Management Respiratory Distress Syndrome Infants Health And Social Care Essay

Respiratory distress syndrome (RDS) is one of the most common consequences of prematurity and a leading cause of neonatal mortality and morbidity as a result of immature lungs. RDS particularly affects neonates born before 32 weeks of gestational age but is also recognised in babies with delayed lung maturation of different aetiology i.e. maternal diabetes. Since its initial recognition there have been vast advances in understating the pathology and management of this complex syndrome. However, in order to understand the pathology behind RDS it is imperative to obtain a good foundation of normal lung maturation and physiological changes that occur in the respiratory system during the transition from fetal to neonatal life.

Physiological Development and Function of the lungs

During intrauterine growth, fetal lung development begins as early as 3 weeks and progresses until 2-3 years. Conventionally it is divided into 5 stages; embryonic, pseudoglandular, canalicular, saccular and finally alveolar1 (Table 1). During the embryonic stage, the lungs develop from the fetal ectoderm to form the trachea, the main bronchi, the five lobes of the lung and the major blood vessels that connect the fetal lungs to the heart; the pulmonary arteries. This is followed by the pseudo glandular stage which results in the formation of the terminal bronchioles and associated primitive alveoli. These then further divide in the Canalicular stage to form the primary alveoli and subsequently the alveolar capillary barrier. This stage also comprises the differentiation of Type 1 and 2 pneumocytes which will later go on to produce surfactant. Thus babies born after 24 weeks, have a chance of survival as the platform for basic gas exchange has begun to develop. During the saccular stage there is further differentiation of type 1 and type 2 pneumocytes and the walls of the airways, in particular the alveoli, thin to enlarge the surface area present for gaseous exchange. This is followed by the alveolar stage which occurs through the transition form fetal to neonatal life up until 2-3 years. The hallmark of this stage is alveolar formation and multiplication to augment the surface area available for gas exchange to meet the increasing respiratory demands as the infant grows.

Stage

Time period

Structural Development

Embryonic

0-7 weeks

Trachea, main bronchi and five lobes of the lungs develop from the fetal ectoderm. Pulmonary arteries form and connect to heart.

Pseudoglandular

7-17 weeks

Formation of terminal bronchioles and alveoli

Canalicular

17-27 weeks

Formation of alveoli-capillary barrier and differentiation of type I and II pneumocytes

Saccular

28-36 weeks

Walls of airway thin for efficacious gas exchange

Alveolar

36 weeks -2 years

Alveolar multiplication

Table 1: Stages of Lung Development

Once the pulmonary epithelium develops, it begins to secret fluid into fetal lungs, the volume and rate of which is imperative for normal lung growth. Another important factor essential for normal lung development and function is the production of surfactant.

At about 24 weeks of gestation the enzymes and lamellar bodies required for surfactant production and storage begin to appear 3. Thus a normal fetus age is not ready to be delivered at this stage due to surfactant deficiency. As type II pneumocytes mature between 32-36 weeks, surfactant production increases and it is stored in the lamellar bodies of these cells.

Surfactant is a complex mixture of phospholipids, neutral lipids and proteins 1, 4 that has a fundamental role in maintaining the alveolar-capillary interface and reducing surface tension. It is secreted as a thin film at the liquid-air barriers to facilitate alveolar expansion and prevent end-expiratory collapse of small alveoli, especially at low alveolar volumes.

A key event in the development of the lungs is the establishment of spontaneous breathing post-delivery. Prior to delivery the fetal lungs decrease lung fluid production and as the lungs mature there is simultaneous maturation of the lung lymphatic system. During labour the mechanical compression of the fetal chest forces about 1/3 of this lung fluid thus preparing the fetus for spontaneous ventilation. This will require several stimuli; including hypoxia, hypercrabia and acidosis as a results of labour5 and hypothermia and tactile stimulation. Furthermore the stress of labour stimulates chemo-receptors in the fetal aorta and carotids to trigger the respiratory centre in the medulla to commence breathing. As the fetus emerges from the birthing canal, the fetal chest re-expands creating negative airway pressure which subsequently draws air into the lungs. This again forces the lung fluid out of the alveoli and allows for adequate lung expansion. As the newborn cries there is further expansion and lung aeration generating positive intrathoracic pressure which maintains alveolar patency and forces any remaining fluid into the lymphatic circulation.

As the neonate adapts to extra-uterine life, the normal muscles of respiration work to maintain breathing (Figure 1). In order to inhale, the diaphragm and external intercostals muscles contract to increase the size of the thorax. This generates negative air pressure in the pleura and lowers the air pressure in the lungs so that the gradient between atmospheric air and alveolar air causes air to enter into the lung of the neonate. As the neonate inhales, the elastic recoil force of the lung increases. Once inspiration ceases, the elastic recoil force of the lung causes expiration. The diaphragm and external intercostals muscles relax, the thorax returns to its pre-inspiratory volume resulting in an increase in intra-thoracic pressure. This pressure is now greater than atmospheric pressure and air moves out of the lungs producing exhalation.

