the daytime. To date no highquality studies have been published that guide how best to wean preterm infants from HFNC, as highlighted by a recent Cochrane review [17], but current common practice is to reduce flow rates by 0.5–1 L/ min every 24 h to a minimum flow of 2–3 L/min [14]. HFNC is a useful intervention for infants experiencing complications from long-term use of a face or nasal mask, or who become intolerant of NIV as they grow older but have impaired gas exchange when receiving only supplementary oxygen. However, a common scenario we see is that infants become dependent on continuous HFNC after ‘stepping down’ from NIV and do not tolerate further weaning. This often reflects the development of atelectasis due to the delivery of lower airway pressures than achieved with NIV, and paradoxically the best treatment approach is to reintroduce nocturnal NIV to re-recruit alveoli and increase the child's respiratory reserve during waking hours (Fig. 2).
Table 3 Examples of clinical features warranting further investigation. Respiratory
Non-respiratory
Stridor or abnormal cry (e.g. hoarse, weak) Wheeze Coughing or desaturation with feeds
Dysmorphic features
Recurrent cyanotic episodes Central hypoventilation
Heart murmur Neuromuscular weakness disproportionate to CGA Skeletal dysplasia
of BPD or death between the two approaches. Complications of long-term NIV relate mainly to prolonged use of a face or nasal mask which can lead to skin trauma, midfacial hypoplasia, and neurodevelopmental delay by acting as a physical barrier to social interaction. Another associated risk is pulmonary aspiration caused by vomiting whilst wearing a face mask. Risk of vomiting is increased when using NIV due to gaseous distension of the stomach. NIV should only be considered suitable for long-term use if the child is stable without respiratory support or in low-flow oxygen when awake and requires NIV only during sleep (‘nights and naps’) for a maximum of 16 h per 24-h day. To minimise aspiration risk, enteral feeds, whether oral or via feeding tube, should ideally be coordinated with breaks rather than given overnight or when the child is unsupervised. In infants with RDS, stopping CPAP abruptly rather than gradually introducing breaks off support (‘cycling’) shortens weaning time and total CPAP duration [12]. However, in infants requiring long-term NIV for established BPD there is no consensus on the best approach to weaning. Our approach is to cycle off support whilst the infant is awake (e.g. starting with a 30-min break 2–3 times per day and gradually increasing the duration of each break), without weaning ventilator pressures, until the child is clinically stable on a ‘nights and naps’ or ≤16 h/day regimen. Depending on the child's history and clinical status, decisions about weaning pressures and ultimately stopping night-time support can then be made either empirically or based on sleep study findings.
6.1.3. LTV via tracheostomy Most preterm infants requiring mechanical ventilation can be weaned onto non-invasive respiratory support or supplementary oxygen after a period of days to weeks. However, a small proportion of infants with severe BPD, especially those with coexisting airway abnormalities, will remain dependent on invasive ventilation or continuous NIV. In such cases, long-term invasive ventilation via tracheostomy may be appropriate. Before referring for tracheostomy it is reasonable to give a trial of low-dose systemic steroids, despite their recognised side effects, in a final attempt to facilitate extubation or weaning. Addressing the exacerbating factors highlighted in Tables 2 and 3 are an imperative part of the decision to tracheostomise. The incidence of tracheostomy placement in preterm infants varies significantly between institutions, ranging from 3.5–14% in published retrospective studies [18–20]. Decisions about timing of tracheostomy placement in severe BPD are challenging and largely non-evidence
6.1.2. High flow nasal cannula therapy Heated, humidified high flow nasal cannula (HFNC) therapy has recently become a popular mode of providing non-invasive respiratory support to infants and children. Its use in the United Kingdom increased from 56% to 87% of neonatal units between 2012 and 2015 [14]. Positive airway pressure is administered via nasal prongs which sit below and external to the nares. The typical flow rate required in neonates and 3
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Fig. 1. Example of an investigative pathway for the LTV dependent premature infant.
carers from the local clinical commissioning group, training carers and family members in tracheostomy management and LTV delivery at home, and ensuring that suitable housing is available. Based on our local data, this process takes a median of 8 months [22]. One approach, based on the above information, is to consider tracheostomy placement for infants with severe BPD in whom (1) efforts to wean from mechanical ventilation using non-invasive methods of respiratory support have proved unsuccessful by term CGA, (2) all common exacerbating factors have been explored and treated, (3) neurocognitive function has been established, and (4) the parents understand and accept the practicalities involved, including prolonged hospital admission and long-term presence of carers in the family home.
based. There is some evidence that earlier tracheostomy insertion (age < 120 days) improves neurodevelopmental outcomes, but this must be balanced against the risk of unnecessary tracheostomy insertion if insufficient time has been spent trying to wean the infant from mechanical support [18]. No correlation has been found between timing of tracheostomy insertion and total duration of mechanical ventilation or time to successful decannulation [21]. Another factor to consider is the impact of tracheostomy insertion on the family. Although the surgery itself is generally straightforward, infants require prolonged hospital stays whilst discharge planning is undertaken and necessary measures are put in place for provision of LTV at home. In the UK, this involves obtaining funding for a team of 4
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Fig. 2. Suggested ventilatory pathway for the LTV dependent premature infant.
which must be closely monitored and has potential for serious side effects, and the finite survival of transplanted lungs. The family should also be made aware that, due to the scarcity of donor lungs suitable for infant recipients, children can spend many months or years waiting for a suitable donor organ and some will never undergo transplant surgery.
6.1.4. Bilateral lung transplant BPD is a rare indication for lung transplantation, due in part to its natural history for improvement over time and in part to the technical challenges and scarcity of suitable donor lungs that makes infant lung transplant for any indication rare. However, a very small subgroup of infants with severe BPD, almost invariably tracheostomy ventilated, may warrant referral for transplant assessment. Reasons to consider transplant referral include severe pulmonary arterial hypertension refractory to medical therapy or escalating ventilatory requirements over time. The latter can occur in infants with severe BPD due to postnatal alveolar growth being insufficient to meet the gas exchange requirements of the child's growing body. In effect, the child ‘outgrows’ their own lungs, often at around 9 months to 1 year of age. Relative contraindications include renal insufficiency, severe growth failure, and poor neuro-cognitive functioning. A fundamental component of assessing suitability for transplant is ensuring that the family are psychologically prepared for, and clearly understand the implications of being listed for surgery. Important discussion points include the various early and late complications of organ transplantation, the need for life-long immunosuppression therapy
6.2. Management of exacerbating comorbidities Various conditions can coexist with BPD in preterm infants and worsen the child's respiratory status (Table 2). These comorbidities should be actively sought as their treatment will often enable an infant apparently dependent on LTV to be weaned. 6.2.1. Gastro-oesophageal reflux and incoordinate swallow Although it is unclear whether there is a causal relationship between BPD and gastro-oesophageal reflux (GOR), the two conditions have shared risk factors including prematurity and intragastric tube feeding and frequently coexist. As preterm infants, particularly those with neurodevelopmental delay, have immature pharyngeal swallowing reflexes and oesophageal motility, an ‘unsafe’ swallow can result 5
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hospitalisation and duration of hospital admission in infants with BPD [29].
which puts them at risk of aspirating oral intake or refluxed liquid. The risk of reflux-aspiration is further increased in LTV dependent preterm infants due to gastric distension by positive pressure ventilation. This risk can be reduced by treating symptomatic infants, or those with positive GOR investigations, with anti-reflux medications and consulting a speech and language therapist before introducing oral feeds. In cases of severe reflux-aspiration refractory to medical therapy, surgery (e.g. Nissen fundoplication) should be considered as a means of protecting the lungs.
