Human lung development falls into distinct stages: the pseudoglandular stage from 5 to 17 weeks gestation, the canalicular stage from 16 to 26 weeks gestation, the saccular stage between 24 and 38 weeks and the alveolar stage from 36 weeks until 2 years. During the canalicular phase, there is ongoing branching of the respiratory bronchioles with thinning of the airway epithelium, so that by the end of this period there is some capability for gas exchange. During the saccular stage, the peripheral airways widen into saccules which then form the alveolar ducts, the precursor to alveoli. Infants born during this period do not have fully functioning terminal airways; there are fewer, thick-walled gas exchange units. The true alveolar stage does not start until 36 weeks gestation and continues postnatally until about 2 years of age. The development of fully functional alveoli is also dependent on development of the surrounding mesenchyme and the alveolar capillaries.

The transition from fetal life to newborn life involves multiple processes. The most important adaptation is the conversion of the lungs from a fluid-filled unit to air-filled spaces, capable of working as a gas exchange organ. In utero, the terminal airways are full of fluid secreted from the pulmonary epithelial cells. This fluid is an important determinant of lung growth. The volume of fluid is equivalent to functional residual capacity (FRC) post delivery. Following delivery, lung fluid is cleared. This process is slower and less efficient in preterm infants (Egan et al. 1984). The sequence of lung inflation, fluid clearance and rising pH controls the early fall in pulmonary vascular resistance and initial oxygenation. The action of the respiratory muscles overcomes the resistive properties of the airways to develop FRC and tidal volume (Sinha et al. 2008). Antenatal, perinatal and resuscitation events interact to affect the processes of lung fluid clearance, FRC development and maintenance of adequate tidal volume.

RDS is characterised by stiff non-compliant lungs with low levels of surfactant. Premature lungs have insufficient alveolarisation, decreased functional surface area, increased distance from alveoli to adjacent capillaries and reduced surfactant synthesis and show less hysteresis than normal lungs. The terminal airways collapse at end of expiration due to high surface tension. Tidal volumes are small and the dead space is relatively large. Infants are able to increase their respiratory rate to compensate for the low tidal volume. This means they may be able to maintain their minute volume, but the work of breathing is doubled (Hjalmarson and Olsson 1974; McCann et al. 1987). Most infants have some surfactant at birth (Reynolds et al. 1968) but levels fall within a few hours as alveolar protein leak inhibits function (Ikegami et al. 1983). Without exogenous surfactant infants tire, minute volume falls and hypoxia and acidaemia follows. This further increases surfactant inhibition.

Hyaline membranes are the characteristic histological finding in RDS and have given the disease its alternative name of hyaline membrane disease. In immature, stiff, surfactant deficient lungs, alveolar epithelial cell death starts to occur in the first hour after birth. Dead cells detach from the basement membrane, denuded patches appear, and protein leak leads to interstitial oedema. Hyaline membranes form; they consist of plasma protein, fibrin, cellular debris, red blood cells, macrophages and proteinaceous exudate. The material lines or fills the air spaces inhibiting gas exchange. Most of the protein leak occurs over the first 24 h (Ikegami et al. 1992). During this time the hyaline membranes, which are initially patchy, become more confluent. Ischaemia exacerbates RDS with epithelial necrosis occurring in the terminal airways. Asphyxiated infants have more severe RDS (Linderkamp et al. 1978) and respond less well to surfactant treatment (Skelton and Jeffery 1996).

After 24 h, inflammatory cell numbers increase and macrophages start to ingest the membranous material. Epithelial regeneration commences after 48 h and surfactant production starts to increase. Microscopically, the surfactant deficient lung is characterised by collapsed air-spaces alternating with hyper-expanded areas, vascular congestion and hyaline membranes. The lungs remain non-compliant and atelectatic until surfactant reappears at 36–48 h (Kanto et al. 1976). Hyaline membranes are broken down by the seventh day but will persist for longer if the infant is receiving mechanical ventilation. Healing is hyperplastic with shedding of the bronchiolar epithelial cells. Proteinaceous material in the terminal airways induces scarring and fibrosis in the developing alveoli and ultimately can lead to bronchopulmonary dysplasia or chronic lung disease (CLD).

The diagnosis of RDS is made on the basis of the clinical picture and the chest x-ray which demonstrates decreased lung volumes and a bell-shaped chest. Uniform infiltrates described as a ‘ground glass’ appearance involve all lobes of the lungs. Air bronchograms are seen as the infiltrate outlines the larger airways that remain air filled. In severe cases, the infiltrates are such that the cardiac and diaphragmatic borders become indistinct giving a ‘white-out’ appearance. Infants increase their respiratory rate, take smaller volume breaths and use accessory muscles to assist with their increased work of breathing. This results in nasal flaring and rib, sternal and subcostal recession. Infants attempt to stop alveolar collapse at end expiration by closing the glottis, resulting in grunting. As the infant tires, cyanosis develops and the infant develops apnoeic episodes with desaturations. Infants with RDS have decreased urine output and commonly become oedematous. The differential diagnosis includes infection (particularly group B streptococcal infection), persistent pulmonary hypertension of the newborn, aspiration pneumonia, lung malformations and upper airway obstruction, transient tachypnoea of the newborn, meconium aspiration syndrome, air leak syndromes, pulmonary haemorrhage, asphyxia, congenital heart disease, primary neurological or neuromuscular disease and inborn errors of metabolism.

The effects of RDS on lung function vary with gestational and postnatal age. Newborns with normal lungs quickly develop an FRC of about 30 mL/kg (McCann et al. 1987). FRC is the volume of gas remaining in the lungs at the end of normal expiration, preventing alveolar collapse and allowing the lung to operate at optimal efficiency. Less mature infants have lower lung volumes, including a lower FRC; however, tidal volume remains about the same at 4–6 mL/kg (Hislop et al. 1986). These effects proportionally increase the physiological dead space to 60–80 % of tidal volume, compared with 30–40 % of tidal volume in healthy lungs (Avery et al. 1981). To compensate for this increased dead space, infants with RDS increase their respiratory rates. For infants without RDS, a rise in respiratory rate can lead to gas trapping; however, in babies with RDS, an increased respiratory rate may be enough to help maintain necessary FRC and avoid end-expiratory alveolar collapse. Newborn FRC already approaches alveolar closing volume, so a reduction in FRC permits atelectasis to readily develop. Further loss of FRC occurs due to vascular congestion, interstitial oedema and proteinaceous exudates.

Infants with RDS try to preserve lung function by delaying contraction of the diaphragm to delay the loss of thoracic volume and keep the alveoli inflated (Davis and Bureau 1987). Infants also contract the laryngeal muscles to keep the upper airway closed until late expiration, and then when these muscles relax, the abdominal muscles contract. The explosive release of air sounds as a grunt. Grunting helps to delay air escape from the lung and maintains FRC. It has been demonstrated that when an endotracheal tube is inserted, the loss of these mechanisms result in a fall in arterial oxygenation (Harrison et al. 1968). Surfactant treatment helps to increase lung volumes, so that lower positive pressures are required for ventilation. Higher lung volumes are maintained even when positive pressure is reduced because FRC increases following surfactant treatment (Goldsmith et al. 1991). Most lung volume improvement is seen when exogenous surfactant containing surfactant proteins are used (Rider et al. 1993). As FRC improves oxygenation improves. This normally occurs as lung fluid clears (Engle et al. 1983) or following surfactant treatment (Edberg et al. 1990) or when using distending pressure, such as mechanical ventilation (Richardson and Jung 1978). In an infant with RDS, the FRC returns to normal by about day 7.

Infants with RDS have less compliant, more resistant lungs. This results in a short time constant, meaning that gas leaves the terminal airways more quickly than in normal lungs. Surfactant-deficient lungs, with high surface tension in the alveoli, exhibit collapse in expiration of the smaller alveoli. This leads to overdistension of the larger alveoli that have remained open. Compliance is reduced as fewer terminal air spaces are ventilated, and those that are open become overdistended. Alveolar instability affects compliance as the critical opening and closing pressures vary. This means that alveoli open and shut suddenly, smaller ones then stay closed and open alveoli overfill. There is increased resistance in the lungs due to reduced cross-sectional area of the patent airways to the distal lung units. During spontaneous breathing the activity of the respiratory muscles tries to overcome elastic resistance and inertia of the tissues by increasing the change in intrapleural pressure, resulting in distortion of the compliant chest wall. Pulmonary compliance improves more slowly, following surfactant administration, than the rapid improvement seen in FRC (Edberg et al. 1990). This is reflected by quick improvement in oxygenation, compared with the relatively slower fall in carbon dioxide. The reduced compliance slowly returns to normal around day 7.