Figure 1: The Mechanics of breathing6

For most neonates, this transition from fetal to extra-uterine life is uneventful and completed during the first 24 hours of life. The neonate is able to establish good lung function, maintain cardiac output and thermoregulate. However, for a certain population of neonates, usually those that are born early and thus called preterm, this transition is less smooth and it is these babies that will require the support and care of the whole paediatric department.

Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) is the most prevalent disorder of prematurity and despite a better understanding of its aetiology and pathology, RDS still accounts for significant neonatal mortality and morbidity. The incidence RDS is inversely proportional to gestational age2 such that it decreases with advancing gestational age, from about 60-80% in babies born at 26-28 weeks, to about 15-30% in babies born at 32-36 weeks 1. Risk factors for developing RDS are summarised in Table 2 and include maternal illness, complications during pregnancy and labour and neonatal complications

Table 2: Risk Factors for RDS1

Respiratory distress presents early in post-natal life particularly during the phase of transition from fetal to extra-uterine life. These babies will present with signs of grunting, cyanosis, nasal flaring, intercostal and subcostal recession, increased respiratory effort, and less commonly apnoeic episodes and circulatory failure. The severity of symptoms experienced are related to the pathology of disease and it is important to identify babies at greatest risk and commence management early in order to prevent respiratory complications such as chronic lung disease (previously called bronchopulmonary dysplasia), pulmonary hypertension and in adverse cases respiratory failure and even death.

Identifying normal transition and respiratory distress is largely based on evaluating the risk factors for RDS, assessing the severity of symptoms and close neonatal observation if in doubt. Babies that are born close to term or those via caesarean section may display a difficult albeit a normal transition. These babies present with transient tachypnoea of the newborn in the first few hours with respiratory rates of about 100 breaths per minute and increased oxygen requirements. Symptoms are short lived, self limiting in most cases and usually relived by oxygen. Neonates who suffer from RDS will present with worsening symptoms of longer duration, respiratory rates of 120 and increased respiratory effort with a longer requirement for oxygen. Recovery if plausible usually begins after 72 hours and is associated with decreased oxygen requirements and better functional residual capacity.

Pathophysiology of Respiratory Distress Syndrome

Since its initial recognition, more than 30-40 years ago, much has been elucidated about the pathophysiology of this complex syndrome. In the premature neonate, the structurally immature and surfactant deficient lung is unable to maintain the basic lung mechanics required for adequate ventilation. As aforementioned lung mechanics rely on surfactant production, alveolar multiplication and maturity for effective gas exchange, chest wall elasticity and a functionally developed diaphragm. It is therefore evident that premature neonate who lack surfactant and have structurally immature lungs will develop RDS, atelectasis and abnormal lung function. In these neonates the essential first breaths are followed by a secondary pathological cascade characterised by tissue damage, protein leakage into the alveolar space and inflammation, which may resolve or progress to BDP or chronic lung disease of prematurity (CLD)7.

In neonates with RDS, end-expiration results in the collapse of alveoli due to surfactant deficiency and a subsequent reduction in the functional residual capacity (FRC). The FRC is the volume available for gaseous exchange i.e the volume of gas left in the lungs after exhalation. It is determined by an intricate balance between the collapsing and expanding forces of the chest wall and lungs7. An ideal FRC enables the best possible lung mechanics, efficient ventilation and gaseous exchange.

As the FRC is reduced at end-expiration due to alveolar collapse due to high surface tension, the pressure that will be required to re-inflate the already immature lungs is increased. This in turn increases the respiratory effort needed for adequate gas exchange which presents clinically as increased respiratory rate and subcostal/intercostal recession. Moreover reaching an optimal FRC may be further impeded by both surfactant deficiency and by the preterm infant’s impaired ability to clear fetal lung fluid. Radiographically a chest x-ray will show the characteristic “ground-glass ” appearance with diminished lung volumes and the cardinal features of respiratory stress, tachypnoea, nasal flaring, intercostals recession, subcostal recession, increased breathing effort and grunting will begin to manifest early on.

Despite this effort to breathe, alveolar ventilation remains poor. As these areas are receiving an adequate blood supply this produces a ventilation/perfusion mismatch resulting in right to left intrapulmonary shunting1. The lungs are unable to maintain good gas exchange and blood oxygen saturation and the level of carbon dioxide begins to increase resulting in respiratory acidosis, hypoxaemia and hypercarbia. The neonate further struggles to breath and attempts to generate higher negative pleural pressures to ventilate the lungs. The ensuing acidosis further diminishes surfactant production and neonates deteriorate rapidly as blood oxygen saturations plummet. The natural progression of the disease if left untreated will lead to pulmonary oedema, right-sided heart-failure and ultimately the most devastating outcome, neonatal death.

Therefore the management of these neonates requires an aggressive multi-disciplinary team approach based on the pathology of these aforementioned homeostatic mechanisms. Alongside this the basic principles of neonatology; thermoregulation, nutritional support, efficacious cardiovascular support and infection control, are all fundamental in achieving the best therapeutic goal. Ultimately the aim is to provide adequate ventilatory support, allow the lungs to heal, impede further pulmonary injury, correct hypoxaemia and acidosis and above all to keep the neonate alive.