6.3.1.2. Azithromycin. Azithromycin prophylaxis is commonly prescribed for children with a history of frequent respiratory illnesses. It has been hypothesised that its ability to down-regulate cytokine production during viral illnesses may be of benefit to infants with BPD, and it is currently the target for experimental studies [30]. 6.3.2. Postnatal corticosteroids Early administration of systemic corticosteroids to ventilated preterm infants reduces their risk of developing BPD and facilitates extubation. However, their use is limited by an increased risk of severe adverse outcomes including cerebral palsy, retinopathy of prematurity, and gastrointestinal bleeding or perforation. Based on this risk factor profile, the routine use of steroids in preterm infants is not recommended and decisions about treatment in LTV-dependent infants should be made on a case-by-case basis. Inhaled steroids have been proposed as a means of minimising systemic effects and are effective in reducing rates of BPD. However, increased mortality rates have been reported and their effect on neurodevelopment has not yet been established [31].
6.2.2. Pulmonary hypertension Pulmonary hypertension (PH) is reported in up to a quarter of all infants with BPD, and up to 40% of those with severe BPD [11,23]. Prevalence is inversely proportionate to gestational age and birth weight and is increased in infants with structural cardiac abnormalities. Diagnosis of PH is associated with a significantly longer duration of respiratory support and increased mortality risk [24]. Its initial management involves optimising gas exchange, avoiding hypoxia, and treating coexisting reflux-aspiration or structural cardiac defects. In severe cases refractory to these measures, pulmonary vasodilator therapy (e.g. sildenafil) may be considered, although the efficacy of vasodilator therapy in PH secondary to lung disease is debatable.
6.3.3. Diuretics The role of diuretics in BPD is controversial; although their use in BPD can facilitate weaning from respiratory support, they have not been found to improve other clinical outcomes including total duration of respiratory support, and they place the infant at risk of electrolyte imbalance which can contribute to growth failure.
6.2.3. Structural cardiac disease Preterm infants are more than twice as likely to have a cardiac malformation as term infants, which contributes to their increased risk of PH [25]. In LTV-dependent infants, treatment may lead to improvement of respiratory status. Small case series of transcatheter device closure of atrial septal defects in preterm infants with lung disease report improved PH and reduced supplementary oxygen requirement [26]. 80% of infants born at ≤28 weeks will have a patent ductus arteriosus (PDA) at 4 days of age. Although many remain asymptomatic or close spontaneously, medical or surgical closure is commonly performed in preterm infants as prolonged patency is associated with higher rates of BPD development, PPV requirement and death. However, improved outcomes following routine PDA closure have not been demonstrated. Surgical PDA ligation has, in fact, been identified as an independent risk factor for BPD, as well as carrying a risk of other respiratory complications including chylothorax and vocal cord paralysis [27]. These risks lessen when ligation is delayed, suggesting that a ‘watch and wait’ approach to PDA management should be adopted in the stable preterm infant with BPD. Pulmonary vein stenosis (PVS) is an increasingly well recognised abnormality for which prematurity appears to be a major risk factor. In many cases affected infants have a normal echocardiogram at birth, so a high index of suspicion and serial investigation with ultrasound and/or cardiac catheterisation is required for diagnosis. PVS carries a high mortality rate which is largely attributable to the development of severe PH. A mortality rate of 50% is reported for coexisting PVS and BPD, which is higher than described when BPD and PH coexist in the absence of PVS. Unfortunately, this condition responds poorly to the available management options, and transcatheter balloon dilatation appears to offer only short-term benefit [28].
6.3.4. Vitamin A supplementation Vitamin A has been investigated as a therapeutic target as it is required for normal lung development and preterm infants are often deficient. A small reduction in BPD risk has been demonstrated from intramuscular administration to infants with birth weight < 1000 g, but with no effect on durations of mechanical ventilation or hospital admission [32]. Its painful route of administration, the need for multiple dosing, and an increased risk of sepsis are potential barriers to its use. Studies of oral supplementation are underway. 6.3.5. Caffeine Caffeine is a respiratory stimulant which has a well-established role in the management of apnoea of prematurity and can facilitate weaning from mechanical ventilation. A 37% reduction in BPD development has been reported following early caffeine treatment, which may relate to a reduced likelihood of requiring mechanical ventilation. Reduced rates of death of neurodevelopmental disability at 18 months, but an increased risk of necrotising enterocolitis, are also described [33]. 7. Outcomes for preterm infants requiring LTV The outcome data for premature infants with BPD requiring LTV can be considered in two ways: 1. The timing and likelihood of weaning off all ventilatory support with lung growth in this group of children. 2. The long-term cardiorespiratory sequelae in those children able to wean off all support.
6.3. Medical therapies 6.3.1. Prevention of respiratory exacerbations Children with BPD are particularly susceptible to severe respiratory illnesses that in some cases can lead to respiratory failure or death. An important component of their management and follow-up after hospital discharge is reducing the risk of such events.
7.1. Weaning off ventilatory support The natural history of BPD is for improvement with lung growth as the child grows, enabling gradual weaning from respiratory support in most cases. Very limited data exist regarding the duration of non-invasive LTV in infants with severe BPD or the likelihood of an eventual successful wean. In terms of LTV via tracheostomy, a study from our
6.3.1.1. Anti-RSV prophylaxis. Monthly administration of respiratory syncytial virus (RSV) humanised monoclonal antibody during the winter viral season leads to a significant reduction in RSV-related 6
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8. Summary
centre found that the median duration of home ventilation prior to tracheostomy decannulation was 1.7 years [22]. A study of 165 tracheostomy ventilated infants in the USA reported a median duration of 12 months from tracheostomy insertion to PPV independence and 1.3 years from tracheostomy insertion to decannulation amongst infants with birth weight ≤ 1000 g (of whom 95% had BPD) [34]. Readiness for weaning of LTV is best assessed using serial sleep studies which include continuous measurement of CO2. Direct visualisation of the airway (e.g. with microlaryngobronchoscopy) should also be performed prior to decannulation to rule out acquired anatomical abnormalities. Unfortunately, infants with BPD have a higher mortality than preterm infants without clinically significant lung disease, and some infants with severe BPD will die without ever weaning from LTV. Deaths are usually attributable to respiratory failure, pulmonary hypertension or respiratory infection. Poorer survival rates are seen amongst infants with the greatest disease severity, small for gestational age infants, and those with pulmonary hypertension [35]. The prematurity and respiratory outcomes (PROP) study reported 27 deaths from a primary respiratory pathology at between 2 weeks chronological age and 40 weeks CGA, indicating a BPD-attributable mortality rate of 6–11% depending on the definition of BPD used [7]. This accounted for 43% of all postnatal deaths in their cohort. Similar mortality rates of 6–20% have been reported amongst tracheostomy ventilated infants with BPD, and sadly death from respiratory failure can still occur after months of apparent stability.