Arterial carbon dioxide levels rise in RDS due to alveolar underventilation from atelectasis and the proportional increase in dead space. Most hypoxia in RDS is due to right-to-left shunting. Small shunts exist across the foramen ovale (if right atrial pressure is higher than left atrial pressure) and the ductus arteriosus (which is often patent in infants with RDS for 48 h). These shunts only account for about 10 % of the shunt in RDS (Seppanen et al. 1994) and are more important in other lung pathologies such as persistent pulmonary hypertension. In RDS, the most important shunt is intrapulmonary, as capillary blood travels through unventilated, or hypoventilated, atelectatic areas of the lung. Pulmonary arterial pressure normally falls rapidly, to half of the in utero level, soon after birth, but in RDS it can remain high for the first week (Evans and Archer 1991). The pulmonary pressure is proportionately higher in infants with more severe RDS and can exacerbate the hypoxia seen in RDS.

Ideally prevention of RDS would focus on avoiding preterm birth. Addressing social deprivation and reducing rates of genital tract infection and preterm rupture of the membranes, both of which increase preterm delivery, could reduce RDS rates. If preterm labour occurs, or maternal disease necessitates preterm delivery, pharmaceutical intervention such as tocolytics may prolong pregnancy for 48 h. This is sufficient time to administer steroid treatment and reduce the risk of RDS. Antibiotics for suspected infection, or for membrane rupture, reduces progression to preterm delivery (Gomez et al. 1995). Other factors which impact on RDS development include asphyxia and drug depression of the infant. Care in avoiding intra- and postpartum asphyxia and minimal use of maternally administered opiates, anaesthetics, benzodiazepines and magnesium sulphate may also reduce rates of RDS.

Synthetic steroids given antenatally as betamethasone or dexamethasone, to women at risk of preterm delivery, reduce rates of RDS (odds ratio (OR) 0.63, 95 % confidence interval (CI) 0.44, 0.82). Neonatal deaths are reduced (OR 0.6, 95 % CI 0.48, 0.75) (Crowley 1995) as are rates of germinal matrix/intraventricular haemorrhage and necrotising enterocolitis (Ward 1994). The widespread uptake of antenatal steroid use has had a dramatic impact on the epidemiology of RDS over the last 20 years. Steroids induce enzymes for surfactant synthesis, induce genes for synthesis of surfactant protein (Mendelson et al. 1993), improve the quality of the surfactant produced (Ueda et al. 1995; Lanteri et al. 1994), mature the lung tissue and increase the number of alveolar divisions (Lanteri et al. 1994). The optimal timing of steroid administration has been shown to be 24–168 h prior to delivery (Crowley 1995). Some benefit can be seen with doses given 4–24 h prior to delivery (Sen et al. 2002). There is limited evidence of benefit below 28 weeks gestation (Garite et al. 1992) or beyond 34 weeks gestation (Liggins and Howie 1972). Steroids appear to be safe in terms of effect on maternal pregnancy-induced hypertension (Lamont et al. 1983), prolonged rupture of the membranes (Crowley 1995) and maternal diabetes. No long-term adverse outcomes have been demonstrated in infants following a single course of antenatal steroids (Dessens et al. 2000).

Repeated courses of steroids continue to improve neonatal outcomes in terms of lung function but may be detrimental to fetal growth and brain function (Aghajafari et al. 2002). A randomised controlled trial (RCT) in Australia demonstrated that repeated doses of antenatal corticosteroids reduced neonatal morbidity, compared with a single course, without changing neurosensory disability or body size at age 2 (Crowther et al. 2007). Another RCT of repeated versus single-steroid courses found a non-statistically significant increased rate of cerebral palsy in the repeated course group (Wapner et al. 2007); this question warrants further study. A retrospective review of infants who received multiple courses of steroids, compared with infants who received no antenatal steroids, showed that repeated courses were associated with decreased head circumference, decreased body mass index and decreased salivary cortisol at age 6–10 years (Chen et al. 2008). A Cochrane review of multiple doses of antenatal steroids published in 2007 concluded that further long-term data were required (Crowther and Harding 2007), and a review of this topic published in mid-2009 concluded that concerns about brain growth following repeated courses of antenatal corticosteroid currently warranted restriction of use to a single course (Newnham and Jobe 2009).

Risk factors for RDS have been well demonstrated, with prematurity being the most important. Incidence of RDS is inversely proportional to gestational age; the majority of infants born before 28 weeks gestation will have some degree of respiratory distress. RDS remains a significant problem until around 34 weeks of gestation (Lewis et al. 1996); by 35–36 weeks gestation, incidence falls to 2 % (Rubaltelli et al. 1998). Not only are preterm lungs less mature in terms of surfactant synthesis, but epithelial protein leak is worse in these infants, leading to increased surfactant inhibition. Preterm infants are more at risk of other factors that impact on the incidence of RDS such as asphyxia, hypoxia, cold and hypotension.

Infants of diabetic mothers are at higher risk of developing RDS as they have abnormal surfactant synthesis (Ojomo and Coustan 1990), and insulin delays the maturation of type 2 alveolar cells delaying surfactant production (Gross et al. 1980). Maternal hypertension and prolonged membrane rupture protect against RDS. Stress raises the fetal cortisol and induces lung maturation.

Maternal alcohol use (Ioffe and Chernick 1987), smoking (Lieberman et al. 1992) and opioid and cocaine abuse all reduce RDS in the infant. Heroin is known to mature surfactant systems, and animal models of antenatal cocaine use have shown that cocaine induces surfactant synthesis (Sosenko 1993).

Antenatal steroids protect against RDS (see section on Epidemiology of RDS).

Male infants are at higher risk of developing RDS and suffer a more severe course. Incidence in males is 1.7 times higher, and males are more likely to die from the condition (Farrell and Avery 1975). This gender difference appears to be related to the effects of androgens which delay the maturation of the lecithin-sphingomyelin ratio and delay production of phosphatidylcholine in surfactant (Torday 1992).

Race plays a part in risk of RDS with infants of black race relatively protected. Black infants have about a one-third lower incidence than Caucasians (Hulsey et al. 1993). This protection exists even in the most immature infants (Kavvadia et al. 1998). When looking at lecithin-sphingomyelin ratio to assess lung maturity, for the same ratio more Caucasian infants develop RDS than black infants (Richardson and Torday 1994). It is hypothesised that there may be allelic variation in surfactant proteins causing this disparity (Rishi et al. 1992).

Growth-restricted infants are more likely to develop RDS, and the disease is more severe, compared with normal weight infants of the same gestation. Growth restriction is not as strong a risk factor as gestation, so a preterm infant of similar weight to a growth-restricted older infant is more likely to develop RDS than a growth-restricted child (Piper et al. 1996).

In multiple pregnancies the second, or higher birth order infant, is at more risk of developing RDS, as are infants born following a rapid labour.

Genetic conditions resulting in surfactant protein deficiencies are a rare cause of RDS, e.g. autosomal recessive surfactant protein B deficiency. Partial protein deficiencies and polymorphisms of parts of the proteins have also been described (Cole et al. 2000; Makri et al. 2002). A family history of a sibling with RDS increases the risk for the subsequent infant.

Thyroid activity is involved in the development of surfactant systems; hypothyroid infants with RDS have lower surfactant levels than those with normal thyroid function, although the majority of hypothyroid infants do not develop RDS (Cuestas et al. 1976; Dhanireddy et al. 1983).

Infants born by caesarean section (CS) are at higher risk of developing RDS. Infants born by CS after a period of time in labour have more surfactant in their airway than those born without labour (Callen et al. 1979). CS without labour is associated with more RDS and transient tachypnoea of the newborn (Annibale et al. 1995; Cohen and Carson 1985; Morrison et al. 1995). Risk of RDS following elective CS without labour continues to fall between 37 and 40 weeks of gestation.

Asphyxia results in reduced lung perfusion, and ischaemia causes capillary damage. Recovery and reperfusion cause protein leak from damaged capillaries, worsening RDS (Jefferies et al. 1984). The function of surfactant decreases with acidosis and low temperature; below 34 °C surfactant cannot spread, and therefore cold or acidotic infants are more likely to develop RDS (Gluck et al. 1972).

