SYMPOSIUM: NEONATOLOGY
Respiratory support for preterm infants e the Cochrane evidence and beyond
intensive care environment, obstetric departments and those who care for ex-premature infants.
Lung development Lung development is broadly divided into five overlapping stages, as summarised in Table 1. Although infants born at the limits of viability (23e24 weeks gestational age at birth) are capable of gas exchange, the lung is in an immature stage of development (late canalicular and early saccular stage).
Christopher Course Mallinath Chakraborty
Support strategies before birth Corticosteroids The use of antenatal corticosteroids before anticipated preterm birth is one of the key interventions that has resulted in improved survival of premature infants. Corticosteroids accelerate fetal lung maturity and surfactant synthesis. Use of antenatal corticosteroid use has been shown to reduce the risk of fetal and neonatal death (relative risk [RR] 0.77, 95% confidence interval [CI] 0.67e0.89), respiratory distress syndrome (RR 0.66, CI 0.59 e0.73), and need for and duration of mechanical ventilation and non-invasive respiratory support. No reduction has been shown in the rates of air leak or CLD following antenatal steroids. Survival is improved when antenatal corticosteroids are received for deliveries between 26 and 30 weeks gestation, with rates of RDS being reduced for deliveries between 26 and 35 weeks gestation. No difference in outcome has been shown for infants born at less than 26 weeks gestation; however, there is a paucity of data in this group. There is a reduced rate of neonatal death when antenatal corticosteroids are received even less than 24 hours prior to delivery. A reduction in the rates of RDS has been seen for infants born up to seven days following administration of steroids; however there is no evidence for benefit beyond this time. Repeat courses of antenatal steroids seem to reduce the incidence of RDS, compared to a single course, more than seven days before preterm delivery; however, it also reduces mean birth-weight, and concerns have been raised over the long-term consequences of repeated in-utero steroid exposure. Most of the trials included within the review have used different dosing strategies, and there is little data currently to suggest which dose is optimal. No increase in maternal sepsis has been shown with antenatal steroid use, and a reduction in early onset neonatal sepsis (within the first 48 hours of life) has been demonstrated. Data for multiple pregnancies, although limited, shows similar outcomes for mother and fetus when compared to singleton pregnancies. There is currently a lack of evidence comparing the two main corticosteroids used, betamethasone and dexamethasone. No evidence to support an increased rate of cerebral palsy in those infants who received dexamethasone compared to betamethasone was found, but it did show an increase in rates of puerperal sepsis in mothers treated with dexamethasone.
Abstract Respiratory failure is the commonest morbidity of newborn infants, often necessitating support. While respiratory support of newborn infants is life-saving, it is strongly associated with long-term sequelae. Modes of support for newborn infants, especially preterm infants, have been evolving over the last four decades. Key developments have ensured improvement in survival and outcomes of these vulnerable infants. A large body of evidence has been collected on the appropriate respiratory management of preterm newborn infants. The Cochrane Neonatal Group has been at the forefront of collecting all published evidence and pooling them together into high-quality meta-analyses. In this review, we present a summary of the key Cochrane reviews to guide our practice, with a few future perspectives.
Keywords continuous positive airway pressure; infant premature; intubation; non-invasive ventilation; respiratory distress syndrome newborn; ventilation
Introduction Respiratory distress syndrome (RDS) is the commonest morbidity following preterm birth, and a major contributor to early neonatal death and long-term sequelae. RDS, and resulting respiratory failure, occurs in these infants secondary to immature lung development, surfactant deficiency and immaturity in other organs. In those infants presenting with RDS, a substantial proportion go on to develop Chronic Lung Disease (CLD), and remain at high risk of on-going respiratory morbidity into childhood and adulthood. Respiratory support of preterm infants has been evolving over the last 30 years, guided by laboratory and clinical studies, and this evidence has been pooled together in multiple Cochrane meta-analyses. This review summarises the current Cochrane evidence supporting choices in neonatal respiratory support, and is aimed at healthcare professionals working within the neonatal
Christopher Course MBBCh BSc is Paediatrics Trainee in the Wales Deanery, Regional Neonatal Intensive Care Unit, University Hospital of Wales, Cardiff, UK. Conflict of interest: none declared.
Antibiotics Infection and chorioamnionitis have been linked as a common mechanism of precipitating premature delivery. Administration of antibiotics (usually erythromycin) to mothers with preterm rupture of membranes has been shown to reduce rates of chorioamnionitis, neonatal infection, surfactant & oxygen
Mallinath Chakraborty MBBS DCh MRCPCH PhD is Consultant Neonatologist in the Regional Neonatal Intensive Care Unit, University Hospital of Wales, Cardiff, UK. Conflict of interest: none declared.