Management of RDS

As aforementioned the aim of treatment is to promote lung healing and reduce further pulmonary insults. We have already established that with increasing gestational age, particularly post-32 weeks, the infant will require less aid to help it cope with the transition from fetal to neonatal life. However, before 32-weeks there is an increased propensity to develop RDS and as the neonate is unable to cope, some form of respiratory support is required. Over the past 40 years there have been numerous management therapies including ventilatory support, surfactant therapy, nitric oxide therapy and supportive therapeutics strategies amongst others. The mainstay of treatment today remains supportive and involves the use of antenatal steroids, surfactant replacement therapy, continuous positive airway pressure and mechanical ventilation, which all aim to address the pulmonary insufficiency that manifest in these individuals

Antenatal Glucocorticoids

Glucocorticoid receptors are expressed in the fetal lung at early gestation and as the fetus grows stimulate surfactant production post-32 weeks. Alongside receptor expression there is an increase in fetal cortisol levels at late gestation9, which coincides with lung maturation, type II pneumocyte differentiation, surfactant synthesis as well as alveolar thinning. If birth occurs before this increase in serum cortisol, the pulmonary system has not matured adequately and therefore there is an increased propensity to develop RDS. Thus a single dose of glucocorticoids such as dexamethasone or betamethasone in the antenatal period promotes lung maturation.

One of the first published reviews that showed the efficacy of antenatal steroids in preterm labour was produced by Crowley in 19958. Crowley showed that steroids given in preterm labour were effective in preventing RDS and improving neonatal mortality rates. Since then several randomised controlled clinical trials have evaluated the efficacy of steroids in reducing RDS. A recent Cochrane review of 21 trials assessed the effects of antenatal corticosteroids, given to women expected to go into preterm labour, on fetal/neonatal mortality and morbidity8. The authors concluded that a single dose of antenatal steroids promoted fetal lung maturation thereby reducing the risk of RDS and the need for assisted respiratory management. The mechanisms by which glucocorticoids are thought to exert their efficacy are described below.

Firstly, glucocorticoids stimulate phospholipid production. Phospholipids are a major component of endogenous surfactant and as a result augment surfactant synthesis in the biochemically immature and surfactant deficient lung 9, although the exact mechanisms by which this occurs remains to be elucidated. Secondly glucocorticoids enhance lung maturation and development. As aforementioned, in order to produce surfactant, fetal lungs must produce type II pneumocytes which will then generate lamellar bodies in which surfactant is stored. Glucocorticoids enhance this process, promoting pulmonary epithelial cell maturity and differentiation into type II pneumocytes9. Furthermore glucocorticoids cause a decrease in pulmonary interstitial tissue thereby decreasing alveolar wall thickness. A thin alveolar wall thickness facilitates efficacious gaseous exchange and will therefore assist ventilation and oxygenation of the neonate once born thus decreasing the chances of developing RDS. Another known benefit of antenatal glucocorticoids is found in reducing oxidative stress on the immature lung and prevention of pulmonary oedema9.

This accumulative evidence suggests that glucocorticoids are essential for normal pulmonary development and giving a single dose to mothers at risk of preterm birth may substantially decrease the chances of the infant developing RDS.

Surfactant Therapy

As discussed before, endogenous surfactant has a fundamental role in maintaining the alveolar-capillary interface in order to prevent end-expiratory alveolar collapse. This is achieved by thin spread of surfactant around the alveoli which ultimately acts to reduce surface tension. The most important component of surfactant which achieves this fundamental function is a phospholipid called dipalmitoylated phopshatidylcholine (DPPC)11. DPPC also stabilises the alveoli at end expiration, further preventing alveolar collapse. Alongside DPPC the synergistic actions of surfactant proteins (SP) SP-B and SP-C also lower surface tension11. Thus a deficiency in surfactant will cause alveolar collapse, decrease pulmonary compliance, increased pulmonary vascular resistance and produce ventilation-perfusion mismatch. Hence the aim of exogenous surfactant therapy is to reverse this pathological cascade and ultimately prevent alveolar collapse thereby limiting pulmonary damage and improving ventilation.

Since the first clinical trial assessing the use of surfactant in managing neonatal RDS by Fujiwara in the 1980s10, our understanding of the composition, structure and function of surfactant has progressed vastly. In this uncontrolled trial the chest x-rays of 10 babies diagnosed with RDS, both clinically and radiologically, showed significant improvement after exogenous modified bovine surfactant was administered with a decreased requirement for ventilation. Since then several randomised controlled trials12 have shown that surfactant therapy, alongside antenatal steroids and ventilation continues to improve neonatal morbidity and mortality.

Both natural (derived from an animal source) and synthetic (manufactured chemically) surfactants are available to use in managing RDS. Meta-analysis of trials comparing the two types of surfactant have shown that natural surfactants show a more rapid response in improved lung compliance and oxygenation12 thereby reducing neonatal mortality. Furthermore natural surfactants are less sensitive to inhibition by accumulative products of lung injury such as serum proteins.