Most very premature infants will need some form of respiratory support in the first few minutes of life. Most resuscitation guidelines are drawn up with term infants in mind and may not translate accurately to preterm infants at high risk of RDS and BPD. Until recently premature infants were routinely stabilised using 100 % oxygen; many were intubated and given surfactant as a standard procedure, regardless of their respiratory effort. We now know that 100 % oxygen is not the best choice of gas to use (Saugstad et al. 2008) and several studies are underway to determine the most appropriate initial oxygen concentration to use, as well as the best oxygen saturations to target (Castillo et al. 2008). Centile charts for normal oxygen saturations for preterm infants are now being developed (Dawson et al. 2009a). There are good theoretical, clinical and animal data for using positive end-expiratory pressure (PEEP) at delivery. Animal data have demonstrated that PEEP reduces alveolar-arterial oxygen gradient (Probyn et al. 2004), protects from lung injury (Jobe et al. 2002), preserves the surfactant pool (Michna et al. 1999), improves oxygenation and improves ventilation-perfusion matching (Schlessel et al. 1989; Finer et al. 2004). PEEP also accelerates formation of FRC (Siew et al. 2009) and protects the lungs by keeping the alveoli open (Nilsson et al. 1980). Using a resuscitation device that is able to give PEEP would seem advantageous but so far has not shown improved outcomes in terms of saturations at 5 min or need for endotracheal intubation (Dawson et al. 2009b). Use of CPAP to treat preterm infants has been shown to reduce rates of endotracheal intubation (Lindner et al. 1999; Lundstrom 2003; Stevens et al. 2007), but the disadvantage is that any surfactant treatment is delayed. PEEP or CPAP from the delivery room onward has been shown to be as good as initial ventilation and surfactant treatment, but not any better (Morley et al. 2008), and is discussed further in the CPAP section of this chapter. CPAP and sustained inflations can be used to help the infant establish FRC (te Pas et al. 2009a; te Pas and Walther 2007). It is important to carefully control any positive pressure support given in the delivery room to avoid damaging the lungs. Animal studies have shown that even a few large volume inflations can damage newborn lungs (Bjorklund et al. 1997; Dreyfuss and Saumon 1992; Hernandez et al. 1989) and currently the majority of respiratory support systems used in the delivery room do not allow the clinician to measure the delivered volume (Schmolzer et al. 2010). In the absence of respiratory function, monitoring the initial stabilisation and transfer from the delivery room to the neonatal intensive care unit (NICU) should be guided by oxygen saturations and chest movement. However, Tracy et al. suggest that this clinically determined ventilation commonly results in hypocarbia, hyperoxia or both (Tracy et al. 2004).

Infants with RDS should be nursed in a thermo-neutral environment, with cardiovascular and respiratory monitoring. Once initial examination is complete, infants should be handled as little as possible and nursed prone to maximise oxygenation and respiratory muscle coordination (Hand et al. 2007; Leipala et al. 2003; Wells et al. 2005). As RDS is clinically indistinguishable from sepsis, infants with ongoing respiratory symptoms should have intravenous access, blood sent for full blood count, a chest x-ray, septic markers and blood culture and should receive antibiotics.

Infants with significant increased work of breathing should not initially receive enteral feeds, but be managed with intravenous fluid titrated against urine output and plasma sodium. Very low birth weight infants who are likely to need ongoing respiratory support require early parental nutrition for optimal lung growth and recovery. Anaemia and coagulation abnormalities need to be carefully controlled; blood pressure should be maintained with crystalloid and if necessary with inotropic support. Arterial oxygen levels should be kept between 50 and 75 mmHg (7–10 kPa); ongoing clinical trials, such as BOOST2, aim to determine the optimal oxygen saturations for this group of infants. The European Consensus Guidelines on the Management of Neonatal RDS currently recommend that oxygen saturations, in infants receiving supplemental oxygen, should be kept below 95 % (Sweet et al. 2007). Hypocarbia must be avoided due to the effect on cerebral blood flow (Garland et al. 1995). A degree of permissive hypercarbia appears safe (Miller and Carlo 2007) and is associated with lower rates of BPD (Thome and Ambalavanan 2009).

Infants with the mildest degree of RDS may need only supplemental oxygen and good general care. Supplemental oxygen may be delivered into the isolette, given directly as subnasal oxygen or delivered via a hood or head box. With increasing disease severity, oxygen requirements climb, work of breathing increases, the infant tires, carbon dioxide (PaCO₂) levels rise and the pH falls. The infant may have desaturations or apnoeas at which point positive pressure support is required. The British Association of Perinatal Medicine (BAPM) suggests instigation of CPAP support if the inspired oxygen requirement reaches 40 %, if the pH falls below 7.25 or if the PaCO₂ rises above 50 mmHg (6.7 kPa) (British Association of Perinatal Medicine T 2005).

CPAP was first used in neonates in 1971 (Gregory et al. 1971) and has grown hugely in popularity, particularly over the last 15 years. It has been advocated as a gentler form of respiratory support (Jacobsen et al. 1993) and has been shown to have many physiological benefits. These include decreasing the likelihood of upper airway collapse and decreasing upper airway resistance by splinting and increasing the cross-sectional area of the pharynx (Miller et al. 1990). CPAP reduces obstructive apnoeas (Miller et al. 1985) and alters the shape of the diaphragm, improving lung compliance and decreasing lung resistance (Gaon et al. 1999). It allows larger tidal volumes for the same respiratory effort and conserves surfactant. CPAP has also been demonstrated to increase FRC (Richardson and Jung 1978; Richardson et al. 1980), stabilise the chest wall (Locke et al. 1991), improve lung volumes (Harris et al. 1976; Yu and Rolfe 1977) and improve oxygenation (Durand et al. 1983).

Increasing numbers of preterm infants are managed with CPAP support from birth, but concerns remain about pneumothorax rates and the delay in any surfactant treatment required. Clinicians have become interested in a technique that incorporates a brief period of intubation, to administer surfactant, followed by rapid extubation to CPAP which may overcome these problems. The technique has become known as INSURE (intubation-surfactant-extubation), and several studies have tested this method against standard ventilation techniques (Blennow et al. 1999; Bohlin et al. 2007; Thomson 2002; Verder et al. 1999).

Systematic review has shown that in infants at high risk of early RDS, early prophylactic surfactant in the first 2 h of life is better than later selective surfactant use with respect to BPD, death and air leak (Soll and Morley 2001). It has also been reported that quick intubation for surfactant delivery was most efficacious when done early (Blennow et al. 1999; Bohlin et al. 2007) with improved oxygen, less mechanical ventilation and less BPD (Thomson 2002; Verder et al. 1999; Verder 2007).

Meta-analysis of six INSURE papers (Stevens et al. 2007) has shown reduction in BPD in the INSURE group, compared with traditional treatment of surfactant and ongoing ventilation (RR 0.51 95 % CI 0.26, 0.99). The review also found that INSURE-treated infants had less need for mechanical ventilation (RR 0.67, 95 % CI 0.57, 0.79) and fewer air leaks (RR 0.52, 95 % CI 0.28, 0.96) but had an increase in surfactant use. Stratified analysis, by oxygen requirement at study entry, found that a lower threshold of intervention, at an inspired oxygen below 45 %, resulted in lower rates of pneumothorax (RR 0.46, 95 % CI 0.23, 0.93) and less BPD (RR 0.43, 95 % CI 0.20, 0.92). Higher thresholds were associated with higher rates of patent ductus arteriosus (RR 2.15, 95 % CI 1.09, 4.13). Further studies comparing INSURE with ongoing ventilation, published since the meta-analysis, have added further weight to its findings (Rojas et al. 2009). The REVE trial also compared the INSURE technique with ongoing ventilation post-surfactant treatment, and the results suggest that the technique has most benefit for the youngest infants at 25–26 weeks gestation (Truffert et al. 2008).

The technique may not be risk-free; it still requires intubation which has inherent risks, and data suggest that INSURE results in a period of depressed brain activity (van de Berg et al. 2010). These studies have not answered the question of whether it is better to treat infants with the INSURE technique or to treat with CPAP alone and give rescue surfactant, via brief intubation, only if CPAP support is insufficient. One small Scandinavian study has addressed this question and found that the INSURE group had better oxygenation and reduced need for mechanical ventilation (Verder et al. 1994) compared with the CPAP and rescue surfactant group. The large multicentre CURPAP study also aimed to answer this question (Sandri et al. 2008), and the presented results show that there were no differences between groups in the need for mechanical ventilation, or for the combined outcome of death or BPD (Sandri et al. 2009). The implication for clinicians is that CPAP with rescue surfactant was no worse than prophylactic surfactant followed by CPAP support. There is a need to individualise initial CPAP support with early rescue surfactant based on clinical criteria. The Vermont-Oxford Network is now running a three-armed trial comparing traditional intubation, surfactant and ongoing ventilation with either INSURE or CPAP and rescue surfactant (Sinha et al. 2008).

High-flow nasal cannulae deliver gas at 2–8 L/min into the nose, via small prongs which are loose fitting in the nostrils. The technique has evolved from subnasal oxygen treatment at low flows, less than 2 L/min, as clinicians have attempted to support more infants without using traditional CPAP. The use of humidified high-flow systems has increased rapidly over the last few years, particularly as it is felt that the system is easier to use (Shoemaker et al. 2007) and provides more patient comfort.