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Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Course C, Chakraborty M, Respiratory support for preterm infants e the Cochrane evidence and beyond, Paediatrics and Child Health (2016), http://dx.doi.org/10.1016/j.paed.2015.12.011
SYMPOSIUM: NEONATOLOGY
Summary of stages of lung development Stage
Gestational age (weeks)
Key changes
Embryonic
3e8
C C C
Pseudo-glandular
6e17
C C C
Canalicular
16e26
C C C
C
Saccular
24e38
C
C C
Alveolar
36e2 years
C C C
Lung bud Main trachea, and two main bronchi Lobes of lungs Branching of conducting airways Development of airway epithelium Development of blood vessels Completed airway tree Formation of gas exchange surface: acini Epithelium differentiates into alveolar epithelial cells Development of capillary network around acini Gas exchange saccules lined by type I and type II epithelial cells Synthesis of surfactant starts Thinning of interstitial tissue Formation of mature alveoli Development of secondary crests Thinning of air-blood barrier
Table 1
administration overall, and the risk of delivery within seven days of the membranes rupturing. However, the picture is mixed. There is no effect of prenatal antibiotics on perinatal mortality, RDS or numbers of infants requiring mechanical ventilation. Although use of antibiotics in this situation has shown reduced rates of abnormal pre-discharge cranial ultrasound scans, there has been a suggestion of a small increase in rates of cerebral palsy in later childhood.
positive end expiratory pressure (PEEP) in resuscitation of preterm infants. Take home messages It is reasonable to start resuscitation in air, increasing oxygen concentration if needed.
Ongoing respiratory support: mechanical ventilation Conventional ventilation Mechanical ventilation for critically ill neonates was introduced in the 1960s and seems to reduce overall mortality in preterm infants. However, the trials that support this were from the 1960s and 1970s, employing clinical strategies that are not comparable to modern mechanical ventilation techniques. The advent of synchronised ventilation, whereby a positive pressure inflation delivered by the ventilator coincides with spontaneous inspiration by the infant, aimed to decrease the risk of thoracic air leaks, and deliver more effective gas exchange whilst utilising lower pressures. Cochrane reviews suggest reduction in ventilation days with triggered ventilation modes. However, no improvements in rates of CLD or death have been shown. Prior to the 1990s, all ventilation modes used the ‘timecycled’ method of synchronisation; more modern ventilators can use a flow sensor to synchronise the ventilator-delivered breaths, called ‘flow-cycled’ (where the airflow of the infant taking a breath triggers the ventilator). A limited number of studies were reviewed comparing flow-cycled and time-cycled synchronisation, but owing to paucity of data no conclusions could be drawn. Before the era of surfactant, long inspiratory times and low respiratory rates were used to ventilate premature lungs with decreased compliance. Longer inspiratory times (of 0.66e2.0
Take home messages A single course of steroids should be considered as routine intervention in threatened preterm delivery. Multiple courses may have short term benefits; they are not yet routinely recommended. Use of prophylactic antibiotics for preterm rupture of membranes may delay delivery of the infant, and should be considered.
Respiratory support at birth A Cochrane review examined the evidence regarding the optimal oxygen concentration with which to initiate resuscitation, suggesting infants resuscitated in room air have improved survival, while infants resuscitated in 100% oxygen take longer to establish spontaneous respiratory effort. No differences were noted in rates of CLD, retinopathy of prematurity, neurodevelopmental outcomes, physiological variables, or failure of resuscitation between the groups. Most infants randomised to room air had back-up 100% oxygen available. Additionally, less than a quarter of trial infants were born premature. Currently, the recommendation is to initiate newborn resuscitation in room air with supplementary oxygen available if required. There is currently no high quality evidence to support the use of
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for infants up to 72 hours old improved outcomes, with regard to a decreased risk of mortality and pneumothorax, compared to a single dose. Multiple dosing of synthetic surfactants also improved oxygenation requirement and reduced need for ventilator support. Studies have looked at outcomes for early (prophylactic) vs. delayed (for ventilated infants with established RDS) administration of surfactant. A review from 2012 found that those infants with RDS requiring mechanical ventilation who received early surfactant (either animal or synthetic) had improved outcomes with regard to pneumothorax, pulmonary interstitial emphysema, CLD, and mortality. Many of the early trials into the use of surfactant showed that prophylactic or early administration of surfactant was more beneficial than late use. A review from 2012 looked at prophylactic vs. selective surfactant use in preterm infants, and found that although in trials prior to the routine use of continuous positive airways pressure (CPAP) the data continued to favour prophylactic surfactant use, in those trials where infants were routinely stabilised using CPAP, the most benefit from surfactant came when it was selectively used in those infants who were failing non-invasive support, showing a reduced rate of CLD or death. An alternative technique for surfactant administration called INSURE is in clinical practice. In this technique, infants are intubated, given surfactant and either briefly ventilated (for up to one hour) or extubated to CPAP immediately. Infants who receive early rescue surfactant using INSURE have lower rates of CLD and air leaks, and a reduced need for mechanical ventilation, when compared to infants who received surfactant later and had continued mechanical ventilation.