BPD is a common complication of prematurity which can lead to prolonged hospital admissions and LTV dependency. Respiratory support should be delivered using the least invasive approach that achieves adequate gas exchange, and with the goal of preventing the development of complications (e.g. skin trauma, pulmonary hypertension). Despite the now widespread use of NIV in preterm infants with BPD, there is a limited evidence base to guide weaning strategies or inform long-term prognosis, and these areas should be a target for future research. Disclosures The authors have no conflicts of interest or disclosures regarding this manuscript. References [1] W.H. Northway Jr., R.C. Rosan, D.Y. Porter, Pulmonary disease following respiratory therapy of hyaline-membrane disease. Bronchopulmonary dysplasia, N. Engl. J. Med. 276 (7) (1967) 357. [2] A.T. Shennan, M.S. Dunn, A. Ohlsson, et al., Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period, Pediatrics 82 (4) (1988) 527. [3] A.H. Jobe, E. Bancalari, Bronchopulmonary dysplasia, Am. J. Respir. Crit. Care Med. 163 (2001) 1723. [4] R.A. Ehrenkranz, M.C. Walsh, B.R. Vohr, et al., Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. National Institutes of Child Health and Human Development Neonatal Research Network, Pediatrics 116 (6) (2005) 1353. [5] E. Kaplan, E. Bar-Yishay, D. Prais, et al., Encouraging pulmonary outcome for surviving, neurologically intact, extremely premature infants in the postsurfactant era, Chest 142 (3) (2012) 725–733. [6] S. Cazzato, L. Ridolfi, F. Bernardi, et al., Lung function outcome at school age in very low birth weight children, Pediatr. Pulmonol. 48 (8) (2013) 830–837. [7] B.B. Poindexter, R. Feng, B. Schmidt, et al., Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program, Ann. Am. Thorac. Soc. 12 (12) (2015) 1822–1830. [8] P. Bowen, N.C. Maxwell, Management of bronchopulmonary dysplasia, Paediatr. Child Health 24 (1) (2014) 27–31. [9] M.C. Walsh, D. Wilson-Costello, A. Zadell, et al., Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia, J. Perinatol. 23 (6) (2003) 451–456. [10] N.L. Maitre, R.A. Ballard, J.H. Ellenberg, et al., Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach, J. Perinatol. 35 (5) (2015) 313–321. [11] M.C. Guaman, J. Gien, C.D. Baker, et al., Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia, Am. J. Perinatol. 32 (10) (2015) 960–967. [12] G. Lista, F. Castoldi, P. Fontana, et al., Nasal continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in preterm babies with respiratory distress syndrome: a randomised control trial, Arch. Dis. Child. Fetal Neonatal Ed. 95 (2010) 85–89. [13] B. Lemyre, M. Laughon, C. Bose, P.G. Davis, Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants, Cochrane Database Syst. Rev. 12 (2016) CD005384. [14] S. Shetty, A. Sundaresan, K. Hunt, et al., Changes in the use of humidified high flow nasal cannula oxygen, Arch. Dis. Child. Fetal Neonatal Ed. 101 (2016) F371–F372. [15] B.J. Manley, Nasal high-flow therapy for preterm infants: review of neonatal trial data, Clin. Perinatol. 43 (4) (2016) 673–691. [16] Wilkinson, C. Andersen, C.P.F. O'Donnell, et al., High flow nasal cannula for respiratory support in preterm infants, Cochrane Database Syst. Rev. 2 (2016) CD00640. [17] R.C. Farley, J.L. Hough, L.A. Jardine, Strategies for the discontinuation of humidified high flow nasal cannula (HHFNC) in preterm infants, Cochrane Database Syst. Rev. 6 (2015) CD011079. [18] S.B. DeMauro, J.A. D'Agostino, C. Bann, et al., Developmental outcomes of very preterm infants with tracheostomies, J. Pediatr. 164 (6) (Jun 2014) 1303–1310. [19] K. Murthy, R.C. Savani, J.M. Lagatta, et al., Predicting death or tracheostomy placement in infants with severe bronchopulmonary dysplasia, J. Perinatol. 34 (7) (Jul 2014) 543–548. [20] K.D. Pereira, A.R. MacGregor, C.M. McDuffie, R.B. Mitchell, Tracheostomy in preterm infants: current trends, Arch. Otolaryngol. Head Neck Surg. 129 (12) (2003) 1268–1271. [21] J. Cheng, J. Lioy, S. Sobol, Effect of tracheostomy timing in premature infants, Int. J. Pediatr. Otorhinolaryngol. 77 (11) (2013) 1873–1876. [22] E. Edwards, M. O'Toole, C. Wallis, Sending children home on tracheostomy dependent ventilation: pitfalls and outcomes, Arch. Dis. Child. 89 (3) (Mar 2004) 251–255.
7.2. Long-term cardiorespiratory sequelae of BPD 7.2.1. Respiratory Hospital readmission is common amongst preterm infants after discharge from the NICU, with respiratory disorders accounting for up to half of readmissions in the first 2 years of life. Infants with BPD are twice as likely to be re-hospitalised compared to preterm infants without lung disease [36,37]. The majority of these respiratory illnesses, which can be severe or even life threatening, are caused by viruses like RSV and occur during the child's first winter after NICU discharge. Individuals with BPD are subsequently more likely to suffer from recurrent wheezing episodes during early childhood. Compared to asthmatic children without a history of BPD, children with BPD are more likely to have neutrophilic airway inflammation, lower values of exhaled nitric oxide, and reduced response to inhaled β2 agonists [38]. Although respiratory symptoms generally improve over time, pulmonary function abnormalities often persist into adulthood even in the absence of symptoms. Fixed airway obstruction, air trapping (i.e. increased ratio of residual volume to total lung capacity), and airway hyper-reactivity on provocation testing are common findings [39]. Structural abnormalities including emphysema, air trapping, bronchial wall thickening, and linear or subpleural opacities are also commonly seen on cross-sectional imaging in adults with a history of BPD and correlate with BPD severity [24,40].
7.2.2. Pulmonary hypertension The strong association between ‘new BPD’ and PH is in part due to their shared pathogenesis as a prematurity-related developmental disorder, and in part to the development of secondary PH in infants with BPD. Risk factors for PH development in this group include chronic hypoxia, oxygen toxicity and barotrauma which lead to vasoconstriction and pulmonary vascular remodelling, and impaired production of substances required for angiogenesis (e.g. nitric oxide and VEGF). Premature infants also have a higher incidence of structural cardiac abnormalities which further increase the risk of PH development.
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[32] B.A. Darlow, P.J. Graham, M.X. Rojas-Reyes, Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants, Cochrane Database Syst. Rev. 8 (2016) CD000501. [33] B. Schmidt, R.S. Roberts, P. Davis, et al., Long-term effects of caffeine therapy for apnea of prematurity, N. Engl. J. Med. 357 (2007) 1893–1902. [34] A.E. Overman, M. Liu, S.C. Kurachek, et al., Tracheostomy for infants requiring prolonged mechanical ventilation: 10 years' experience, Pediatrics 131 (2013) e1491–e1496. [35] E. Khemani, D.B. McElhinney, L. Rhein, et al., Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era, Pediatrics 120 (6) (2007) 1260. [36] E. Ralser, W. Mueller, C. Haberland, et al., Rehospitalization in the first 2 years of life in children born preterm, Acta Paediatr. 101 (1) (2011) e1–e5. [37] S.J. Gross, D.M. Iannuzzi, D.A. Kveselis, R.D. Anbar, Effect of preterm birth on pulmonary function at school age: a prospective controlled study, J. Pediatr. 133 (2) (1998) 188. [38] E. Baraldi, G. Bonetto, F. Zacchello, M. Filippone, Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation, Am. J. Respir. Crit. Care Med. 171 (1) (Jan 1, 2005) 68–72. [39] E. Baraldi, M. Filippone, Chronic lung disease after premature birth, N. Engl. J. Med. 357 (19) (2007) 1946–1955. [40] D.C. Chambers, C.P. Murray, J. Louw, et al., Lung disease in young adult survivors of moderate and severe bronchopulmonary dysplasia – a future indication for lung transplantation? J Heart Lung Transplant 27 (2) (2008) S108.