Surfactants need direct delivery to lungs and usually require intubation with short periods of assisted ventilation. Traditionally two therapeutic approaches have been established in managing RDs with surfactant. The first adopts the use of surfactant prophylactically, with surfactant given immediately after birth to enable the neonate to cope with extra-uterine life. The obvious benefit of this approach is that surfactant is administered to the baby before severe RDS develops resulting in long-term pulmonary sequelae for the neonate. However this technique is invasive, as surfactant administration requires endotracheal intubation, it is expensive and furthermore it may result in the unnecessary treatment of neonates. Moreover poor intubation with failed attempts and prolonged apnoeic episodes may further damage the lungs resulting in CLD. Despite this, there is a strong body of evidence for prophylactic use of surfactant and current guidelines state that all preterm babies born before 27 weeks of gestation, who have not been given antenatal steroids should be intubated and given surfactant at birth7.

The second therapeutic approach evaluates the role of surfactant in rescue treatment used in neonates with an established diagnosis of RDS requiring ventilation and oxygen. The advantages of rescue treatment include that it is reserved for neonates in whom RDS is confirmed and it may decrease the morbidity associated with unnecessary intubation. The obvious disadvantage is that delay in surfactant delivery may allow for irreversible lung injury to develop with decreased efficacy of surfactant administration12.

Several studies have aimed to clarify the issue between prophylactic and rescue surfactant treatment. A randomised trial by Rojas et al. showed the benefits of surfactant delivery within 1h of birth in neonates born between 27-31 weeks14 with an established diagnosis of RDS who were treated with continuous positive airway pressure soon after birth. 279 infants were randomly assigned either to the treatment group (intubation, very early surfactant, extubation, and nasal continuous positive airway pressure) or the control group (nasal continuous airway pressure alone). The results of this study demonstrated that infants in the treatment group i.e. those treated with surfactant, showed a decreased need for mechanical ventilation with a decrease in the incidence of CLD and pneumothoraces. Neonatal mortality rates were similar between both groups.

A meta-analysis by Soll and Morley compared the effects of prophylactic surfactant to surfactant treatment of established respiratory distress syndrome (i.e. rescue treatment) in preterm infants33. The authors analysed eight studies comparing the use of prophylactic and rescue surfactant treatment and concluded that the majority of the evidence demonstrated a decrease in the incidence of RDS when surfactant was given prophylactically. Moreover the meta-analysis showed that infants treated with prophylactic surfactant had a better clinical outcome with a reported decrease in the risk of pneumothorax, pulmonary interstitial emphysema, CLD and mortality33.

As a result of such studies most neonatal units continue to practice delivery of surfactant prophylactically in preterm babies at high risk of RDS. However, some literature still debates whether there are any real advantages of prophylactic surfactant over rescue treatment. What is evident is that surfactant therapy should play a fundamental role in the management of RDS. Future trials will need to further assess the indications for surfactant therapy in treating neonatal RDS and perhaps in the management of other pulmonary insufficiency disorders that affect the neonate. Although much remains to be elucidated about the complex pulmonary surfactant system, since its introduction 25 years ago, surfactant therapy has been at the forefront of reducing RDS and its role in decreasing neonatal mortality and morbidity cannot be disputed.

Mechanical ventilation

Mechanical ventilations is one of the cornerstones of neonatal intensive care units and regardless of the modality used, the primary function is to maintain adequate oxygenation and ventilation. The goals of mechanical ventilation are:

to establish efficacious gaseous exchange

to limit pulmonary insult and CLD

to reduce the respiratory effort and work of breathing of the patient

To achieve these basic goals several techniques, devices and therapeutic options are available to the neonatologist that can be either invasive or non-invasive.

Continuous Positive Airway Pressure

The use of CPAP; continuous positive airway pressure, in the treatment of RDS was first described in the 1970’s and has since been identified as a important management strategy. CPAP applies positive end expiratory pressure (PEEP) to the alveoli throughout inspiration and expiration so that the alveoli remain inflated thereby preventing collapse. The pressure required to re-inflate the lungs is reduced as partially inflated alveoli are easily to inflate than completely collapsed ones.

Animal studies with premature lambs have shown the benefits of nasal CPAP over mechanical ventilation. CPAP acts to lower the markers for CLD for example granulocytes, and markers of white cell activation, increases the amount of surfactant available, improves oxygenation and lastly corrects ventilation/perfusion mismatching2, 15. Moreover CPAP produces a more regulated pattern of breathing in neonates by stabilising the chest wall and reducing thoracic distortion16.

Like surfactant therapy there are two ways in which CPAP can be administered. The first method, InSUrE: intubation, surfactant and extubation, adopts a brief intubation to administer surfactant and extubation to CPAP approach and the second is the Columbia method in which babies are started on CPAP in the delivery room and are only mechanically ventilated, and intubated if the need for surfactant is established.