Traditional CPAP delivery has disadvantages using of tight-fitting head wraps, the need for careful positioning, compression of the nose and nasal trauma, and it is sometimes poorly tolerated by the infant. The use of small cannulae to generate positive pressure could reduce many of these issues; however, early equipment, developed from the original low-flow systems, were poorly heated and humidified. This limited their use due to risk of nasal mucosa injury, mucosal bleeding, thickened secretions and nosocomial infection (Kopelman and Holbert 2003; Woodhead et al. 2006). The development of heated humidified high-flow gas delivery via nasal cannulae (HHHFNC) may circumvent these issues. Such circuits are reported to decrease work of breathing and prevent re-intubation more effectively than high flow from a standard, non-heated, non-humidified nasal cannula (Woodhead et al. 2006).

Studies have shown that HHHFNC, at relatively low flows of 1–2 L/min, can generate a positive pressure in the airway of preterm infants (Sreenan et al. 2001); however, HHHFNC does not currently allow the measurement of delivered pressure, without a separate invasive process such as an oesophageal pressure probe. Some data exist suggesting that HHHFNC does not produce excessive distending pressures (Kubicka et al. 2008; Saslow et al. 2006) and that very high flows would be needed to generate significant positive pressure. Other data has demonstrated high and variable delivered pressures (Shoemaker et al. 2007; Campbell et al. 2006), and reports exist that demonstrate potentially hazardous pressures, especially in very small infants (Sreenan et al. 2001; Quinteros et al. 2009; Chang et al. 2005).

Specific gas flow to obtain a certain delivered pressure is unknown; the pressure generated in the pharynx will depend on leak at the nose (Lampland et al. 2009), which in turn depends on the size of the patients nostril, and the presence of any secretions sealing the nares. Some algorithms exist to guide flow selection, but they depend on a consistent level of leak being present, which is not necessarily the case in practice (Wilkinson et al. 2008). If the infant’s mouth is closed and the cannulae become functionally ‘sealed’ in the nares due to secretions or tight-fitting cannulae, then flow will continue to increase the nasopharyngeal pressure until an outlet is found. This could result in significant lung and gastrointestinal overdistention. A recent report describes development of subcutaneous scalp emphysema, pneumo-orbitis and pneumocephalus during HHHFNC use (Jasin et al. 2008). Not all HHHFNC systems contain a pressure-limiting safety valve to protect against inadvertent high pressure, but such a system should be incorporated into future designs (Lampland et al. 2009). One further concern with HHHFNC has been adequate humidification and heating of the circuit. Anecdotal reports exist of condensation in the tubing and cannulae during flows at the lower end of the range of ‘high flow’, resulting in water droplets coalescing to obstruct flow or enter the nares.

Initial studies with ‘high-flow’ systems showed disadvantages when compared with CPAP (Campbell et al. 2006); however, partial humidification and relatively low flows were used. More recent studies have found work of breathing and lung compliance were improved during HHHFNC compared with CPAP (Saslow et al. 2006); ventilator days were decreased without adverse effects such as air leak, intraventricular haemorrhage, nosocomial infection or BPD (Shoemaker et al. 2007); and frequency and severity of apnoea and bradycardia were reduced (Shoemaker et al. 2007; Woodhead et al. 2006; Sreenan et al. 2001; Holleman-Duray et al. 2007).

It is possible that the jet of gas delivered in HHHFNC may penetrate the nasal dead space very efficiently. As the nasal compartment contributes up to 50 % of the overall respiratory resistance (Hall et al. 2002), this effect could contribute to a reduced work of breathing compared with conventional CPAP prongs. The uptake of HHHFNC by numerous neonatal units has not been accompanied by obvious changes in neonatal outcome, but the technique has not been systematically studied. The American Association of Respiratory Care 2002 Clinical Practice Guideline (Myers 2002) states that flow for nasal cannula treatment in newborn infants should not exceed 2 L/min and acknowledges that even this flow may be excessive for the extremely low birth weight infant. There is a need for high-quality RCTs to delineate the range of delivered pressure for a given flow, for all sizes of preterm infants. Until the results of these trials are available, if an infant requires CPAP, then it can more safely be delivered with a standard device (Davis et al. 2009; So et al. 1992). A multicentre, prospective, randomised comparison of CPAP compared with HHHFNC in infants greater than 1,000 g and 28 weeks gestation, from birth or following extubation, is currently underway.

NIPPV includes modes of non-invasive ventilation, characterised by CPAP augmented with mechanical inflations to a set pressure. The peak (PIP) and end-expiratory pressures, inflation rate and time can all be manipulated during NIPPV. Terminology used to describe NIPPV is varied, reflecting the different inflation strategies applied through the nasal interface. Terms include synchronised nasal intermittent positive pressure ventilation (SNIPPV) (Aghai et al. 2006; Bhandari et al. 2007; Kulkarni et al. 2006; Santin et al. 2004), nasopharyngeal-synchronised intermittent mandatory ventilation (NP-SIMV) (Friedlich et al. 1999), nasal synchronised intermittent mandatory ventilation (N-SIMV) (Kiciman et al. 1998), nasal synchronised intermittent positive pressure ventilation (nSIPPV) (Moretti et al. 1999), nasal intermittent mandatory ventilation (NIMV) (Kugelman et al. 2007) and non-invasive pressure support ventilation (NI-PSV) (Ali et al. 2007). Nasal bi-level positive airway pressure (N-BiPAP) (Migliori et al. 2005) is also used but may be more indicative of a technique using a narrow PIP-PEEP pressure difference, long inspiratory times and low rates, during which the infant continues to breathe undisturbed.

Neonatal endotracheal intubation and ventilation emerged in the 1960s, and although many infants survived due to this intervention (Henderson-Smart et al. 2002), it quickly became apparent that ventilation had inherent risks: ventilator-induced lung injury (Dreyfuss and Saumon 1998), infection, development of BPD (Avery et al. 1987; Heimler et al. 1988; Pandya and Kotecha 2001) and upper airway problems. While there is now considerable debate about which preterm infants need mechanical ventilation, there have also been dramatic changes in the way neonatologists are able to deliver mechanical ventilation. The British Association of Perinatal Medicine (BAPM) suggests that infants have failed CPAP support and require ventilation if they have persistent or major apnoeas with bradycardia, become acidotic below pH 7.25 or require more than 60 % oxygen (British Association of Perinatal Medicine T 2005).

Early animal work investigating HFOV demonstrated that there was more lung damage with the high magnitude pressure changes used in conventional ventilation than with the high mean airway pressure (MAP) used in HFOV (Hamilton et al. 1983). Animal data has shown less protein leak in RDS when using HFOV, compared with conventional ventilation (Niblett et al. 1989). Initial trials of HFOV used low lung volume strategies. This technique may be ideal for infants with established air leak syndromes, but when infants with RDS were studied, no pulmonary benefits were found with HFOV, and higher rates of IVH were seen (The HIFI Study Group 1989). Many of the infants enrolled in the early studies would not have had continuous carbon dioxide monitoring and may have had undetected hypocarbia contributing to the poor outcomes seen (The HIFI Study Group 1989; Greisen et al. 1987; Froese and Kinsella 2005). Further animal data demonstrated that optimising lung volume prolonged the effect of exogenous surfactant (Froese et al. 1993) and that when starting HFOV it was important to fully recruit the lung using a short period of higher airway pressure. A brief period of overdistension is less damaging than the persistent atelectasis seen in the low-volume approach (Bond and Froese 1993), and the open lung technique results in more even distribution of tidal volume and less alveolar overdistention (Frerichs et al. 2003). Froese et al. suggested that how the HFOV technique is applied is more important than the choice of mechanical device generating the oscillations (Froese and Kinsella 2005).

The next wave of clinical trials used high lung volume strategies, where clinicians reduced inspired oxygen before reducing the MAP. Acute and chronic pulmonary advantages of HFOV were then seen compared with conventional ventilation (Gerstmann et al. 1996). However, the results were not reproduced in later trials where all the infants received steroids, exogenous surfactant and early CPAP after delivery (Thome et al. 1999), all of which result in a more open lung ventilation technique in both groups. Improvements in conventional ventilation, increasing PEEP, decreasing tidal volume and synchronising inflations, have meant that the advantages of HFOV have been greatly reduced (Courtney et al. 2002). Now the pulmonary benefits of lower BPD rates and shorter duration of ventilation are only seen in infants with the most severe disease, who require high oxygen requirements (>60 %) post surfactant (Courtney et al. 2002). Routine HFOV for all RDS has not been shown to be beneficial and is now often reserved for the subset of infants with severe disease. The BAPM guidelines suggest conversion to HFOV, from conventional ventilation, for infants who have failed to respond to surfactant therapy and optimisation of conventional ventilation and who still have an oxygen requirement above 60 % and peak pressures above 30 cm H₂O (British Association of Perinatal Medicine T 2005).