[23] G.K. Revanna, A. Kunjunju, A. Sehgal, Bronchopulmonary dysplasia associated pulmonary hypertension: making the best use of bedside echocardiography, Prog. Pediatr. Cardiol. 46 (2017) 39–43. [24] N. Principi, G.M. Di Pietro, S. Esposito, Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies, J. Transl. Med. 16 (1) (2018) 36. [25] K. Tanner, N. Sabrine, C. wren, Cardiovascular malformations among preterm infants, Pediatrics 116 (2005) e833–e838. [26] V.C. Thomas, R. Vincent, A. Raviele, et al., Transcatheter closure of secundum atrial septal defect in infants less than 12 months of age improves symptoms of chronic lung disease, Congenit. Heart Dis. 7 (2012) 204–211. [27] W.E. Benitz, COMMITTEE ON FETUS AND NEWBORN, Patent ductus arteriosus in preterm infants, Pediatrics 137 (1) (2016) e20153730. [28] N.L. Swier, B. Richards, C.L. Cua, et al., Pulmonary vein stenosis in neonates with severe bronchopulmonary dysplasia, Am. J. Perinatol. 33 (07) (2016) 671–677. [29] The PREVENT Study Group, Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis, Pediatrics 99 (1) (1997) 93–99. [30] R.A. Mosquera, A.M. Gomez-Rubio, T. Harris, et al., Anti-inflammatory effect of prophylactic macrolides on children with chronic lung disease: a protocol for a double-blinded randomised controlled trial, BMJ Open 6 (9) (2016) e012060. [31] D. Bassler, R. Plavka, E.S. Shinwell, et al., Early inhaled budesonide for the prevention of bronchopulmonary dysplasia, N. Engl. J. Med. 373 (16) (2015) 1497–1506.
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Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Investigation and management of the long-term ventilated premature infant M.F.A. Wright, C. Wallis
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Department of Respiratory Paediatrics, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK
A R T I C LE I N FO
A B S T R A C T
Keywords: Prematurity Chronic lung disease Long-term ventilation Tracheostomy
Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, and despite significant advances in neonatal care over recent decades its incidence has not diminished. Although most affected infants have mild disease requiring a short period of oxygen supplementation or respiratory support, severely affected infants can become dependent on positive pressure support for a prolonged duration. In such cases, investigations should be carried out to ascertain whether there are secondary disease processes exacerbating the child’s respiratory status. In case of established severe BPD, respiratory support with non-invasive or invasive positive pressure ventilation is required. In this paper we discuss the indications for, and practicalities of, the various modalities available. Potential cardiorespiratory sequelae of BPD include recurrent respiratory infections, childhood wheezing illnesses, abnormalities of lung structure and function, and pulmonary hypertension.
1. Introduction A common reason for seeking a respiratory specialist opinion in the neonatal unit is for the ex-preterm infant with bronchopulmonary dysplasia who is unable to wean from respiratory support. This problem can lead to a protracted hospital admission far beyond expected for a preterm infant, who would generally be discharged home without respiratory support by the time they are term corrected gestational age (CGA). This paper reviews the various reasons for long-term ventilatory support (LTV) in premature infants, approach to investigation and management, and the long-term outcomes. 2. Defining BPD When first described in 1967, the name bronchopulmonary dysplasia (BPD) was given to the clinical scenario of premature infants with severe respiratory distress syndrome (RDS) remaining hypoxic and dependent on supplementary oxygen at 28 days of life and demonstrating typical chest radiograph changes [1]. This definition has evolved over time due to increasing survival of extremely preterm and very low birthweight infants, amongst whom an oxygen requirement at 36 weeks postmenstrual age was found to be more predictive of longterm pulmonary outcomes [2]. In 2001, the United States National Institute of Child Health and Human Development (NICHD) modified this definition further to include a BPD severity category and stratification according to the infant's gestational age at birth (Table 1) [3]. These criteria are now widely used by healthcare professionals for the
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diagnosis of BPD. However, it should be noted that although the NICHD definition more accurately predicts pulmonary outcomes, including the need for medications and likelihood of rehospitalisation, at 18–22 months CGA than its predecessors [4], it does not correlate with results of pulmonary function testing at 8–10 years of age [5,6]. 3. Epidemiology BPD is the most common chronic lung disease of infancy, with up to 10,000 new cases seen in the USA each year. Recent studies indicate an incidence of 32–59% amongst infants born at ≤28 weeks gestation, depending on the definition of BPD used [7]. Incidence is inversely proportionate to gestational age and higher amongst infants with intrauterine growth restriction (IUGR), with infants born at < 1250 g accounting for 97% of cases [8]. The incidence of BPD has changed little over recent decades despite advances in neonatal medicine over this period. The continued high prevalence of BPD may be in part to its changing pathogenesis and the improved survival of infants with extremely low gestational age and birth weight. 4. Pathogenesis BPD develops due to a combination of genetic predisposition and environmental factors, and most commonly affects premature infants due to the increased susceptibility of the immature lung to infective and mechanical insults which lead to an inflammatory response. Historically, BPD was attributed to a proinflammatory state
Corresponding author. E-mail addresses: [email protected] (M.F.A. Wright), [email protected] (C. Wallis).
https://doi.org/10.1016/j.earlhumdev.2018.08.015
0378-3782/ © 2018 Elsevier B.V. All rights reserved.
Please cite this article as: Wright, M., Early Human Development, https://doi.org/10.1016/j.earlhumdev.2018.08.015
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Table 1 Bronchopulmonary dysplasia diagnostic criteria. (Adapted from Jobe et al. [3]). Gestational age
< 32 weeks
≥32 weeks
Time point of assessment
36 weeks PMA or discharge home, whichever comes first Treatment with > 21% O2 for at least 28 days, plus: Breathing room air at 36 weeks PMA or discharge, whichever comes first Need for < 30% O2 at 36 weeks PMA or discharge, whichever comes first Need for ≥30% O2 and/or positive pressure (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first
> 28 days but < 56 days postnatal age or discharge home
Mild BPD Moderate BPD Severe BPD
Breathing room air by 56 days postnatal age or discharge, whichever comes first Need for < 30% O2 at 56 days postnatal age or discharge, whichever comes first Need for ≥30% O2 and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge, whichever comes first
Abbreviations: BPD = bronchopulmonary dysplasia; NCPAP = nasal continuous positive airway pressure; PMA = postmenstrual age; PPV = positive pressure ventilation.