Several studies have shown the benefit of the first approach. A study by Verder et al. randomised 68 neonates with moderate to severe RDS; 35 infants were randomised to surfactant therapy following a short period of intubation and then extubation to CPAP and 33 neonates were randomised to nasal CPAP alone. The results of this study showed that infants in the earlier group had a reduced need for ventilation; 21% in comparison to 63% in the second group16,17. Another similar trial by Haberman et al. assessed the use of surfactant with early extuabtion to CPAP and subsequently the results showed a decreased need and duration for mechanical ventilation12. Furthermore a recent Cochrane review of six studies using the InSuRE method showed that neonates with RDS treated with early surfactant therapy followed by nasal CPAP, were less likely to need mechanical ventilation and develop air leaks in comparison to neonates that were treated with the Columbia approach (i.e. early CPAP therapy followed by surfactant if needed)17, 18. A more recent review by the same authors further confirmed the findings of the initial review and the relative risk for developing CLD was 0.51 (95% CI 0.26-0.99) with early surfactant treatment and nasal CPAP when comparing the two methods18.

The Columbia method requires the stabilisation of neonates with CPAP in the delivery room with intubation and surfactant therapy used as necessitated. This approach was adopted when retrospectives studies done by Avery et al. and later Van Marter et al. evaluated the clinical outcomes in multiple neonatal units across the US2. In both cases a lower incidence of CLD was observed in the Columbia University Hospital which adopted CPAP as a primary treatment strategy as opposed to intubation and mechanical ventilation like other units. Leading on from this Ammari et al.. evaluated the Columbia method recently. The outcomes of 261 neonates with birth weight < 1250g that were managed on respiratory support, either CPAP or ventilators, were reviewed at 72 hours. Their results showed that infants started on CPAP were more mature and weighed heavier at 3 weeks in comparison with those that were ventilator started with a lower mortality rate reported in the CPAP group (9%) than in the ventilator group (66%). The results of this study highlighted that perhaps a large number of very preterm babies (gestation <27w) could benefit from early CPAP treatment.

So far the evidence base for the Columbia method has been derived from retrospective cohort studies with a lacking in RCTS and therefore a lack of stronger evidence. One RCT that had aimed to evaluate the Columbia method was the recent COIN trial by Morley. This study evaluated whether the incidence of death or BPD would be reduced by CPAP rather than intubation and ventilation shortly after birth13. 610 neonates born between 25-28 weeks were randomised to CPAP or intubation and ventilation at 5minutes after birth and surfactant was administered at the neonatologists’ discretion. The results of the study demonstrated that at 28 days of gestation, infants in the CPAP group had a decreased need for supplemental oxygen and fewer deaths2,13. However worrying results from this study were that approximately 46% of babies in the CPAP group went onto require intubation and had a higher rate of pneumothoraces13.

There are few randomised control trials assessing the benefit of CPAP alone in managing RDS and the results of the Columbia Hospital study have been irreproducible in other centres. The mainstream use of CPAP for managing RDS remains to start CPAP in the delivery room, after intubation for surfactant treatment. There is not enough evidence to show that CPAP alone can prevent RDS and associated complications in comparison with invasive ventilation. The evidence does suggest that there is a decrease in complications with surfactant therapy and CPAP but the relationship with CLD is less transparent.

At present there are two RCTs ongoing that may provide further insight into the role of CPAP in RDS when complete. The first trial is the SUPPORT study, which is randomising infants between 24-27 weeks to CPAP beginning in the delivery room with stringent criteria for subsequent intubation, or intubation with surfactant treatment within 1 h of birth with continuing mechanical ventilation2. The second is the trial by the Vermont-Oxford Network in which infants born at 26-29 weeks gestation will be randomised after 6 days into one of three groups; (1) intubation, early prophylactic surfactant, and subsequent stabilisation on mechanical ventilation; (2) intubation, early prophylactic surfactant, and rapid extubation to CPAP; and lastly (3) early stabilisation with nasal CPAP, with selective intubation and surfactant administration according to clinical guidelines2. The immediate management of the RDS neonate with CPAP remains controversial and maybe the results of these ongoing RCTS will provide invaluable answers to the many uncertainties surrounding this device.

Nasal intermittent positive pressure ventilation

Another relatively recent development in non-invasive ventilation that has evolved from NICU ventilator machines and CPAP devices is the use of NIPPV for managing RDS. Sometimes called BiPAP (for bi-level positive airway pressure), this form of non-invasive ventilation is able to provide two levels of airway pressure, without the need for intubation. BiPAP maintains positive pressure throughout respiration but with a slightly higher pressure during inspiration. By doing so BiPAP/NIPPV is able to assist neonatal breathing by:

reducing the work of breathing

improving tidal volume

increasing blood oxygen saturation and increasing removal of CO2 thereby limiting hypoxaemia and respiratory acidosis.

As the neonate inhales, the NIPPV device generates a positive pressure thereby assisting the neonates spontaneous breath and providing ventilatory support. This is at a slightly higher positive pressure. As the neonate begins to exhale, the pressure drops, but a positive airway pressure remains in the lungs to prevent alveolar collapse and thus increase gaseous exchange.