seconds) increased the risk of air leak and pre-discharge mortality, compared to a shorter inspiratory time of 0.33 seconds. No difference in rates of CLD was demonstrated. Longer inspiration times are also more likely to lead to asynchrony with the ventilator, and patient discomfort. Animal studies implicated over-distension of the lung parenchyma (volutrauma) as a key mechanism of lung injury, leading to CLD. Modern neonatal ventilators with flow sensors can target a set tidal volume for each breath, as opposed to more traditional time-cycle, pressure-limited ventilation. Volume targeted ventilation (VTV) has been shown to significantly reduce the combined outcome of CLD and death (RR 0.73, CI 0.57e0.93), as well as pneumothorax, duration of ventilation, hypocarbia and the combined outcome of periventricular leukomalacia and Grade 3 e4 intra-ventricular haemorrhage (IVH). The short-term benefits of VTV suggest it could be the mode of choice in preterm infants; however there is little data currently assessing long-term outcomes. There is currently a paucity of data regarding the optimal tidal volume to use, but most studies have used a volume between 4 and 6 ml/kg. Oscillation High frequency oscillatory ventilation (HFOV) is a supraphysiological method of providing respiratory support, by creating a constant distending pressure (mean airway pressure, MAP) to the lungs with pressure variations (up to 900 per minute) around the MAP, creating small tidal volumes. For preterm infants, although there are very few studies into this area, rescue HFOV has not been shown to provide better outcomes than conventional ventilation, apart from a reduction in air leaks. Although it was theorised that elective HFOV may provide a better alternative to conventional ventilation, a review of seventeen trials comparing elective HFOV to conventional ventilation in preterm infants showed no improvement in mortality. The evidence suggested a borderline significant improvement in rates of CLD for those receiving elective HFOV, but showed a significant improvement in those infants who had not received surfactant. There was a small, but significant, increase in the rates of air leaks for infants receiving HFOV. This review was limited by the studies included using different equipment to generate the HFOV.
Inhaled nitric oxide Inhaled nitric oxide (iNO) is a potent vasodilator of the pulmonary vascular network and is commonly used for term infants with persistent pulmonary hypertension, hypoxaemia and severe respiratory failure. A review has shown no improvement in survival or rates of CLD in hypoxic preterm infants treated with iNO, with no additional benefit on neurological outcomes. Analgesia and paralysis Although mechanical ventilation is a life-saving intervention, it is also a potentially uncomfortable and painful one for neonates. Opioids have been found to significantly reduce objective pain scores, although there is substantial heterogeneity in scores utilised by studies. They seem to make no difference to length of ventilation (in days), mortality, rates of BPD, or neurodevelopmental outcome. There is also a suggestion that preterm neonates who received opioids may take longer to reach full enteral feeds, and can have significant hypotension. From the few studies comparing analgesia and sedation whilst ventilated there is no significant difference between the two. Infants who are ventilated and breathing in asynchrony with the ventilator are potentially exposed to more discomfort and increased barotrauma. A review of ventilated preterm infants who underwent neuromuscular paralysis (all with pancuronium) found no difference in mortality, air leak, oxygen dependency, duration of ventilation, or rates of CLD for paralysed ventilated infants, but did show a reduction in rates of IVH for the paralysed group breathing in asynchrony.
Surfactants RDS is caused by either a deficiency or dysfunction of pulmonary surfactant. Initial clinical studies examined whether an animal derived surfactant delivered to the infant at birth would help to improve outcome. One of the first reviews of these papers found that prophylactic administration of surfactant reduced the rates of pneumothorax, pulmonary interstitial emphysema and the combined outcome of CLD or death, but not CLD alone. It also improved oxygenation and ventilator requirements by 48e72 hours of life. The studies included in this trial used a mixture of surfactant types derived from porcine, modified bovine, calf lung or human amniotic fluid sources. Early synthetic surfactants had lower protein contents compared to natural surfactants, and comparative reviews between the two types showed that, although synthetic surfactants still made a clinical improvement, natural surfactant products were superior. A Cochrane review in 2009 suggested that multiple doses of animal-derived surfactant
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Dexamethasone seems to have short-term benefits; however, it is not routinely recommended due to serious longterm neurodevelopment risks.