A Cochrane review has concluded that there is no clear evidence that prophylactic HFOV offers important advantages over conventional ventilation, in treating premature infants with RDS. There may be a small reduction in the rate of BPD, but the evidence is weak; future HFOV trials should focus on infants who are at the highest risk of BPD (Henderson-Smart et al. 2007). It is still to be determined whether a conventional ventilation strategy that aims to minimise volutrauma and atelectotrauma by using open lung ventilation, low tidal volumes and high PEEP is any different from HFOV (van Kaam and Rimensberger 2007).

There has been one study examining the application of high-frequency oscillations via nasal prongs showing improved PaCO₂ and pH, compared with standard CPAP (Colaizy et al. 2008); further investigation of this method may be warranted.

This mode of ventilation is a modification of HFOV that delivers very short inflation times of 0.02 s via a small bore injector cannula, in the frequency range of about 4–8 Hz. HFJV is not routinely used for infants with RDS. One study demonstrated that HFJV reduced rates of BPD in preterm infants, compared with conventional ventilation (Keszler et al. 1997), but a second study was stopped early due to higher rates of IVH seen in the HFJV group (Wiswell et al. 1996).

ECMO describes the use of modified cardiopulmonary bypass for patients with reversible lung disease, in whom maximal standard therapy has failed. It has become accepted for the treatment of several neonatal conditions, allowing time for lung healing. Catheter size and the need for systemic anticoagulation means that the technique is usually limited to infants greater than 2 kg in weight and more than 34 weeks gestation (Revenis et al. 1992). This excludes the majority of infants likely to have severe RDS. Infants at lower gestations have reduced survival (Hirschl et al. 1993) and a significantly increased risk of IVH (Hardart and Fackler 1999). IVH is four times more likely at 34 weeks gestation than at term (Neonatal ECMO Registry of the Extracorporeal Life Support Organisation 2004). Mature infants with life-threatening RDS show benefit from ECMO treatment with survival rates of more than 80 % (Bahrami and Van Meurs 2005).

PLV involves instilling perfluorocarbon into the lungs; perfluorocarbon is capable of gas transport, and during PLV the volume of liquid instilled replaces FRC. Conventional gas ventilation is applied in addition. PLV has been shown to reduce lung injury in animal models, but there is limited data in preterm infants with RDS (Ambalavanan and Carlo 2006). One non-randomised study showed a higher than expected rate of survival in infants with severe RDS, in whom conventional treatment was failing (Leach et al. 1996).

Stepping down from mechanical ventilation is a topic of as much interest as escalation of support; however, there is very little research into the best practice of weaning. There is some evidence to suggest that the AC mode of ventilation is superior to SIMV modes for weaning (Dimitriou et al. 1995; Chan and Greenough 1994), as low SIMV rates can increase oxygen consumption and increase work of breathing (Roze et al. 1995). However, a survey of UK practice in 2006, more than a decade after this evidence was published, found that 73 % of neonatal units used SIMV mode for weaning infants from ventilation (Henderson-Smart et al. 2007). There have been several methods investigated to test whether an infant is ready for extubation, the key factors being an infant’s respiratory drive and their lung compliance.

Use of CPAP following extubation has been shown to be superior to head box oxygen, if the CPAP pressure is at least 5 cm H₂O (Davis and Henderson-Smart 2003). In addition, use of NIPPV has been shown to prevent more extubation failures than CPAP alone (Davis et al. 2001). Weaning from NIPPV has not been studied, and weaning from CPAP has been the subject of very few studies. One study suggests decreasing CPAP support to pressures of 4–5 cm H₂O and then stopping (Singh et al. 2006); this is the alternative to ‘cycling’ the infant through increasing periods of time off CPAP. The ‘cycling’ method has not been shown to have any significant advantages and prolongs the time the infant spends on CPAP support (Soe et al. 2006).

Currently the data are not conclusive to support or refute either starting with ventilation and weaning quickly or starting with minimal support and only escalating care if the infant is not managing. Ideal ventilation delivers consistent tidal and minute volumes, responds quickly to changing demands and allows the infant to breathe at the lowest pressures with the least work of breathing. Further RCTs comparing different modalities, for specific clinical conditions, are required before any single mode can be justified as being superior to another.

The introduction of surfactant replacement in the late 1980s reduced mortality due to RDS but left NICUs with the burden of survivors with BPD, as survival increased, so did the rate of BPD (Hintz et al. 2005). Debate continues today about the need for surfactant administration, which surfactant to use, the most appropriate timing for surfactant delivery, the best dose and optimal mode of surfactant delivery, to treat RDS and prevent BPD. Surfactant has been shown to decrease rates of pneumothorax by 30–65 % and decrease mortality by up to 40 % (Halliday 2005).

Nitric oxide is a potent pulmonary vasodilator and has been shown to have profound effects on gas exchange (Gaston et al. 1994). Its use improves ventilation-perfusion mismatching, allowing improved oxygenation and reduced ventilation. Inhaled nitric oxide has been shown to be beneficial in term infants with respiratory disease, but the results are less clear, and more variable, in infants below 34 weeks gestation (Van Meurs et al. 2005; Schreiber et al. 2003; Lindwall et al. 2005). There may be some short-term benefits, but no long-term advantages have been demonstrated in premature infants (Subhedar et al. 1997). Prophylactic low dose nitric oxide in preterm infants does not reduce the risk of developing BPD (Mercier et al. 2009). Concerns remain regarding the effects of the drug on the developing brain and possible risk of intracranial bleeding (Van Meurs et al. 2005).

It is impossible to differentiate between RDS and severe postnatal, or congenital, infection. Blood cultures and antibiotic treatment, with a penicillin and an aminoglycoside, for 48 h until blood cultures are shown to be negative, are standard therapy for infants with presumed RDS.

Methylxanthines have proven benefit in treating apnoea of prematurity. A recent large RCT has shown improved survival without neurodevelopmental disability (Schmidt et al. 2007), reduced rates of BPD and shorter duration of respiratory support (Schmidt et al. 2006a) in infants treated with caffeine. These benefits would suggest that preterm infants with RDS, who may or may not develop apnoea of prematurity, could benefit from treatment with methylxanthines.

Heliox is a gas mixture in which the nitrogen has been replaced with helium. This mixture decreases pulmonary resistance and resistive work of breathing. It is hypothesised that this might improve lung function and reduce energy expenditure in infants with severe lung disease. Early observational data show that mechanical ventilation with heliox mixture does reduce resistive work of breathing and ventilatory requirements, as well as improving gas exchange in ventilated preterm infants (Migliori et al. 2009). Other reports suggest it may be useful in the treatment of pulmonary interstitial emphysema (Phatak et al. 2008). Heliox treatment, combined with CPAP, for extremely low birth weight infants is currently being studied as part of a randomised trial.

Frusemide (furosemide) increases resorption of lung fluid and produces short-term improvements in lung function. However, the early use of diuretics in preterm infants can increase the risk of patent ductus arteriosus as frusemide stimulates production of prostaglandin E2. Repeated use of diuretics in premature infants increases the risk of ototoxicity and aminoglycoside ototoxicity (Hey Ee 2003), as well as the possibility of inducing hypovolaemia and low systemic blood pressure. Systematic review of diuretics for RDS shows no benefit on mortality, BPD, duration of mechanical ventilation, duration of oxygen treatment or length of hospital stay (Brion and Soll 2001). The trials included in the Cochrane review were completed before generalised use of antenatal steroids or surfactant replacement, but to date there is no evidence in favour of routine use of diuretic treatment in RDS (Wiswell et al. 2007). The use of diuretics should be reserved for oliguric infants with fluid retention and deteriorating lung function.

Opioids have regularly been used to provide analgesia and sedation for ventilated infants with RDS. Recent systematic review found no significant benefits in terms of mortality, duration of mechanical ventilation or neurodevelopmental outcomes to warrant routine use of opioids in this population (Bellu et al. 2005). Adverse effects of morphine, such as delaying achievement of full enteral feeds, need to be considered when considering opioid treatment (Menon et al. 2008). Midazolam is also commonly used for sedation of ventilated newborns, but again systematic review found no advantages when compared with either placebo or morphine. Midazolam use increased rates of adverse events including hypotension, death, longer duration of hospital stay, and more IVH and periventricular leukomalacia. The authors concluded that routine use of midazolam for sedation should not be recommended (Ng et al. 2003). Neuromuscular paralysing agents are sometimes used to abolish spontaneous breathing patterns in infants with asynchronous respiratory effort. Cochrane review has shown that agents such as pancuronium have the potential to decrease air leak and IVH in such infants. Uncertainty regarding the long-term pulmonary and neurological effects of paralysing agents means that routine usage is not currently recommended (Cools and Offringa 2005).