In each case, an investigation pathway should be developed that targets the most likely diagnosis based on the child's history and clinical features. However, it should be noted that whilst most of the conditions that may mimic BPD are rare and the presence of a second unrelated disease process is relatively unusual, the conditions we describe as potential exacerbating factors in Table 2(a) are collectively very common in preterm infants and should generally be the initial focus of further investigation (Fig. 1). Prevention of BPD development is the subject of extensive research and beyond the scope of this article. Areas of interest include: (a) antenatal management, (b) use of endotracheal surfactant, (c) non-invasive respiratory support in the early neonatal period, (d) the role of medications such as vitamin A and corticosteroids.
resulting from oxygen toxicity, ventilator-induced lung injury, and shearing injury to alveoli resulting from surfactant deficiency. The resulting high levels of proinflammatory cytokines and growth factors (e.g. IL-1, IL-6, ICAM-1, TNF-α and TGF-β) ultimately lead to fibrosis of lung parenchyma and small airways. Cases resulting from these insults are now regarded as ‘old BPD’. Over recent years there has been an apparent change in the pathogenesis of BPD due to advances in the early management of preterm infants, including the introduction of antenatal steroids and endotracheal surfactant, increased use of noninvasive ventilation (NIV) in the delivery room, and a less aggressive approach to mechanical ventilation. A different clinical picture described as ‘new BPD’ has now emerged, in which the main aetiological factor is a developmental disorder of lung growth resulting from extreme prematurity. Lung growth abnormalities are typified by fewer numbers of large, oversimplified alveoli and a smaller total surface area for gas exchange. Compared to ‘old BPD’ the airways are relatively spared with less smooth muscle hypertrophy and fibrosis. As development of the pulmonary vasculature is also affected, pulmonary hypertension frequently coexists with ‘new BPD’.
6. Management of LTV-dependent BPD Management of LTV-dependent BPD can be considered as having 3 separate components: 1. Provision of long-term ventilatory support to infants with BPD 2. Management of exacerbating comorbidities 3. Potential medical therapies
5. Diagnosis and investigation The diagnosis of BPD is made clinically, usually based on the definition proposed by the NICHD (Table 1). As well as a persistent requirement for respiratory support, affected infants typically have a history of significant prematurity or IUGR with examination findings including tachypnoea and the use of accessory muscles of respiration. Bilateral reticulo-nodular opacifications and hyperinflation are common chest radiograph features. No biomarkers have yet been identified that can reliably predict which preterm infants will be affected. Proposals that BPD diagnosis should be based on physiological tests such as a 60-min room air challenge have not been widely adopted [9,10]. In typical cases of mild to moderate BPD, additional investigations are not necessary and weaning of respiratory support and oxygen supplementation is achieved as the child grows. In infants with an atypical presentation or clinical course, further investigation may be required to identify any factors that might be exacerbating their lung disease (Table 2(a)) and to rule out other conditions that might be masquerading as, or coexisting with, BPD (Table 2(b)). Our institutional practice is to investigate children who meet any of the following criteria:
6.1. Long-term ventilatory support of infants with BPD In each case of BPD, the goals of the clinician should be to stabilise the child on the least invasive mode of respiratory support that will achieve acceptable gas exchange, to prevent the development of treatment related side effects, and to wean the child from respiratory support as soon as this can be safely achieved. Various methods of respiratory support exist, and their individual frequency of use varies considerably between treatment centres [11]. Our suggested approach to respiratory management is summarised in Fig. 2. 6.1.1. Non-invasive positive pressure In recent years, NIV has become widely used to facilitate weaning of infants with BPD from mechanical ventilation and prevent the recurrence of respiratory failure necessitating reintubation. Continuous positive airway pressure (CPAP) involves the delivery of a constant distending pressure to the airways to maintain alveolar inflation and prevent atelectasis. Intermittent positive pressure ventilation (IPPV) superimposes an intermittent peak pressure on CPAP at a set respiratory rate which, depending on the ventilator used, can be synchronised with the infant's spontaneous breaths. In neonates and small infants, NIV is delivered via a nasal mask or prongs, whereas in the larger infant a fullface mask can also be used. Studies of NIV in preterm infants consistently show advantages of IPPV over CPAP, including reduced rates of respiratory failure, reduced need for intubation or surfactant administration, and earlier hospital discharge [12,13]. However, there are no apparent differences in rates
1. Infants who remain dependent on positive pressure support at term CGA. 2. Infants who have a persistently high supplementary oxygen requirement over time. 3. Infants with atypical clinical features (Table 3). 4. Infants with respiratory compromise disproportionate to their degree of prematurity and postnatal age.
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Table 2 Conditions that can exacerbate underlying BPD. a. Conditions more common in the premature infant • • • • • •
Gastro-oesophageal reflux with aspiration lung disease Incoordinate swallow with aspiration lung disease Airway malacia Subglottic stenosis following intubation Congenital heart disease e.g. patent ductus arteriosus, pulmonary vein stenosis Pulmonary hypertension
b. Dual pathologies that may coexist with and exacerbate BPD Lung parenchyma
Interstitial lung disease (ILD) e.g. surfactant dysfunction disorders Lung growth abnormality e.g. pulmonary hypoplasia, Trisomy 21 Primary ciliary dyskinesia Cystic fibrosis Upper airway lesions e.g. laryngeal web or cleft, complete tracheal rings Compressive vascular lesions e.g. vascular ring or sling Immunodeficiency Neuromuscular weakness e.g. congenital myopathy, metabolic or mitochondrial diseases Congenital heart disease e.g. atrial septal defect (ASD), transposition
Airways Non-respiratory
young infants is 6–8 L/min. Its main perceived advantages over NIV are that the interface is simpler to apply, less likely to cause skin trauma, and better tolerated [15]. A 2016 Cochrane review found HFNC to be comparable to other forms of non-invasive support for initial management of preterm infants with RDS, with no differences in rates of treatment failure, reintubation or BPD, and reduced rates of nasal trauma and pneumothorax. Two studies reported reduced duration of hospital admission when weaning off HFNC compared to CPAP [16]. Although HFNC is becoming more readily available in the home setting, it must be delivered from a fixed source and no portable device is currently available. As such, it is appropriate for nocturnal use only, and eligible infants should be stable on supplementary oxygen or without any respiratory support during the daytime. To date no highquality studies have been published that guide how best to wean preterm infants from HFNC, as highlighted by a recent Cochrane review [17], but current common practice is to reduce flow rates by 0.5–1 L/ min every 24 h to a minimum flow of 2–3 L/min [14]. HFNC is a useful intervention for infants experiencing complications from long-term use of a face or nasal mask, or who become intolerant of NIV as they grow older but have impaired gas exchange when receiving only supplementary oxygen. However, a common scenario we see is that infants become dependent on continuous HFNC after ‘stepping down’ from NIV and do not tolerate further weaning. This often reflects the development of atelectasis due to the delivery of lower airway pressures than achieved with NIV, and paradoxically the best treatment approach is to reintroduce nocturnal NIV to re-recruit alveoli and increase the child's respiratory reserve during waking hours (Fig. 2).
Table 3 Examples of clinical features warranting further investigation. Respiratory
Non-respiratory
Stridor or abnormal cry (e.g. hoarse, weak) Wheeze Coughing or desaturation with feeds
Dysmorphic features
Recurrent cyanotic episodes Central hypoventilation
Heart murmur Neuromuscular weakness disproportionate to CGA Skeletal dysplasia
of BPD or death between the two approaches. Complications of long-term NIV relate mainly to prolonged use of a face or nasal mask which can lead to skin trauma, midfacial hypoplasia, and neurodevelopmental delay by acting as a physical barrier to social interaction. Another associated risk is pulmonary aspiration caused by vomiting whilst wearing a face mask. Risk of vomiting is increased when using NIV due to gaseous distension of the stomach. NIV should only be considered suitable for long-term use if the child is stable without respiratory support or in low-flow oxygen when awake and requires NIV only during sleep (‘nights and naps’) for a maximum of 16 h per 24-h day. To minimise aspiration risk, enteral feeds, whether oral or via feeding tube, should ideally be coordinated with breaks rather than given overnight or when the child is unsupervised. In infants with RDS, stopping CPAP abruptly rather than gradually introducing breaks off support (‘cycling’) shortens weaning time and total CPAP duration [12]. However, in infants requiring long-term NIV for established BPD there is no consensus on the best approach to weaning. Our approach is to cycle off support whilst the infant is awake (e.g. starting with a 30-min break 2–3 times per day and gradually increasing the duration of each break), without weaning ventilator pressures, until the child is clinically stable on a ‘nights and naps’ or ≤16 h/day regimen. Depending on the child's history and clinical status, decisions about weaning pressures and ultimately stopping night-time support can then be made either empirically or based on sleep study findings.