Infant position seems to make little difference in the efficacy of ventilation, apart from infants who are nursed in the prone position, who show better oxygenation and a decreased frequency of desaturation. This seems to be most useful for infants who are stable on ventilation or weaning ventilation. Oral intubation seems to result in lower incidence of post-extubation atelectasis compared to nasal intubation.
Non-invasive respiratory support Extubation of preterm infants onto non-invasive ventilation (NIV) such as nasal CPAP (nCPAP) has been shown to be beneficial. There is robust evidence that infants who receive nCPAP, with a PEEP equal or greater than 5cm H2O following extubation, have reduced risk of requiring further mechanical ventilation than infants who are extubated onto oxygen alone, or a PEEP less than 5cmH2O. This improvement is evident even in infants who do not receive methylxanthines pre-extubation. CPAP also shows benefits for infants failing oxygen therapy alone, reducing their need for mechanical ventilation. Nasal intermittent positive pressure ventilation (NIPPV) is another form of non-invasive respiratory support, which differs from CPAP in that it provides an intermittent inflation pressure on-top of a continuous PEEP. NIPPV appears to be superior to CPAP at preventing apnoea, respiratory failure and intubation in preterm infants who have been extubated from mechanical ventilation, or are having frequent and severe episodes of apnoea. Thus, a mode of non-invasive respiratory support should be considered routine for all preterm infants who are undergoing an extubation attempt. A continuous distending pressure (in the form of CPAP or continuous positive pressure) applied after birth has been shown to prevent atelectasis and preserve existing surfactant stores. Additionally, application of a continuous distending pressure after birth reduces the combined rate of death or use of mechanical ventilation, and overall mortality. Therefore, with the known risk of lung injury with mechanical ventilation, it appears preferable to stabilise infants on non-invasive respiratory support if they are spontaneously breathing at birth, rather than prophylactic intubation. High flow nasal cannulae (HFNC) deliver a heated and humidified air, or blended air and oxygen, supply via tapered nasal cannulae at flow rates more than1e2 litre/min. They have become increasingly popular in neonatal units over the past few years as a form of minimally invasive respiratory support, and tend to be used as a step-down from CPAP, and in some infants as the primary mode of support or following extubation. HFNC is thought to work by flushing out the dead-space in the airways, but may also provide a PEEP. A meta-analysis of recent trials found that HFNC was similar in efficacy to other modes of NIV in preterm infants when used as primary support (odds ratio [OR] of failure of therapy, 1.02, CI 0.55e1.88), as well as after extubation (OR 1.09, CI 0.58e2.02). There were no significant differences in odds of death (OR 0.48, CI 0.18e1.24) between the groups. Preterm infants supported on HFNC had significantly lower odds of nasal trauma (OR 0.13, CI 0.02 e0.69). However, limited data was available from extreme preterm infants, and caution needs to be exercised in this gestational age group.
Take home messages Synchronised ventilation is likely to be more physiological, and is routinely practiced in neonatal care. Exogenous surfactant replacement, as prophylaxis or for rescue treatment of RDS, is of proven value and should be routine. Natural surfactants seem to be clinically superior to current synthetic surfactants. Volume targeted ventilation significantly improves shortterm outcomes in preterm infants, and should be considered as a primary mode. Although they reduce pain, routine use of opioids is not recommended.
Weaning and extubation from mechanical ventilation Failed extubation and subsequent re-intubation may well result in additional stress and trauma to the preterm infant, and there have been several studies examining the best way to prepare the infant for a successful extubation. A trial of CPAP via the endotracheal tube (ETT) prior to extubation, instead of extubating the infant from low-rate mechanical ventilation, showed increased risk of extubation failure, possibly due to increased apnoeas; direct extubation from lowrate ventilation is recommended. It is felt that ETT CPAP increases the infant’s work of breathing, and the infant may tire prior to extubation. Systemic corticosteroids are commonly used to prepare an infant for extubation if they have been mechanically ventilated for a prolonged period, have required higher ventilator settings or have failed previous extubation attempts. Steroids may help to reduce upper airway swelling (caused by the endotracheal tube) and reduce inflammation in the lungs. Early (less than8 days) use of dexamethasone has been shown to significantly reduce the need for reintubation in those infants who are at higher risk for extubation failure. However, serious long-term concerns remain regarding neurodevelopmental outcome, and therefore if it is used, the dose and duration of treatment should be as restricted as possible. Preterm infants can have poor respiratory drive, and this can complicate weaning and extubation from mechanical ventilation. Methylxanthines (the most commonly used preparation is caffeine) have been shown to greatly improve extubation success by one week of age. Additionally, methylxanthines have been shown to decrease rates of CLD, cerebral palsy/poor neurodevelopmental outcome and mortality. Therefore it is common practise for all preterm infants to begin caffeine treatment as soon as possible.