NIPPV may be a potential beneficial treatment for the management of babies with RDS and has been used in NICU’s since the 1980s. Recently multiple studies have aimed to evaluate the efficacy of NIPPV in stabilising neonates. A randomised controlled prospective study by Kulgeman et al.. found that NIPPV was more successful than NCPAP in the initial treatment of RDs in preterm infants19. Kulgeman and his colleagues randomised infants <35 gestational age to either NCAP or NIPPV with 41 infants randomised to NCPAP and 43 to NIPPV. The results established that the failure rate in the NIPPV group was les in comparison to the CPAP group (25.6% vs. 48.8%, respectively, p=0.04).These findings not only documented the beneficial used of NIPPV over CPAP, but also demonstrated that there was a decreased incidence of CLD; 2% in the NIPPV group in comparison to 17% in the NCPAP group, (p-value <0.05)19.

A further study by Sai and colleagues also established the advantages of NIPPV over CPAP in managing RDs and reducing the need for mechanical ventilation and intubation in preterm infants. In their study 76 neonates between 28-34 weeks gestation with RDs at 6h of birth were randomised either to ‘early NIPPV’ (37 neonates) or ‘early CPAP’ (39 neonates) after surfactant use20. Firstly they documented that the failure rate with NIPPV was less in comparison to the CPAP group (p=0.024) and secondly that the need for intubation and mechanical ventilation by 7 days was less with NIPPV (18.9% vs. 41%, p=0.036)20. However unlike the study by Kulgeman and colleagues Sai et al. did not document a significant difference in the incidence of CLD but this can be attributed to the small sample size rather then there not being a statistical difference. In addition to the aforementioned results, Sai and colleagues also reported that the failure rate with NIPPV was less in two subgroups; (1)in neonates born at 28-30 weeks (p=0.023) and (2) neonates who did not receive surfactant (p=0.018).

As well as evaluating NIPPV against CPAP, two other RCTs evaluated the use of NIPPV compared to conventional mechanical ventilation. In the first study by Bhandari et al.. randomised 41 infants with RDS to receive synchronized NIPPV or conventional ventilation post surfactant and extubation21. 20 infants were assigned to synchronised NIPPV and 21 to conventional ventilation. The authors found that conventional ventilation produced a higher incidence of BPD or death than NIPPV (52% vs. 20%, respectively, p=0.03). The second study by Manzar and colleagues enrolled 16 neonates with RDS to NIPPV. None of the infants in this study required intubation or had significant complications related to NIPPV20,22.

An additional study by Moretti et al.. compared the effects of synchronized NIPPV against conventional NCPAP in decreasing extubation failures in preterm infants ventilated for RDS. In their study NIPPV proved more effective than NCPAP in smoothing the transition between mechanical ventilation and spontaneous breathing23. Infants who required intubation within 48h of birth and weighed < 1250g were randomised to either receive NIPPV (32 infants) or CPAP (31 infants). 94% of infants receiving NIPPV could be extubated successfully, in comparison to only 62% in the NCPAP group (p=0.005)23.

In a recent meta-analysis Davis et al.. aimed to determine whether using NIPPV in comparison to NCPAP decreases the rate of extubation failure and prevent respiratory complications. The authors noted a decrease in extubation failure in infants treated with NIPPV and also a clinically significant decrease in the risk of respiratory failure in infants who were extubated to NIPPV24. Davis and colleagues reported that the number needed to treat (NTT) for NIPPV as 3 (95% CI 2, 5). This result is clinically beneficial as it identifies that only 3 neonates need treatment with NIPPV to prevent one failure of extubation. The authors concluded that NIPPV is a beneficial tool in augmenting the effect of NCPAP in the preterm infant as it reduces the rate of extubation failure, symptoms of extubation failure and respiratory failure.

Whilst NIPPV may avoid some of the adverse effects related to CPAP and mechanical ventilation as well preventing extubation failures literature comparing the benefits of NIPPV to NCPAP is sparse. Larger studies evaluating the use of NIPPV as a primary therapy in providing respiratory support in surfactant treated infants are needed. Only then perhaps will the true benefits of this treatment unveil themselves.

Intermittent Mandatory Ventilation

Before vast advances in understanding mechanical ventilation and the development of new strategies, intermittent mandatory ventilation, IMV, was one of the only available modes of mechanical ventilation. Unlike newer techniques, with IMV the rate of mechanical breaths delivered by the ventilator was predetermined by clinicians that often resulted in asynchrony with the respiratory effort of the neonate leading to ineffective gas exchange and potential air leaks. However as technology has leaped in the 21st century, newer modes of ventilation to overcome this asynchrony have been developed.

High Frequency Ventilation

One technique that appeared to hold great promise for the management of RDS was high frequency ventilation (HFV) that aims to employ very low tidal volumes with high respiratory rates. This is thought to result in lower alveolar pressure thereby reducing the incidence of ventilator induced lung injury which is characteristically associated with high pressures and volumes of gas delivered by mechanical ventilators. There are three types of HFV devices including high-frequency oscillatory ventilation (HFOV), high-frequency flow interrupters (HFFI) and high-frequency jet ventilation

(HFJV)16. Whilst these techniques were initially held great hope for the management of RDS, several RCTs have shown limited benefits with increased concerns regarding the safety of these modalities.

