Stimulus for the first breath

Fetal breathing activity ceases during labour. Following birth, one of the most important stimuli to the onset of breathing is cooling. Audiovisual, proprioceptive and touch stimuli recruit central neurons and increase central arousal ( ; ). Hypoxia mediated by central chemoreceptors is important, but peripheral chemoreceptor activity is not critical to the onset of respiration ( pp. 454–455 ). The median time for the onset of respiratory activity is 10 seconds ( ).

A high negative pressure is required to overcome the high flow resistance and inertia of liquid in the airways, as well as the surface tension at the air–liquid interface ( ). Both and recorded inspiratory pressures during the first breath of greater than 20 cmH ₂ O, but not in all infants. Subsequently, using a dual-pressure tip transducer, demonstrated that pressures of greater than 20 cmH ₂ O were the norm. Expiration is active for the first few breaths, with pressures ranging from 18 to 115 cmH ₂ O; this may aid the distribution of ventilation and facilitate further fluid clearance from the lungs.

Oxygen

Haemoglobin increases the oxygen transport capacity of the blood 70-fold over that of plasma. As a consequence, the majority of oxygen in whole blood is transported as oxyhaemoglobin (HbO ₂ ) and only a small proportion is dissolved in solution. The haemoglobin concentration is regulated by a renal sensing mechanism, which operates to maintain a balance between the oxygen supply and requirement of the renal tissues. A decrease in concentration or arterial oxygen saturation of haemoglobin or an increase in haemoglobin affinity for oxygen increases erythropoietin production. Haemoglobin is a tetramer: each of the four subunits contains a haem moiety (porphyrin and one atom of ferrous iron) attached to a polypeptide (globin) chain. The four iron atoms can each combine with an oxygen molecule; they remain in the ferrous state, that is, the reaction is oxygenation rather than oxidation. In adult haemoglobin, the four globin chains are predominantly α ₂ β ₂ (HbA), whereas in the fetus they are α ₂ γ ₂ (HbF). The quarternary structure of haemoglobin determines its affinity for oxygen: uptake of oxygen by haemoglobin results in a change of position of the haem moieties, facilitating further oxygen binding. The result is that the oxygen–haemoglobin dissociation curve (the relationship of the percentage oxygen saturation of haemoglobin to the P o ₂ ) has a characteristic sigmoid shape. The oxygen–haemoglobin disssociation curve is affected by the pH, temperature and concentration of 2,3-diphosphoglycerate (2,3-DPG). A rise in temperature or fall in pH (Bohr shift) shifts the curve to the right, which means that a higher P o ₂ is required for haemoglobin to bind to a given amount of oxygen. This is quantified as the P ₅₀ , the P o ₂ at which the haemoglobin is half saturated with oxygen. The higher the P ₅₀ , the lower the affinity of haemoglobin for oxygen. 2,3-DPG is formed from a product of glycolysis and thus its concentration falls when the pH is low. 2,3-DPG binds preferentially to the β chains of deoxygenated haemoglobin. An increase in 2,3-DPG causes more oxygen to be liberated, that is, the oxygen dissociation curve is shifted to the right.

The fetus and newborn

Compared with in the adult, fetal red blood cells (RBCs) are larger, have a shorter half-life and differ in ultrastructure. They also differ with regard to their mechanical, osmotic, thermal and acidic fragility, and contain haemoglobin F (HbF), which is less easily denatured in alkaline or acidic solutions than is adult haemoglobin. The γ chains of HbF have the same number of amino acids as the β chains, but differ in sequence by 39 amino acids. The γ chains of HbF have poorer binding to 2,3-DPG. The effect of 2,3-DPG on the P ₅₀ of fetal haemoglobin is approximately 40% of the effect on the P ₅₀ of adult haemoglobin. The oxygen tension of fetal blood is one-fifth to one-quarter that of the adult, but the fetal arterial blood oxygen content and oxyhaemoglobin saturation are similar to those of the adult. This results from the high oxygen-carrying capacity and the increased oxygen affinity of HbF. The latter facilitates the movement of oxygen from mother to fetus. Oxygen delivery to the fetal tissues is sustained because the steep fetal oxygen dissociation curve means that a small decrease in oxygen tension results in a major change in oxyhaemoglobin saturation and unloading of oxygen.

In the term newborn, 70–80% of the haemoglobin is HbF: in preterm babies, about 90% of haemoglobin is HbF. Birth, intrauterine hypoxia and haemolytic disease of the newborn do not cause a change in the proportions of HbA and HbF at any given gestational age. Near term, however, the demand for accelerated erythropoeisis leads preferentially to synthesis of HbA. During the first year, HbF decreases from 70% to less than 2% of the total haemoglobin.