Numerous pharmacologic agents have been used to treat infants with BPD; these are further discussed in Sect. 32.​1.​4, 32.​1.​7, and 48.​1.​3 of this book.

Overall mortality from RDS is between 5 and 10 % and is rare in infants of birth weight greater than 1,500 g (Rennie 2005). Death from RDS occurs most frequently between days 2 and 7 of life. Infants who receive prolonged ventilation from birth have lower survival rates and higher rates of impairment (Gaillard et al. 2001; Walsh et al. 2005).

The definition of BPD has evolved over recent years from the original description of oxygen dependency at 28 days with corresponding x-ray changes (Northway et al. 1967). It has now been shown that oxygen dependence at 36 weeks corrected gestational age correlates better with long-term morbidity (Shennan et al. 1988). Infants born below 32 weeks gestation are assessed at 36 weeks corrected age, or at hospital discharge, whichever is sooner, and BPD is classified as mild, moderate or severe. Infants who need supplemental oxygen at 28 days of age, but who are in air at 36 weeks corrected age, have mild disease. Infants requiring up to 30 % oxygen at 36 weeks corrected age have moderate disease, and infants requiring more than 30 % oxygen, or positive pressure support, have severe disease. Infants born after 32 weeks gestational age are assessed by the same criteria at 56 days of age, or at hospital discharge, whichever is sooner (Jobe and Bancalari 2001).

It is difficult to predict infants who will go on to develop BPD from the appearance of the initial x-rays as the findings depend upon the amount of fetal lung fluid present and the phase of respiratory cycle in which the x-ray was taken. Positive pressure support and early surfactant use improve the x-ray appearance so early images are a poor guide to outcome (Kanto et al. 1978). The incidence of BPD in very low birth weight infants ranges from 15 to 50 %; quoted incidence varies as the proportion of extremely low birth weight babies in different studies varies (Sinha and Donn 2006). The oxygen saturation target, and ventilation strategy of individual neonatal units, influences the number of infants receiving supplemental oxygen and therefore the quoted rates of BPD. Numbers of infants with BPD have increased over recent years, and this may reflect the increased survival of very low birth weight infants. Many factors affect the risk of developing BPD: the degree of prematurity, the severity of the disease, oxygen toxicity, effects of ventilator-induced lung injury (barotrauma, volutrauma, atelectasis, shear trauma and biotrauma), PDA and the presence or absence of air leak. Infants who develop BPD commonly have exacerbations of their lung disease in childhood, requiring readmission to paediatric wards both in the first year (Mutch et al. 1986) and throughout childhood (McCormick et al. 1993). These infants are at risk of serious decompensation should they contract bronchiolitis, and regimens exist for respiratory syncytial virus prophylaxis to specific groups of children with BPD.

Although most infants with RDS have normal neurological outcomes, those who require prolonged ventilation and develop BPD have more neurological sequelae than those with mild disease not requiring ventilation (Anderson and Doyle 2006). One follow-up study showed that infants with RDS who required prolonged continuous ventilation, for at least 28 days, were more likely to die or have abnormal neurological outcome, than those requiring less ventilation. The study also showed that very low birth weight infants with major cranial ultrasound abnormalities who had prolonged ventilation, all either died or had abnormal neurodevelopmental outcome (Thomas et al. 2003).

The host defences in the lung of the newborn infant are less well developed than those of older children and adults. Polymorphonuclear neutrophils have reduced phagocytic and microbicidal activities as well as diminished capacity for chemotaxis and adhesion (Hill 1987). Natural killer cells, while normal in number, have reduced cytolytic activity against target cells. Circulating complement levels are reduced to around 50 % of levels seen in older children. Transmission of maternal IgG antibodies across the placenta confers a degree of immune protection. However, the neonate is poorly protected against organisms that predominantly evoke IgA or IgM antibodies. Importantly, preterm infants miss out on the placental transfer of antibodies which mostly occurs late in the third trimester of pregnancy.

As a result of impaired host defences, infections are more common and cause greater disruption of normal lung structure and function in both term and preterm neonates.

Bacterial infections commonly give rise to inflammation of the pleura, infiltration and destruction of the bronchopulmonary tissue and exudate containing leukocytes and fibrin within the alveoli and small airways (Davies and Aherne 1962). An interstitial pattern with infiltration of mononuclear cells and lymphocytes is more typically seen in viral pneumonia.

Damage to the lungs occurs due to direct injury by the invading microorganisms and indirectly as a result of inappropriate or excessive responses by the host defence system. Direct injury is mediated by microbial enzymes, proteins and toxins that disrupt host cell membranes and metabolism. For example, group B streptococcal (GBS) pneumonia is characterised by exudative pulmonary oedema and alveolar haemorrhage. The organism appears to injure lung microvascular endothelial cells via a pore-forming hemolysin (Gibson et al. 1999). Inflammation attracts phagocytes which release substances that may help defend the body against the invading organisms but may result in poorly regulated cascades which damage host tissues.

Injury leads to an increased airway smooth muscle tone, mucous secretion and debris within the airways. In turn, this causes increased airway resistance, partial or total airway obstruction and atelectasis or air trapping. Surfactant inactivation by proteinacious exudate exacerbates the impairment of lung function. Gas exchange is impaired by increased barriers to alveolar diffusion, intrapulmonary shunting and ventilation-perfusion mismatch. An increased metabolic demand of the lungs and other tissues to which the infection may have spread exacerbates these problems.

Some bacterial infections are associated with typical pathological features. Staphylococcus aureus and Klebsiella pneumoniae cause extensive tissue damage and may lead to abscess formation and empyema.

Early onset pneumonia presents within the first 3 days of life. Transplacentally acquired pneumonia is a relatively rare form of early onset pneumonia. It includes those pneumonias caused by rubella virus, cytomegalovirus, Treponema pallidum and Listeria monocytogenes. Many of these infants are stillborn or die in the first days of life.

More commonly it is due to aspiration of infected amniotic fluid before or at the time of delivery. In developed countries, group B streptococcus (GBS) is the most common bacterial pathogen, but gram-negative organisms such as E. coli are also prevalent. In contrast, E. coli is the main organism in developing countries. Blood cultures are frequently positive when these organisms are involved. Listeria species, herpes simplex virus, candida, enterovirus and adenovirus have also been reported.

Initial treatment with a penicillin (penicillin G or ampicillin) and an aminoglycoside (gentamicin) is appropriate pending blood cultures. Acyclovir should be started if herpes simplex virus pneumonia is suspected. As the clinical and radiological signs of pneumonia are not specific, treatment of all cases of respiratory distress with appropriate antibiotics is the safest option.

Late-onset pneumonia, beyond the first 72 h of life, may be caused by the same organisms, but Staphylococcus aureus, coagulase-negative Staphylococci and gram-negative bacilli are most common. Blood cultures are frequently negative in late-onset pneumonia.

Choice of antibiotics is governed by the resistance profiles of the setting. Where drug-resistant staphylococci are prevalent, the combination of vancomycin and gentamicin provides suitable cover.

Race and economic factors are associated with risk of early neonatal pneumonia. A study conducted in the 1960s showed that black infants who died in the first 48 h of life had an incidence of pneumonia of 27.7 %, compared with 11.3 % of white infants. The difference was consistent across all weight groups (Fujikura and Froehlich 1967). Similar differences were found by Naeye et al. in a series of consecutive autopsies of newborn and stillborn infants. Black infants had significantly higher rates of pneumonia (37 %) than Puerto Rican (22 %) or white infants (20 %). They also found that babies from families with the lowest income had significantly higher rates of pneumonia than infants from higher income families (Naeye et al. 1971).

Late-onset bacterial pneumonia may occur in nursery epidemics as a result of an infected health care worker or contaminated equipment. Viral epidemics have also been reported. Respiratory syncytial virus and influenza virus are amongst the causative organisms, and direct contact and droplets are the most common modes of spread.

Ascending infection from the maternal genital tract is the most common mode of acquisition of early onset pneumonia. Therefore, prolonged rupture of the membranes, variously defined as beyond 18 or 24 h duration, is an important risk factor for neonatal pneumonia. Signs of maternal infection, e.g. maternal fever and uterine tenderness, may give early warning of an infant at risk. Frequent pelvic examinations during labour are also considered a risk factor. Persistent fetal tachycardia is a relatively specific sign of infection, and its presence on CTG during labour should be communicated to those responsible for postnatal care of the infant.

Vaginal and rectal carriage of GBS occurs in 10–20 % of pregnant women. Infants at highest risk for GBS are those whose mothers carry the organism but have little or no circulating anti-GBS immunoglobulin. Approximately 1 % of infants born to carrier mothers become infected. Early onset GBS disease affects 1.8 per 1,000 live births.