A recent meta-analysis by Cools et al. evaluated the effect of HFOV in comparison to CMV (conventional mechanical ventilation) in reducing the incidence of CLD, mortality and other complications associated with preterm birth26. The authors included seventeen RCTS which compared HFOV and CMV in preterm infants with pulmonary dysfunction mainly due to RDS requiring assisted ventilation. Their outcomes reported no evidence of effect on mortality at 28 – 30 days of age and although a possible reduction in the rate of CLD with HFOV use was reported the evidence for this was inconsistent across the studies. The authors thus concluded that there is not enough substantial evidence to indicate advantages for the elective use of HFOV over CMV in preterm infants. Due to the inconsistency of evidence supporting HFOV, further studies are much needed to evaluate the effects of HFV on CLD, pulmonary outcomes and long-term sequelae in preterm infants.

Apart from the inconsistency in evidence concerns regarding the safety of high frequency ventilation have been raised. Initial concerns were raised in the HIFI study published in 1989, in which an association between HFOV and poor neurological outcome and subsequent disability was first established28. These concerns were echoed by Wiswell et al. who documented a higher rate of interventricular haemorrhage (IVH) and periventricular leukomalacia (PVL) with HFJV than CMV, as a result of hypocarbia7. As both of these complications are associated with adverse neurological outcomes, more studies probed this cause of concern further.

However a meta-analysis by Clark et al.. failed to verify the initial findings by Wiswell et el. The authors analysed nine studies comparing HFV and CMV to determine if neonates treated with HFV were at greater risk of developing either PVL or IVH in as compared to neonates treated with CMV for RDS. Overall, PVL and IVH were over represented in the HFV group however the results were largely influenced by the HIFI trial28. Once the authors excluded the results of this outdated trial, there was no difference in HFV and CMV in the occurrence of either PVL or IVH28. Thus the authors concluded that the association between HFV and poor neurological sequelae are primarily influenced by the HIFI trial and subsequent trials do not show confirm this association.

A recently published RCT, the UKOS trial, by the United Kingdom Oscillatory Study Group aimed to determine whether HFOV reduced mortality and CLD in preterm infants. A total of 797 infants between 23-28 weeks gestational were randomised to either conventional mechanical ventilation (397 infants) or high-frequency oscillatory ventilation (400 infants) within one hour after birth27. The results of the study showed that CLD or death occurred in 66% of infants assigned to the HFOV group and in 68% in the CMV group. As there were a similar incidence of CLD and death in each group, the authors postulated that there was no significant difference in the results obtained from both groups. Moreover the authors further concluded that HFOV is not associated with a significant increase in cerebral lesions as the prevalence of hemorrhagic brain lesions visible on ultrasound in their study was lower among infants who received HFOV27.

Whilst HFV does appear to show some benefit over CMV the evidence is not overwhelming enough to translate into a clinical policy for the management of RDS. Studies will need to evaluate the effect of HFV in very early management of RDS by randomising infants within hours of birth to HFV, CMV, CPAP, surfactant and other modalities of management, in relation to CLD and other outcomes. The results of such a study could shape ventilator policies for the future and ultimately decrease the effects of CLD and thus limits resource use in NICUs.

Patient Triggered ventilation

The aim of patient triggered ventilation, PTV, is to synchronise the infant’s respiratory effort with the mechanical ventilator so that the infant can trigger positive pressure inflations7. There are several modalities in which PTV can be delivered including synchronized intermittent mandatory ventilation (SIMV), Assist/Control ventilation (ASV) and pressure support ventilation (PSV). Several RCTs evaluating the different modes of PTV have established the short term benefits of this modality including decreased duration of mechanical ventilation and reduction in air leaks25. A recent meta-analysis of ventilation in RDS by Greenough et al.. showed that ASV and SIMV was associated with a shorter during of ventilation in comparison to conventional mechanical ventilation but neither demonstrated a significant reduction in the incidence of BPD25. The authors further concluded that whilst PTV demonstrated some short term benefits, more RCTs assessing the long term benefits of PTV as well as other short term outcomes are needed before this form of neonatal ventilation can be incorporated into clinical practice and guidelines.

Weaning

Although mechanical ventilation is often a life saving intervention, it is associated with a high rate of ventilator induced injury and hence it is vital to decrease the duration of mechanical ventilation in an attempt to decrease any associated morbidity. In order to do achieve this, it is of utmost importance that protocols initiating and guiding the weaning process of paediatric patients, to aid them from the transition from mechanical ventilation to spontaneous breathing, are developed. Although the evidence base in this area is lacking, a RCT by Shultz et al.. demonstrated shorter weaning periods when infants were randomised to protocol directed weaning as oppose to clinician directed weaning29. Results from this were echoed by Restrepo et al.. who also compared ventilator weaning time in a retrospective study. The results of the study showed that there was a significant decrease in ventilator weaning time (P= .005) is protocol directed patients as compared to non-protocol patients30. However both studies reported no significant difference in the duration of ventilation.

Another important issue concerning weaning is potential extubation failure and increased stay in special units for ventilated patients. As the incidence of mechanical ventilation is rising along with a rise in the number of preterm births, potentially a much greater burden will be placed on NICUs and healthcare resources in the future. Therefore it is important to identify risk factors for extubation failure in mechanically ventilated patients as this ultimately means longer ventilation time and thus an increased cost.