6.1.3. LTV via tracheostomy Most preterm infants requiring mechanical ventilation can be weaned onto non-invasive respiratory support or supplementary oxygen after a period of days to weeks. However, a small proportion of infants with severe BPD, especially those with coexisting airway abnormalities, will remain dependent on invasive ventilation or continuous NIV. In such cases, long-term invasive ventilation via tracheostomy may be appropriate. Before referring for tracheostomy it is reasonable to give a trial of low-dose systemic steroids, despite their recognised side effects, in a final attempt to facilitate extubation or weaning. Addressing the exacerbating factors highlighted in Tables 2 and 3 are an imperative part of the decision to tracheostomise. The incidence of tracheostomy placement in preterm infants varies significantly between institutions, ranging from 3.5–14% in published retrospective studies [18–20]. Decisions about timing of tracheostomy placement in severe BPD are challenging and largely non-evidence
6.1.2. High flow nasal cannula therapy Heated, humidified high flow nasal cannula (HFNC) therapy has recently become a popular mode of providing non-invasive respiratory support to infants and children. Its use in the United Kingdom increased from 56% to 87% of neonatal units between 2012 and 2015 [14]. Positive airway pressure is administered via nasal prongs which sit below and external to the nares. The typical flow rate required in neonates and 3
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Fig. 1. Example of an investigative pathway for the LTV dependent premature infant.
carers from the local clinical commissioning group, training carers and family members in tracheostomy management and LTV delivery at home, and ensuring that suitable housing is available. Based on our local data, this process takes a median of 8 months [22]. One approach, based on the above information, is to consider tracheostomy placement for infants with severe BPD in whom (1) efforts to wean from mechanical ventilation using non-invasive methods of respiratory support have proved unsuccessful by term CGA, (2) all common exacerbating factors have been explored and treated, (3) neurocognitive function has been established, and (4) the parents understand and accept the practicalities involved, including prolonged hospital admission and long-term presence of carers in the family home.
based. There is some evidence that earlier tracheostomy insertion (age < 120 days) improves neurodevelopmental outcomes, but this must be balanced against the risk of unnecessary tracheostomy insertion if insufficient time has been spent trying to wean the infant from mechanical support [18]. No correlation has been found between timing of tracheostomy insertion and total duration of mechanical ventilation or time to successful decannulation [21]. Another factor to consider is the impact of tracheostomy insertion on the family. Although the surgery itself is generally straightforward, infants require prolonged hospital stays whilst discharge planning is undertaken and necessary measures are put in place for provision of LTV at home. In the UK, this involves obtaining funding for a team of 4
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Fig. 2. Suggested ventilatory pathway for the LTV dependent premature infant.
which must be closely monitored and has potential for serious side effects, and the finite survival of transplanted lungs. The family should also be made aware that, due to the scarcity of donor lungs suitable for infant recipients, children can spend many months or years waiting for a suitable donor organ and some will never undergo transplant surgery.
6.1.4. Bilateral lung transplant BPD is a rare indication for lung transplantation, due in part to its natural history for improvement over time and in part to the technical challenges and scarcity of suitable donor lungs that makes infant lung transplant for any indication rare. However, a very small subgroup of infants with severe BPD, almost invariably tracheostomy ventilated, may warrant referral for transplant assessment. Reasons to consider transplant referral include severe pulmonary arterial hypertension refractory to medical therapy or escalating ventilatory requirements over time. The latter can occur in infants with severe BPD due to postnatal alveolar growth being insufficient to meet the gas exchange requirements of the child's growing body. In effect, the child ‘outgrows’ their own lungs, often at around 9 months to 1 year of age. Relative contraindications include renal insufficiency, severe growth failure, and poor neuro-cognitive functioning. A fundamental component of assessing suitability for transplant is ensuring that the family are psychologically prepared for, and clearly understand the implications of being listed for surgery. Important discussion points include the various early and late complications of organ transplantation, the need for life-long immunosuppression therapy
6.2. Management of exacerbating comorbidities Various conditions can coexist with BPD in preterm infants and worsen the child's respiratory status (Table 2). These comorbidities should be actively sought as their treatment will often enable an infant apparently dependent on LTV to be weaned. 6.2.1. Gastro-oesophageal reflux and incoordinate swallow Although it is unclear whether there is a causal relationship between BPD and gastro-oesophageal reflux (GOR), the two conditions have shared risk factors including prematurity and intragastric tube feeding and frequently coexist. As preterm infants, particularly those with neurodevelopmental delay, have immature pharyngeal swallowing reflexes and oesophageal motility, an ‘unsafe’ swallow can result 5
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hospitalisation and duration of hospital admission in infants with BPD [29].
which puts them at risk of aspirating oral intake or refluxed liquid. The risk of reflux-aspiration is further increased in LTV dependent preterm infants due to gastric distension by positive pressure ventilation. This risk can be reduced by treating symptomatic infants, or those with positive GOR investigations, with anti-reflux medications and consulting a speech and language therapist before introducing oral feeds. In cases of severe reflux-aspiration refractory to medical therapy, surgery (e.g. Nissen fundoplication) should be considered as a means of protecting the lungs.
6.3.1.2. Azithromycin. Azithromycin prophylaxis is commonly prescribed for children with a history of frequent respiratory illnesses. It has been hypothesised that its ability to down-regulate cytokine production during viral illnesses may be of benefit to infants with BPD, and it is currently the target for experimental studies [30]. 6.3.2. Postnatal corticosteroids Early administration of systemic corticosteroids to ventilated preterm infants reduces their risk of developing BPD and facilitates extubation. However, their use is limited by an increased risk of severe adverse outcomes including cerebral palsy, retinopathy of prematurity, and gastrointestinal bleeding or perforation. Based on this risk factor profile, the routine use of steroids in preterm infants is not recommended and decisions about treatment in LTV-dependent infants should be made on a case-by-case basis. Inhaled steroids have been proposed as a means of minimising systemic effects and are effective in reducing rates of BPD. However, increased mortality rates have been reported and their effect on neurodevelopment has not yet been established [31].
6.2.2. Pulmonary hypertension Pulmonary hypertension (PH) is reported in up to a quarter of all infants with BPD, and up to 40% of those with severe BPD [11,23]. Prevalence is inversely proportionate to gestational age and birth weight and is increased in infants with structural cardiac abnormalities. Diagnosis of PH is associated with a significantly longer duration of respiratory support and increased mortality risk [24]. Its initial management involves optimising gas exchange, avoiding hypoxia, and treating coexisting reflux-aspiration or structural cardiac defects. In severe cases refractory to these measures, pulmonary vasodilator therapy (e.g. sildenafil) may be considered, although the efficacy of vasodilator therapy in PH secondary to lung disease is debatable.
6.3.3. Diuretics The role of diuretics in BPD is controversial; although their use in BPD can facilitate weaning from respiratory support, they have not been found to improve other clinical outcomes including total duration of respiratory support, and they place the infant at risk of electrolyte imbalance which can contribute to growth failure.