The high oxygen affinity of HbF has disadvantages in postnatal life. In particular, the low P ₅₀ decreases the driving potential for oxygen diffusion, limiting the rate at which oxygen can be unloaded ( ). The oxygen consumption of the newborn at minimal activity, even in a thermally neutral environment, increases by 100–150% in the first few days. To meet these demands, the baby’s blood oxygen affinity decreases rapidly over the first 5 days and then more gradually, reaching adult values by 6 months ( ). During the first 5 days, the 2,3-DPG levels rise to above those found in the adult; this decreases blood oxygen affinity by lowering intercellular pH. Prematurely born babies have a lower 2,3-DPG content, lower P ₅₀ and higher fetal haemoglobin concentration. They have a smaller oxygen unloading capacity and do not catch up until 3 months of age ( ).

Carbon dioxide

Carbon dioxide is 20 times more soluble in water than is oxygen. Carbon dioxide is carried in the blood by three mechanisms: the majority as bicarbonate (85%), but also dissolved and in combination with proteins as carbamino compounds. Bicarbonate is formed very rapidly in RBCs, because of the presence of carbonic anhydrase, which catalyses the first part of the following reaction:

Ionic dissociation of H ₂ CO ₃ is fast. HCO ₃ ⁻ then diffuses out of the RBC down a concentration gradient, but H ⁺ cannot follow and binds to haemoglobin. This is facilitated in the presence of reduced haemoglobin, which is a weaker acid than oxyhaemoglobin, and thus deoxygenation of the blood increases its ability to carry carbon dioxide (the Haldane effect). To maintain electrical neutrality, as HCO ₃ ⁻ diffuses out, Cl ⁻ diffuses into the RBC (the chloride shift). These events increase the osmolar content of the RBC, thus the packed cell volume is higher on the venous than on the arterial side of the circulation. Carbon dioxide also combines with the N terminals of amino acids of proteins, particularly haemoglobin, to form carbamino compounds:

The newborn’s blood has a greater carbon dioxide transport capacity. This is because of the high haemoglobin level. In addition, carbon dioxide competes with 2,3-DPG for the haemoglobin binding site, and, since 2,3-DPG binds less avidly with HbF than with adult haemoglobin, more carbon dioxide can be taken up. RBC carbonic anhydrase levels, however, are 25% lower in the neonate and even more so in those born prematurely ( ).

Excitatory

The excitatory neurotransmitters include glutamate, which excites NMDA and non-NMDA receptors; the latter are involved in generating and transmitting respiratory rhythms to spinal and cranial respiratory neurons ( ). The transmission of inspiratory drive is further fine-tuned by presynaptic glutaminergic modulation at the level of the spinal cord. Serotonin (5-hydroxytryptamine (5-HT)) neurons in the medulla oblongata constitute a critical system in the modulation of autonomic and respiratory effector neurons ( ). 5-HT has diverse effects on respiratory neuronal activity, but the most consistent effect is to restore a normal breathing pattern in metabolic states such as hypoxia or ischaemia, which cause apneustic breathing ( ). The developmental profile of 5-HT _2A receptors changes over the first year after birth in the hypoglossal nucleus critical to airway patency ( ).

Inhibitory

Both gamma-aminobutyric acid (GABA) and glycine are essential for generating respiratory rhythm in the primary network. GABA and glycine are released by late and postinspiratory neurons to turn off inspiratory neurons and so facilitate the transition from inspiration to expiration. Adenosine is ubiquitously formed in the body and has both central and peripheral effects. When administered centrally, it depresses ventilation; this effect is most pronounced in young full-term and preterm animal models. If adenosine is given systemically, however, it stimulates breathing, probably by stimulating peripheral chemoreceptors; this effect may be more important in the adult. Adenosine antagonists (theophylline and caffeine) stimulate breathing and also block – but not in humans – hypoxia-induced respiratory depression ( ).

Alveolar type II cells

Alveolar type II cells produce surfactant ( Fig. 27.8 ) ( ). They are compact cuboidal cells, occurring most often at the corners of the air spaces. They cover about 2% of the alveolar surface and account for about 15% of the cell numbers. They differentiate from the columnar epithelium during the canalicular phase of development ( p. 448 ), but are not prominent until about 24 weeks’ gestation, when they can be identified by their osmiophilic lamellar inclusion bodies ( ). The biosynthesis of surfactant phosphatidylcholine occurs in the endoplasmic reticulum of the type II cell. The phospholipid then moves via intracellular pathways towards the lamellar bodies, for secretion into the alveolus. The characteristic feature of the alveolar type II cell is the lamellar body, storage granules of surfactant ( ).