Infected dairy products are considered the most important reservoir for transmission of Listeria monocytogenes. Women with HIV are more susceptible to infection with this organism.

Late-onset pneumonia is strongly associated with assisted ventilation, and the risk is substantially higher for preterm infants. Rates vary according to the stringency of definition. Colonisation of the endotracheal tube is common, but using strict criteria, including positive blood culture of a respiratory pathogen, the rate of late-onset pneumonia in infants ventilated for more than 24 h in the Oxford study was 10 % (Webber et al. 1990). In a single-centre cohort study of ventilated infants of birth weight <2,000 g in St. Louis, the overall rate of ventilator-associated pneumonia was 11 %. Diagnosis was based on focal infiltrates on chest x-ray in combination with antibiotic usage for 1 week. The rate was substantially higher (28 %) in infants <28 weeks gestation (Apisarnthanarak et al. 2003). Using a less strict definition, Halliday et al. reported a pneumonia rate of 35 % in preterm infants ventilated during a randomised trial of surfactant therapy (Halliday et al. 1984). Other risk factors for late-onset pneumonia include neurological impairments leading to aspiration and congenital abnormalities of the lung and airways, e.g. tracheo-oesophageal fistula and cystic adenomatoid malformations. Preventable factors such as poor hand washing (Harbarth et al. 1999) are important in both developed and developing countries.

Successful treatment of neonatal pneumonia depends on consideration of the diagnosis in the differential diagnosis of any unwell newborn infant and early commencement of appropriate antibiotic therapy. The goals of treatment are to eradicate the infection and provide adequate respiratory support to allow intact survival of the infant.

There is less evidence to guide clinicians regarding the ventilation of infants with pneumonia compared with RDS. However, the hierarchy of respiratory support is similar to that for RDS. Requirements should be titrated against an infant’s needs. Regular clinical assessment, in addition to continuous cardiorespiratory and oxygen saturation monitoring, allows the clinician to gauge the infant’s progress and intervene appropriately.

Active infants with respiratory distress whose breathing is regular may only require supplemental oxygen to maintain normal oxygen saturations. Additional support may be required to manage an infant with inadequate respiratory drive or severe lung disease. Sepsis in general and pneumonia in particular are often associated with apnoeic pauses. These occur in term infants but are more common in preterm infants. If apnoeic infants require frequent stimulation, i.e. more often than once per hour, or bag and mask ventilation, then additional support is required. Nasal CPAP may be useful as it reduces the work of breathing and leads to more regular respirations.

Infants with severe respiratory distress, particularly when associated with respiratory acidosis, require intubation and ventilation. Regular assessment of blood gases is essential to avoid the dangers of excessive ventilation, i.e. hypocarbia and volutrauma as well as underventilation and worsening respiratory acidosis.

Supplemental oxygen administration is the foundation upon which treatment for MAS is built and, in many less severe cases, will be the only therapy required (Singh et al. 2009b). Some ventilated infants with MAS require high inspired oxygen concentration for long periods, with few apparent adverse effects. Infants persistently requiring an FiO₂ >0.8 should, however, have measures taken to improve oxygenation (see Table 47.1).

Moment by moment titration of oxygen concentration (or flow) in infants with MAS should be according to SpO₂ level, with a pre-ductal reading to be preferred and the SpO₂ target range being higher (e.g. 94–98 %) than that used in preterm infants. In ventilated infants, oxygen therapy should also be monitored by regular blood gas sampling from an intra-arterial line, preferably in a pre-ductal position in the right radial artery. Suggested target pO₂ range is 60–100 mmHg (pre-ductal). Where there is considerable PPHN, titration of FiO₂ using post-ductal pO₂ values is not advisable.

Of all infants requiring mechanical respiratory support because of MAS, approximately 10–20 % are treated with CPAP only (Wiswell et al. 2000; Dargaville and Copnell 2006; Singh et al. 2009b). Additionally, around one-quarter of infants requiring intubation with MAS receive CPAP before and/or after their period of ventilation (Dargaville and Copnell 2006). CPAP for such infants can be effectively delivered by bi-nasal prongs or a single nasal prong, typically with a CPAP pressure of 5–8 cm H₂O. Tolerance of the CPAP device may be limited given the relative maturity of infants with MAS, and on occasions the associated discomfort will exacerbate pulmonary hypertension to the point where intubation becomes necessary.

Approximately one-third of all infants with a diagnosis of MAS require intubation and mechanical ventilation (Wiswell and Bent 1993; Cleary and Wiswell 1998). This proportion varies according to how assiduously non-ventilated cases are identified in published series and also depends on ventilation practices of individual units. Indications for intubation of infants with MAS include (a) high oxygen requirement (FiO₂ > 0.8), (b) respiratory acidosis, with arterial pH persistently less than 7.25, (c) pulmonary hypertension and (d) circulatory compromise, with poor systemic blood pressure and perfusion (Goldsmith 2008). Except in emergency circumstances, intubation of infants with MAS should be performed with premedication. Significant endotracheal tube leak is a major barrier to effective ventilation in infants with MAS, and in most cases a size 3.5 mm internal diameter endotracheal tube will be required. Once intubated, tolerance of the endotracheal tube will require ongoing sedation with infusions of an opiate (e.g. morphine or fentanyl) (Aranda et al. 2005), possibly supplemented with a benzodiazepine. Additionally, continuation of muscle relaxant drugs is often helpful during the stabilisation period after intubation, particularly in infants with coexistent pulmonary hypertension.

Despite more than four decades of mechanical ventilation for infants with MAS, the ventilatory management of the condition remains in the realm of ‘art’ rather than ‘science’, with very few clinical trials upon which to base definitive recommendations. Physiological principles and published experience of ventilation in MAS do, however, allow some guiding principles to be put forward for conventional ventilation strategy.

Despite the dearth of clinical trial evidence suggesting a benefit (Henderson-Smart et al. 2009), high-frequency oscillatory ventilation (HFOV) has become an important means of providing respiratory support for infants with severe MAS failing conventional ventilation. Published series from large neonatal databases suggest that 20–30 % of all infants requiring intubation and ventilation with MAS are treated with high-frequency ventilation (Dargaville and Copnell 2006; Singh et al. 2009b; Tingay et al. 2007), with most of these receiving HFOV rather than high-frequency jet ventilation (HFJV). Indications for transitioning to HFOV include ongoing hypoxaemia and/or high FiO₂ and, less commonly, respiratory acidosis. In infants with significant atelectasis, adequate lung recruitment may require the application of a mean airway pressure (P _AW) considerably higher than on conventional ventilation (up to 25 cm H₂O in some cases), with a stepwise recruitment manoeuvre likely to be the most effective (Pellicano et al. 2009). Once oxygenation has improved, P _AW should then be reduced; most infants with MAS requiring HFOV can be stabilised using a P _AW around 16–20 cm H₂O, with gradual weaning in the days thereafter (Dargaville et al. 2007). Infants with prominent gas trapping may tolerate the recruitment process poorly, with reductions in oxygenation and systemic blood pressure and the potential for exacerbation of pulmonary hypertension. Recruitment manoeuvres of some form can still be advantageous in this group, with the benefit becoming apparent when the P _AW is reduced.

Choice of oscillatory frequency is critically important in MAS, with experimental studies and clinical experience indicating that frequency should not be higher than 10 Hz and preferably should be set at 8 or even 6 Hz. In experimental models of MAS, high oscillatory frequency (15 Hz) is associated with worsening of gas trapping (Hachey et al. 1998). HFOV can also lend a clinical advantage in infants with significant coexisting PPHN, as the response to inhaled nitric oxide (iNO) is better when delivered on HFOV compared to conventional ventilation (Kinsella et al. 1997). Early reports suggested that up to half of infants with MAS treated with HFOV did not respond adequately and went on to receive ECMO (Carter et al. 1990; Paranka et al. 1995). More recent experience would suggest that only around 5 % of infants treated with HFOV and iNO fail to respond and transition to ECMO (Wiswell et al. 1990).

The combination of atelectasis and gas trapping that can occur in MAS may be better managed with HFJV than HFOV, with the former technique offering the possibility of ventilation at a lower P _AW (Keszler et al. 1986). A number of laboratory investigations have shown HFJV either alone or in combination with surfactant therapy, to be beneficial in animal models of MAS (Keszler et al. 1986; Wiswell et al. 1992, 1994). Clinical studies including infants with MAS appear to confirm the benefit of HFJV compared with conventional ventilation, both in terms of improvement in oxygenation and in avoidance of ECMO (Davis et al. 1992; Engle et al. 1997). Additionally, some infants with MAS failing on HFOV with hypoxaemia and/or respiratory acidosis do show improvements after transition to HFJV using a low frequency (240–360 bpm) and a low conventional ventilator rate (Dargaville (2010), unpublished observations).