6.2.3. Structural cardiac disease Preterm infants are more than twice as likely to have a cardiac malformation as term infants, which contributes to their increased risk of PH [25]. In LTV-dependent infants, treatment may lead to improvement of respiratory status. Small case series of transcatheter device closure of atrial septal defects in preterm infants with lung disease report improved PH and reduced supplementary oxygen requirement [26]. 80% of infants born at ≤28 weeks will have a patent ductus arteriosus (PDA) at 4 days of age. Although many remain asymptomatic or close spontaneously, medical or surgical closure is commonly performed in preterm infants as prolonged patency is associated with higher rates of BPD development, PPV requirement and death. However, improved outcomes following routine PDA closure have not been demonstrated. Surgical PDA ligation has, in fact, been identified as an independent risk factor for BPD, as well as carrying a risk of other respiratory complications including chylothorax and vocal cord paralysis [27]. These risks lessen when ligation is delayed, suggesting that a ‘watch and wait’ approach to PDA management should be adopted in the stable preterm infant with BPD. Pulmonary vein stenosis (PVS) is an increasingly well recognised abnormality for which prematurity appears to be a major risk factor. In many cases affected infants have a normal echocardiogram at birth, so a high index of suspicion and serial investigation with ultrasound and/or cardiac catheterisation is required for diagnosis. PVS carries a high mortality rate which is largely attributable to the development of severe PH. A mortality rate of 50% is reported for coexisting PVS and BPD, which is higher than described when BPD and PH coexist in the absence of PVS. Unfortunately, this condition responds poorly to the available management options, and transcatheter balloon dilatation appears to offer only short-term benefit [28].
6.3.4. Vitamin A supplementation Vitamin A has been investigated as a therapeutic target as it is required for normal lung development and preterm infants are often deficient. A small reduction in BPD risk has been demonstrated from intramuscular administration to infants with birth weight < 1000 g, but with no effect on durations of mechanical ventilation or hospital admission [32]. Its painful route of administration, the need for multiple dosing, and an increased risk of sepsis are potential barriers to its use. Studies of oral supplementation are underway. 6.3.5. Caffeine Caffeine is a respiratory stimulant which has a well-established role in the management of apnoea of prematurity and can facilitate weaning from mechanical ventilation. A 37% reduction in BPD development has been reported following early caffeine treatment, which may relate to a reduced likelihood of requiring mechanical ventilation. Reduced rates of death of neurodevelopmental disability at 18 months, but an increased risk of necrotising enterocolitis, are also described [33]. 7. Outcomes for preterm infants requiring LTV The outcome data for premature infants with BPD requiring LTV can be considered in two ways: 1. The timing and likelihood of weaning off all ventilatory support with lung growth in this group of children. 2. The long-term cardiorespiratory sequelae in those children able to wean off all support.
6.3. Medical therapies 6.3.1. Prevention of respiratory exacerbations Children with BPD are particularly susceptible to severe respiratory illnesses that in some cases can lead to respiratory failure or death. An important component of their management and follow-up after hospital discharge is reducing the risk of such events.
7.1. Weaning off ventilatory support The natural history of BPD is for improvement with lung growth as the child grows, enabling gradual weaning from respiratory support in most cases. Very limited data exist regarding the duration of non-invasive LTV in infants with severe BPD or the likelihood of an eventual successful wean. In terms of LTV via tracheostomy, a study from our
6.3.1.1. Anti-RSV prophylaxis. Monthly administration of respiratory syncytial virus (RSV) humanised monoclonal antibody during the winter viral season leads to a significant reduction in RSV-related 6
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8. Summary
centre found that the median duration of home ventilation prior to tracheostomy decannulation was 1.7 years [22]. A study of 165 tracheostomy ventilated infants in the USA reported a median duration of 12 months from tracheostomy insertion to PPV independence and 1.3 years from tracheostomy insertion to decannulation amongst infants with birth weight ≤ 1000 g (of whom 95% had BPD) [34]. Readiness for weaning of LTV is best assessed using serial sleep studies which include continuous measurement of CO2. Direct visualisation of the airway (e.g. with microlaryngobronchoscopy) should also be performed prior to decannulation to rule out acquired anatomical abnormalities. Unfortunately, infants with BPD have a higher mortality than preterm infants without clinically significant lung disease, and some infants with severe BPD will die without ever weaning from LTV. Deaths are usually attributable to respiratory failure, pulmonary hypertension or respiratory infection. Poorer survival rates are seen amongst infants with the greatest disease severity, small for gestational age infants, and those with pulmonary hypertension [35]. The prematurity and respiratory outcomes (PROP) study reported 27 deaths from a primary respiratory pathology at between 2 weeks chronological age and 40 weeks CGA, indicating a BPD-attributable mortality rate of 6–11% depending on the definition of BPD used [7]. This accounted for 43% of all postnatal deaths in their cohort. Similar mortality rates of 6–20% have been reported amongst tracheostomy ventilated infants with BPD, and sadly death from respiratory failure can still occur after months of apparent stability.
BPD is a common complication of prematurity which can lead to prolonged hospital admissions and LTV dependency. Respiratory support should be delivered using the least invasive approach that achieves adequate gas exchange, and with the goal of preventing the development of complications (e.g. skin trauma, pulmonary hypertension). Despite the now widespread use of NIV in preterm infants with BPD, there is a limited evidence base to guide weaning strategies or inform long-term prognosis, and these areas should be a target for future research. Disclosures The authors have no conflicts of interest or disclosures regarding this manuscript. References [1] W.H. Northway Jr., R.C. Rosan, D.Y. Porter, Pulmonary disease following respiratory therapy of hyaline-membrane disease. Bronchopulmonary dysplasia, N. Engl. J. Med. 276 (7) (1967) 357. [2] A.T. Shennan, M.S. Dunn, A. Ohlsson, et al., Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period, Pediatrics 82 (4) (1988) 527. [3] A.H. Jobe, E. Bancalari, Bronchopulmonary dysplasia, Am. J. Respir. Crit. Care Med. 163 (2001) 1723. [4] R.A. Ehrenkranz, M.C. Walsh, B.R. Vohr, et al., Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. National Institutes of Child Health and Human Development Neonatal Research Network, Pediatrics 116 (6) (2005) 1353. [5] E. Kaplan, E. Bar-Yishay, D. Prais, et al., Encouraging pulmonary outcome for surviving, neurologically intact, extremely premature infants in the postsurfactant era, Chest 142 (3) (2012) 725–733. [6] S. Cazzato, L. Ridolfi, F. Bernardi, et al., Lung function outcome at school age in very low birth weight children, Pediatr. Pulmonol. 