An alveolar type II cell showing two surfactant release mechanisms: lamellar bodies and the constitutive release of surfactant protein A. Surfactant is shown both being phagocytosed by an alveolar macrophage (AM) and being taken back into the cell and reutilised. The inset shows a monolayer which, in the gel phase, is able to withstand very large lateral forces, literally splinting open the alveolus. RER, rough endoplasmic reticulum; LMVB, light multivesicular body; DMVB, dense multivesicular body.

(Reproduced from .)

Lamellar bodies

A mature lamellar body is about 1.5 µm in diameter. They consist of a limiting membrane surrounding about 20–70 close-packed phospholipid bilayers, or lamellae, each with a width of 66 Å, arranged in a hemisphere. The ends of these lamellae abut on to a baseplate, which is probably an extension of the limiting membrane. In the centre is a matrix core of proteinaceous material ( ). Lamellar bodies, isolated from lung tissue by density gradient centrifugation, contain surfactant lipids and the surfactant proteins A, B and C (SP-A, SP-B, SP-C).

Recycling of surfactant

Surfactant may be degraded locally in the alveoli and small airways, the breakdown products being absorbed and recycled by the alveolar cells ( Fig. 27.9 ). More than 90% of the phosphatidylcholine on the alveolar surface is reprocessed; this conserves surfactant components as well as reactivating them to regenerate surfactant. The turnover time is approximately 10 hours ( ). The contribution, therefore, to the alveolar surfactant pool from de novo synthesis is modest.

Illustration of surfactant metabolism based on the saturated phosphatidylcholine component of surfactant. The anabolic pathway for synthesis and secretion links with alveolar transformations of the lamellar surfactant to tubular myelin and the monolayer. Catabolic pathways for phospholipid vesicles are minor pathways in the newborn lung but active in the adult lung. The majority of the surfactant is taken back into type II cells for recycling during the newborn period. MVB, multivesicular body.

(Reproduced from .)

There is negative-feedback regulation of surfactant production mediated by SP-A binding to type II cells ( ). Surfactant secretion is controlled by stretch receptors and stimulated by gas entering the lung, causing alveolar distension ( ). Other factors controlling secretion ( ) include β-adrenergic receptors on alveolar type II cells, which increase in number towards the end of gestation.

Phosphatidylcholine and phosphatidylglycerol

Lipids are the major constituent of surfactant and the most important are phosphatidylcholine (PC) and phosphatidylglycerol (PG), representing 70–80% and 5–10% of the lipids, respectively. Another 10% of the lipids is made up of phosphatidylinositol (PI), phosphatidylserine (PS) and phosphatidylethanolamine (PE). Approximately 60% of the PC has both fatty acids saturated (i.e. disaturated) and, as the primary saturated fatty acid is palmitic acid, the major compound in surfactant is dipalmitoyl phosphatidycholine (DPPC). The palmitic acid residues are non-polar and hydrophobic and orient towards the air, whereas the PC is polar and hydrophilic and associates with the liquid phase ( ). The shape and orientation of the DPPC mean that it generates a stable monolayer and is able to maintain low surface pressures: during expiration the molecules become very closely packed, as the palmitoyl moieties lack the C–C bonds that produce the kinks in the acyl chains ( ). DPPC is relatively rigid at body temperature and cannot adsorb to a surface ( ); its phase transition (melt) is approximately at 41°C. At body temperature, DPPC cannot move rapidly enough to maintain a surface monolayer during the respiratory cycle and a ‘spreading’ agent such as PG is required for normal surfactant function.

PC is synthesised in the endoplasmic reticulum of the type II pneumocytes. There is an increase in surfactant production towards the end of gestation. From 27 to 31 days (term) in rabbits, there is a 10-fold increase in surfactant; during a similar time period, PC increases from 30% to 70% of the total phospholipids, whereas sphingomyelin decreases from 40% to 10%. This change is due to increased synthesis, whereas after birth there is increased secretion. In surfactant from human term and preterm infants, the fractional concentrations of not only DPPC (PC16 : 0/16 : 0), but also palmitoylmyristoyl PC (PC16 : 0/14 : 0) and palmitoylpalmitoleoyl PC (PC16 : 0/16 : 1) increase with maturation ( ); in animal models, the concentrations of the last two phospholipids correlate significantly with respiratory rate.