Implications of RDS and preterm birth on the National Health Service

As aforementioned, respiratory distress syndrome is the most prevalent disorder of prematurity2. Thus any increase in the number of preterm births will ultimately result in an increase in the prevalence of RDS and ultimately contribute to the economic burden placed by prematurity on the NHS. Pre-term infants are vulnerable to problems associated with immaturity, a difficult transition to extra-uterine life and ultimately adverse long-term developmental outcomes. Although 7.2% of all births are pre-term, approximately 10% of all costs are acquired by preterm births31, and therefore every preterm birth imposes an increasing cost to the NHS and ultimately the public sector.

A recent study by Mangham et al. compared economic cost of pre-term birth and term birth from birth to adult life in England and Wales. The researches designed an analytical model to estimate costs to the public sector over the first 18 years following birth, stratified by gestational age at birth. The results of this study identified inversely proportional relationship gestation at birth and the average public sector cost per surviving child. In 2006 cost per preterm child surviving to 18 years compared with a term survivor was estimated at £22 88531. The study attributed the majority of the cost to admissions to neonatal services, for example to neonatal wards and intensive care units, but other relevant costs included management of the preterm birth in the delivery room, outpatient care, community health and social care as well as education amongst other costs.

Furthermore the study also revealed that of the annual £2.496 billion economic cost to the NHS, £1.956 billion, approximately 66%, can be attributed to moderate preterm birth alone; infants born at between 330⁄7 and 366⁄7 weeks gestation31. As we are able to care for infants from 22 weeks, the number of very-preterm babies being cared for on neonatal intensive care units are increasing and constitute a public health concern that costs society almost £2.5billion a year. Mangham and colleagues showed that the costs for caring for a very preterm baby (<33w) and extremely preterm babies (<28 weeks) were substantially increased to £61 509 and £94 190 respectively. As the incidence and severity of RDS increases with decreasing gestational age, RDS may be a significant factor contributing to the cost of caring for these very premature babies.

However the study does not consider the costs places on other services as these preterm babies grow older. For example any neurological insult may result in poor neurodevelopmental growth and be associated with development disorders such a cerebral palsy. IVH and PVL in the neonatal period as a result of ventilator management or oxygen insufficiency may also produce poor neurological outcomes. These infants will require special care and additional support throughout their paediatric and adult lives, placing a further burden on the public sector. As well as the direct cost of managing these babies which incorporates the value of the resources used to manage prematurity such as ventilator instruments, incubators, and training professionals with appropriate skills, there are also indirect costs which pose a substantial public health concern. Indirect costs comprise the value of resources lost to society32 such as loss of labour market productivity affecting economic growth as result of increased mortality and morbidity associated with preterm birth.

The physiological consequences of preterm birth are well established. Early complications such as RDS can result in adverse neurodevelopmental outcomes which are further complicated by iatrogenic insults such as ventilator injury in RDS. Approximately 1/3 of the total economic burden of preterm birth is borne during this neonatal period32, however there is less evidence for the cost of pre-term birth beyond this significant period. Additional costs to early hospitalisation will include costs to local authorities and voluntary organizations in providing skilled carers in later life, special educational establishments, and providing skilled teachers for preterm babies as well an income support. There are further substantial cost to public sector in providing support to families and informal caregivers, such as the costs of travel, child care, and accommodation31 which need identifying. Thus more literature is needed to understand the ongoing medical, educational, and productivity costs borne by the infant, family and the public sector.

Studies like the Mangham et al. are necessary more than ever before and could have fundamental implications for clinical practice and policy formation in the NHS. There may be potential to introduce policies that may reduce the preterm birth thus providing improved outcomes for infants, families and informal carers. Such policies could address issues surrounding the financing and organisation of health care resources ultimately improving the quality of care available to these infants. Models akin to that of Mangham et al. pose great potential to simulate the costs and outcomes of interventions aimed at preventing and managing preterm birth, alleviating its effect as well as facilitate the distribution of resources in paediatric and neonatal units. Furthermore public policies could be introduced to improve healthcare outcomes for preterm infants. However before such policies even begin to emerge on the horizon, a more grounded knowledge into the determinants of preterm birth, its management strategies and its effects is needed.

Conclusion

The management of respiratory distress syndrome in premature infants still remains a controversial issue. Much of the strategies employed depend on personal preference and experience of the managing clinician. Although prenatal and postnatal steroids have vastly reduced morbidity and mortality associated with RDS, chronic lung disease remains a major problem in preterm babies. The implementation of new ventilation therapies such as CPAP and HFV, have established little clinical improvement and the evidence base for effectiveness and long-term outcomes is weak. As the pathophysiology of RDS is multi-factorial studies assessing old and existing therapies in the management of RDS may yield results that could shape future policies and guidelines. Until further RCTs and prospective studies provide a strong evidence base for a particular therapy, clinicians should resists the temptation to favour new therapies and apply a multi-disciplinary approach along with the basic principles of neonatology to produce the best short and long-term outcomes for preterm babies.