48 (8) (2013) 830–837. [7] B.B. Poindexter, R. Feng, B. Schmidt, et al., Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program, Ann. Am. Thorac. Soc. 12 (12) (2015) 1822–1830. [8] P. Bowen, N.C. Maxwell, Management of bronchopulmonary dysplasia, Paediatr. Child Health 24 (1) (2014) 27–31. [9] M.C. Walsh, D. Wilson-Costello, A. Zadell, et al., Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia, J. Perinatol. 23 (6) (2003) 451–456. [10] N.L. Maitre, R.A. Ballard, J.H. Ellenberg, et al., Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach, J. Perinatol. 35 (5) (2015) 313–321. [11] M.C. Guaman, J. Gien, C.D. Baker, et al., Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia, Am. J. Perinatol. 32 (10) (2015) 960–967. [12] G. Lista, F. Castoldi, P. Fontana, et al., Nasal continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in preterm babies with respiratory distress syndrome: a randomised control trial, Arch. Dis. Child. Fetal Neonatal Ed. 95 (2010) 85–89. [13] B. Lemyre, M. Laughon, C. Bose, P.G. Davis, Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants, Cochrane Database Syst. Rev. 12 (2016) CD005384. [14] S. Shetty, A. Sundaresan, K. Hunt, et al., Changes in the use of humidified high flow nasal cannula oxygen, Arch. Dis. Child. Fetal Neonatal Ed. 101 (2016) F371–F372. [15] B.J. Manley, Nasal high-flow therapy for preterm infants: review of neonatal trial data, Clin. Perinatol. 43 (4) (2016) 673–691. [16] Wilkinson, C. Andersen, C.P.F. O'Donnell, et al., High flow nasal cannula for respiratory support in preterm infants, Cochrane Database Syst. Rev. 2 (2016) CD00640. [17] R.C. Farley, J.L. Hough, L.A. Jardine, Strategies for the discontinuation of humidified high flow nasal cannula (HHFNC) in preterm infants, Cochrane Database Syst. Rev. 6 (2015) CD011079. [18] S.B. DeMauro, J.A. D'Agostino, C. Bann, et al., Developmental outcomes of very preterm infants with tracheostomies, J. Pediatr. 164 (6) (Jun 2014) 1303–1310. [19] K. Murthy, R.C. Savani, J.M. Lagatta, et al., Predicting death or tracheostomy placement in infants with severe bronchopulmonary dysplasia, J. Perinatol. 34 (7) (Jul 2014) 543–548. [20] K.D. Pereira, A.R. MacGregor, C.M. McDuffie, R.B. Mitchell, Tracheostomy in preterm infants: current trends, Arch. Otolaryngol. Head Neck Surg. 129 (12) (2003) 1268–1271. [21] J. Cheng, J. Lioy, S. Sobol, Effect of tracheostomy timing in premature infants, Int. J. Pediatr. Otorhinolaryngol. 77 (11) (2013) 1873–1876. [22] E. Edwards, M. O'Toole, C. Wallis, Sending children home on tracheostomy dependent ventilation: pitfalls and outcomes, Arch. Dis. Child. 89 (3) (Mar 2004) 251–255.
7.2. Long-term cardiorespiratory sequelae of BPD 7.2.1. Respiratory Hospital readmission is common amongst preterm infants after discharge from the NICU, with respiratory disorders accounting for up to half of readmissions in the first 2 years of life. Infants with BPD are twice as likely to be re-hospitalised compared to preterm infants without lung disease [36,37]. The majority of these respiratory illnesses, which can be severe or even life threatening, are caused by viruses like RSV and occur during the child's first winter after NICU discharge. Individuals with BPD are subsequently more likely to suffer from recurrent wheezing episodes during early childhood. Compared to asthmatic children without a history of BPD, children with BPD are more likely to have neutrophilic airway inflammation, lower values of exhaled nitric oxide, and reduced response to inhaled β2 agonists [38]. Although respiratory symptoms generally improve over time, pulmonary function abnormalities often persist into adulthood even in the absence of symptoms. Fixed airway obstruction, air trapping (i.e. increased ratio of residual volume to total lung capacity), and airway hyper-reactivity on provocation testing are common findings [39]. Structural abnormalities including emphysema, air trapping, bronchial wall thickening, and linear or subpleural opacities are also commonly seen on cross-sectional imaging in adults with a history of BPD and correlate with BPD severity [24,40].
7.2.2. Pulmonary hypertension The strong association between ‘new BPD’ and PH is in part due to their shared pathogenesis as a prematurity-related developmental disorder, and in part to the development of secondary PH in infants with BPD. Risk factors for PH development in this group include chronic hypoxia, oxygen toxicity and barotrauma which lead to vasoconstriction and pulmonary vascular remodelling, and impaired production of substances required for angiogenesis (e.g. nitric oxide and VEGF). Premature infants also have a higher incidence of structural cardiac abnormalities which further increase the risk of PH development.
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[32] B.A. Darlow, P.J. Graham, M.X. Rojas-Reyes, Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants, Cochrane Database Syst. Rev. 8 (2016) CD000501. [33] B. Schmidt, R.S. Roberts, P. Davis, et al., Long-term effects of caffeine therapy for apnea of prematurity, N. Engl. J. Med. 357 (2007) 1893–1902. [34] A.E. Overman, M. Liu, S.C. Kurachek, et al., Tracheostomy for infants requiring prolonged mechanical ventilation: 10 years' experience, Pediatrics 131 (2013) e1491–e1496. [35] E. Khemani, D.B. McElhinney, L. Rhein, et al., Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era, Pediatrics 120 (6) (2007) 1260. [36] E. Ralser, W. Mueller, C. Haberland, et al., Rehospitalization in the first 2 years of life in children born preterm, Acta Paediatr. 101 (1) (2011) e1–e5. [37] S.J. Gross, D.M. Iannuzzi, D.A. Kveselis, R.D. Anbar, Effect of preterm birth on pulmonary function at school age: a prospective controlled study, J. Pediatr. 133 (2) (1998) 188. [38] E. Baraldi, G. Bonetto, F. Zacchello, M. Filippone, Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation, Am. J. Respir. Crit. Care Med. 171 (1) (Jan 1, 2005) 68–72. [39] E. Baraldi, M. Filippone, Chronic lung disease after premature birth, N. Engl. J. Med. 357 (19) (2007) 1946–1955. [40] D.C. Chambers, C.P. Murray, J. Louw, et al., Lung disease in young adult survivors of moderate and severe bronchopulmonary dysplasia – a future indication for lung transplantation? J Heart Lung Transplant 27 (2) (2008) S108.
[23] G.K. Revanna, A. Kunjunju, A. Sehgal, Bronchopulmonary dysplasia associated pulmonary hypertension: making the best use of bedside echocardiography, Prog. Pediatr. Cardiol. 46 (2017) 39–43. [24] N. Principi, G.M. Di Pietro, S. Esposito, Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies, J. Transl. Med. 16 (1) (2018) 36. [25] K. Tanner, N. Sabrine, C. wren, Cardiovascular malformations among preterm infants, Pediatrics 116 (2005) e833–e838. [26] V.C. Thomas, R. Vincent, A. Raviele, et al., Transcatheter closure of secundum atrial septal defect in infants less than 12 months of age improves symptoms of chronic lung disease, Congenit. Heart Dis. 7 (2012) 204–211. [27] W.E. Benitz, COMMITTEE ON FETUS AND NEWBORN, Patent ductus arteriosus in preterm infants, Pediatrics 137 (1) (2016) e20153730. [28] N.L. Swier, B. Richards, C.L. Cua, et al., Pulmonary vein stenosis in neonates with severe bronchopulmonary dysplasia, Am. J. Perinatol. 33 (07) (2016) 671–677. [29] The PREVENT Study Group, Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis, Pediatrics 99 (1) (1997) 93–99. [30] R.A. Mosquera, A.M. Gomez-Rubio, T. Harris, et al., Anti-inflammatory effect of prophylactic macrolides on children with chronic lung disease: a protocol for a double-blinded randomised controlled trial, BMJ Open 6 (9) (2016) e012060. [31] D. Bassler, R. Plavka, E.S. Shinwell, et al., Early inhaled budesonide for the prevention of bronchopulmonary dysplasia, N. Engl. J. Med. 373 (16) (2015) 1497–1506.
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