Take home messages The use of a mode of non-invasive respiratory support after extubation from mechanical ventilation is clinically beneficial, and should be considered routinely.
Take home messages There is robust evidence of benefit for methylxanthines and they are recommended for routine use.
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HFNC seems to have similar efficacy to other modes of NIV in moderate to late preterm infants.
Regardless of the contributing factors, use of mesenchymal stem cells to stimulate lung growth and repair is an attractive therapy, which needs further research. In summary, robust evidence supporting many areas of neonatal respiratory support has been collected over the last two to three decades. When implemented into practice, they have significantly improved clinical outcomes. However, significant gaps in our knowledge and evidence base remains, which could become attractive research topics. A
Weaning from respiratory support Weaning from respiratory support for preterm infants is a controversial area and many different techniques have been tried with little evidence or research undertaken. Historically, infants have commonly cycled on and off nCPAP for a set number of hours each day in some units, whereas in others CPAP was simply discontinued when it was felt they would manage without support. Only one review has been undertaken into this topic, showing that infants who had their CPAP stopped after weaning to a set pressure spent less total time on CPAP, had lower oxygen requirements off CPAP and shorter hospital stays compared to those infants who cycled on and off CPAP. However the data for this review was limited, with no information on whether different techniques were better for different groups of patients, and there was little information on how the CPAP pressure was being generated in the studies. There are currently no published reviews on weaning HFNC, although one is currently in progress.
FURTHER READING 1 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; CD004454. 2 Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev 2013; 12: CD001058. 3 Tan A, Schulze A, O’Donnell CP, Davis PG. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev 2005; CD002273. 4 Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2012; 3: CD000510. 5 Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2009; CD000141. 6 Wheeler K, Klingenberg C, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane Database Syst Rev 2010; CD003666. 7 Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; CD000399. 8 Cools F, Henderson-Smart DJ, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev 2009; CD000104. 9 Davis PG, Henderson-Smart DJ. Intravenous dexamethasone for extubation of newborn infants. Cochrane Database Syst Rev 2001; CD000308. 10 Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev 2010; CD000139. 11 Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003; CD000143. 12 Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev 2014; 9: CD003212. 13 Kotecha SJ, Adappa R, Gupta N, Watkins JW, Kotecha S, Chakraborty M. Safety and efficacy of high-flow nasal cannula therapy in preterm infants: a meta-analysis. Pediatrics 2015; 136: 542e53.
Summary and future perspectives Prematurity increases the chance of requiring respiratory support. Premature labour and rupture of membranes is a complex condition, with multiple factors contributing to eventual delivery. Several trials and strategies have been attempted to delay preterm birth, including oral antibiotic prophylaxis after premature rupture of membranes, tocolytics to reduce uterine contractions, cervical stitches, and several drugs (ambroxol, magnesium sulphate, betamimetics etc.). The only drug which has shown some benefit in women who are at risk of preterm delivery (previous preterm infant, short cervix) is progesterone, although it did not have any beneficial effect in established preterm labour. Research into identifying treatable causes of prematurity, its prediction and prevention, is urgently needed in the next few years. Neonatal respiratory support has progressed from mechanical ventilation to more non-invasive modes. Two key interventions, which have significantly improved respiratory outcomes of preterm infants, are antenatal corticosteroids and exogenous surfactant replacement therapy. So far, the most reliable method of delivering surfactant is through an endotracheal tube with mechanical ventilation. Knowledge of the adverse effects of mechanical ventilation has increased the popularity of nCPAP, and data from clinical trials have demonstrated their benefits. Both surfactant and nCPAP have individually improved respiratory outcomes after preterm birth. Currently, trials are attempting to combine the beneficial effects of both of these interventions by attempting the deliver surfactant through minimally invasive methods while supporting on nCPAP. CLD is a multi-factorial end effect that is commonly seen in ex-preterm infants. While several risk factors have been identified which contributes to its development, a clear mechanistic pathway is yet to emerge. Attempts to treat CLD have been equally frustrating as attempts at preventing preterm delivery.
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