The pathophysiology of MAS includes inhibition of surfactant in the air spaces, both by meconium and by exuded plasma proteins (Moses et al. 1991; Sun et al. 1993; Herting et al. 2001; Fuchimukai et al. 1987). Preliminary reports of the use of exogenous surfactant given as bolus therapy to ventilated infants with MAS were promising (Auten et al. 1991; Khammash et al. 1993), although it was identified that around 40 % of cases did not respond (Halliday et al. 1996). Four randomised controlled trials of bolus surfactant therapy have been conducted (Findlay et al. 1996; Lotze et al. 1998; Chinese Collaborative Study Group for Neonatal Respiratory Diseases 2005; Maturana et al. 2005), which when analysed together show a benefit in terms of reduction in need for ECMO, but not duration of ventilation or other pulmonary outcomes (El Shahed et al. 2007). In the developed world, bolus surfactant therapy is currently used in 30–50 % of ventilated infants with MAS (Dargaville and Copnell 2006; Singh et al. 2009b). Bolus surfactant therapy should be used judiciously in MAS, choosing infants with severe disease, and treating early, and if necessary, repeatedly (Dargaville and Mills 2005).

Lung lavage using dilute surfactant is an emerging treatment for MAS that offers the potential of interrupting the pathogenesis of the disease by removal of meconium from the air spaces (Dargaville and Mills 2005). Laboratory studies and preliminary clinical evaluations have indicated that lavage therapy may improve oxygenation and shorten duration of ventilation in MAS (Cochrane et al. 1998; Wiswell et al. 2002; Dargaville et al. 2003). A recent randomised controlled trial of large volume lavage using dilute surfactant in infants with severe MAS noted no effect on duration of respiratory support or other pulmonary outcomes, but did find a higher rate of ECMO-free survival in the treated group (Dargaville et al. 2011). A further clinical trial would be necessary to more precisely define the effect on survival.

Steroid therapy has been investigated in MAS for more than three decades, with a number of small clinical trials being conducted, none of which have given a definitive result. One recent trial suggested that dexamethasone therapy could dampen the inflammatory response in MAS, as indicated by levels of tumour necrosis factor-α (Tripathi et al. 2007). In the absence of further trials, steroid therapy cannot be recommended as routine therapy in MAS.

Large randomised controlled trials have demonstrated the effectiveness of iNO in term infants with pulmonary hypertension, with a reduction in need for ECMO, and in the composite outcome of death or requirement for ECMO (Finer and Barrington 2006). Each trial included a large subgroup with MAS; overall more than 640 infants with MAS have been enrolled in iNO trials, although few have reported the outcome for MAS separately. The potential value of delivering iNO during HFOV has been highlighted in one trial, in which the proportion of nonresponders was lowest when the two therapies were combined (Kinsella et al. 1997). Currently around 20–30 % of all ventilated infants with MAS receive iNO (Dargaville and Copnell 2006; Singh et al. 2009b), and around 40–60 % show a sustained response (Gupta et al. 2002; Kinsella et al. 1997).

The approach to an infant with MAS and coexistent PPHN should initially focus on optimising the ventilatory management and, in particular, overcoming atelectasis if this is prominent radiologically. The severity of PPHN should be assessed clinically and by echocardiogram if available. If moderate to severe PPHN persists after appropriate ventilatory manoeuvres and the pO₂ remains at less than 80–100 mmHg in FiO₂ 1.0 (Kinsella et al. 1997; Wessel et al. 1997), iNO should commence at a dose of 10–20 ppm. Higher doses do not appear to result in better oxygenation (Guthrie et al. 2004).

Infants with severe MAS have been treated with ECMO since 1976, and MAS has been the leading diagnosis amongst neonates referred for this therapy (Short 2008). With the advent of newer therapies, the number of infants with MAS treated with EMCO has decreased (Fliman et al. 2006), but survival with ECMO treatment for MAS has remained high (around 95 %) (Short 2008). The usual indication for commencing ECMO is intractable hypoxaemia despite optimisation of the patient’s condition with available therapies (including high-frequency ventilation and iNO and bolus surfactant therapy). Degree of hypoxaemia in this setting has generally been quantified using oxygenation index (OI), where OI = P _AW × FiO₂ × 100 / PaO₂. An OI persistently above 40 despite aggressive standard management has been, and remains, an indication for treatment with ECMO where available (UK Collaborative ECMO Trial Group 1996).

Pneumothorax is a feared complication of MAS which potentiates lung atelectasis and PPHN and compounds the difficulties with management. Around 10 % of all ventilated infants with MAS are reported to have this complication (Wiswell et al. 1990; Dargaville and Copnell 2006). Pneumothorax is associated with an increase in the risk of mortality (Dargaville and Copnell 2006; Lin et al. 2004), in part related to the severity of the associated lung disease, but also to the destabilising influence of the air leak itself. Clinicians should remain attuned to the possibility of pneumothorax in ventilated infants, particularly those prone to gas trapping, and should employ ventilatory strategies to avoid regional and global overdistension wherever possible. Effective treatment requires that air be evacuated from the pleural space immediately once the condition is diagnosed, and then in most instances, an intercostal drainage tube is required to control ongoing air leak.

Other air leak syndromes, including pneumomediastinum and pulmonary interstitial emphysema, are occasionally seen in MAS. Pneumopericardium and pneumoperitoneum are rare. Pneumomediastinum usually requires no treatment unless under significant tension (Masuda et al. 1984). Pulmonary interstitial emphysema in the setting of MAS at times results in the formation of multiple large cysts and can be extremely difficult to treat. The condition is best managed either with HFJV (see Table 47.1) or HFOV at low frequency (5–6 Hz).

Pulmonary haemorrhage (or, more correctly, haemorrhagic pulmonary oedema) occurs in a small proportion of infants with MAS and can occasionally cause severe destabilisation and hypoxaemia (Berger et al. 2000). Transient application of a high airway pressure is usually necessary to drive this oedema fluid back into the interstitium of the lung. This is best achieved using high-frequency ventilation, with P _AW above 30 cm H₂O sometimes required to re-recruit flooded alveoli.

Cases of severe MAS succumbing after a long period of ventilation can have severe distortion of normal lung architecture on post-mortem examination (Chou et al. 1993). Refinements in ventilatory and adjunctive care now mean that fewer infants have long-standing severe chronic lung disease after MAS. Nevertheless, approximately 5–7 % of ventilated infants with MAS remain in oxygen for more than 4 weeks (Dargaville and Copnell 2006; Singh et al. 2009b), and 5 % go home in oxygen (Dargaville and Copnell 2006). A subset of infants who have had MAS in the newborn period will have wheezing and repeated hospitalisations in the first year of life and have demonstrable abnormalities on respiratory function testing (Yuksel et al. 1993). These abnormalities would be expected to largely resolve later in the first decade (see below).

Seizures occur in around 10 % of all ventilated infants with MAS, most usually in the context of a coexistent hypoxic-ischaemic encephalopathy (Singh et al. 2009b; Cleary and Wiswell 1998). Circulatory insufficiency is common, and the majority of infants who have severe MAS and coexistent PPHN are treated with inotrope infusions (Dargaville et al. 2011). Multi-organ failure develops in a small proportion of such infants.

Mortality related to MAS has decreased significantly, with population-based studies suggesting a mortality of 1–2 per 100,000 live births (Sriram et al. 2003; Dargaville and Copnell 2006; Nolent et al. 2004). The case fatality rate in ventilated infants with MAS varies widely in published series (0–37 %) (Cleary and Wiswell 1998) and is influenced by availability of alternative means of ventilation, adjunctive therapies including nitric oxide and ECMO. Approximately one-quarter to one-third of all deaths in ventilated infants with a diagnosis of MAS are directly attributable to the pulmonary disease, with the remainder in large part caused by hypoxic-ischaemic encephalopathy (Dargaville and Copnell 2006; Singh et al. 2009b; Nolent et al. 2004).

Considering all intubated infants with MAS, median duration of ventilation is 3 days (mean 4.8 days) (Dargaville and Copnell 2006). Infants with more severe disease, requiring at least one of HFV, iNO or bolus surfactant, are ventilated for a median of 5 days (Dargaville and Copnell 2006). Median duration of oxygen therapy and length of hospital stay currently stand at 7 and 17 days, respectively (Dargaville and Copnell 2006).

Respiratory compromise after hospital discharge is common in infants who were ventilated with MAS. Up to half of infants will be symptomatic with wheezing and coughing in the first year of life (Yuksel et al. 1993). Older children may exhibit evidence of airway obstruction, hyperinflation and airway hyperreactivity, but appear to have normal aerobic capacity (Swaminathan et al. 1989).