The proportions of the acidic phospholipids PG and PI change with lung development. Initially PI is the primary acidic phospholipid, but with increasing maturation it is replaced by PG. Patients with RDS have low levels of DPPC and absent PG ( ). In poorly controlled diabetic pregnancies, the fetuses have low levels of PG even near term. If RDS progresses to chronic lung disease, the appearance of PG is delayed; PI also predominated with acute lung.

Other lipids

About 10% of the total lipids in surfactant are neutral lipids. These are cholesterol, triacylglycerols and free fatty acids ( ). They appear to be an integral part of the surfactant in lamellar bodies and on the alveolar surface. Cholesterol alters the fluidity and organisation of lipid-rich membranes. Sphingomyelin represents less than 2% of surfactant lipid, and glycolipids and carbohydrates a very small fraction of the surfactant mass. The amount of sphingomyelin, a minor component of surfactant, remains unchanged through gestation and thus the change in the amount of DPPC or lecithin can be assessed by comparing it with the amount of sphingomyelin. Thus, lung maturity can be assessed by measurement of the ratio of lecithin to sphingomyelin, the L : S ratio ( p. 464 ).

Surfactant proteins

Four surfactant-associated proteins – SP-A, SP-B, SP-C and SP-D – have been identified and constitute 5–10% of surfactant by weight ( ).

Phosphatidylcholine synthesis

PC is produced by the cytidine diphosphate (CDP) choline pathway ( Fig. 27.10 ) ( ). Choline is taken up by the cell by facilitated transport and is then phosphorylated by choline kinase to phosphocholine, which in turn is converted to CDP choline (the rate-limiting step), which is then transferred to diacylglycerol to give PC. This produces molecules containing one saturated fatty acid, palmitic acid, and one unsaturated fatty acid, usually oleic acid. This molecule is then remodelled by deacylation to lysophosphatidylcholine, followed by reacylation with a palmitic acid derived from either palmitoyl CoA or a second molecule of lysophosphatidylcholine ( ) to give DPPC. It has been suggested that only 50% of the DPPC is synthesised directly from saturated diacylglycerols as precursors ( ) and the rest by remodelling. Two remodelling mechanisms exist: both involve deacylation of de novo synthesised 1-saturated-2-unsaturated PC to acyl-2-lysophosphatidylcholine. The latter is then either reacylated by reaction with a saturated acylCoA or transacylated in a reaction involving two molecules of lysophosphatidylcholine ( ). Only the former mechanism is quantitatively important. Cholinephosphate cytidylyltransferase (CT), which catalyses phosphocholine to CDP choline, is essentially inactive without lipids; CT activity is activated during fetal lung development and after corticosteroid administration. Several other hormones, including thyroid hormones and insulin, and epidermal growth factor (EGF) influence this sequence of events. PC synthesis via the methylation of PE is of minor importance, except in conditions of choline deficiency ( ).

Pathways in the biosynthesis of phosphatidylcholine, phosphatidylglycerol and phosphatidylinositol.

(Reproduced from .)

Phosphatidylglycerol synthesis

PG is synthesised together with the other acidic phospholipids, PI and PS, from CDP-diacylglycerol, which is in turn derived from phosphatidic acid ( Fig. 27.10 ).

Glucocorticoids

Endogenous cortisol is an important physiological stimulus to fetal lung maturation. In the fetal sheep, there is a marked increase in plasma cortisol concentration at the end of gestation and this is associated with an increase in DPPC in lung tissue and lung lavage fluid ( ). Administration of betamethasone to pregnant rabbits results in an increase in the total amount of phospholipid, as well as an increase in the percentage of PC in the total phospholipids ( ). Cortisol induces fetal lung fibroblasts to produce fibroblast pneumocyte factor, which then stimulates surfactant production by the fetal type II pneumocytes ( ). In animal experiments, glucocorticoids increase lung aeration, decrease the surface tension of the lung extract and increase synthesis of both surfactant phospholipids and proteins ( ). In preterm infants, antenatal treatment with dexamethasone increases the surface activity of surfactant isolated from airway specimens and the ratio of SP-A to PC, but not in offspring of mothers with severe hypertension ( ). Dexamethasone increases pulmonary surfactant secretion through an enhancement of β ₂ -adrenoreceptor gene expression ( ). In a primary culture of rat alveolar cells, while dexamethasone had no effect on the basal secretion rate of PC, it augmented both the PC secretion and the cAMP formation increased by terbutaline, and increased the mRNA expression of β ₂ receptors in type II cells ( ).

Beta-adrenergic drugs

Beta-adrenergic drugs stimulate adenylcyclase and inhibit phosphodiesterases, thereby increasing the amount of intracellular cAMP, which in turn increases the production ( ) and secretion of surfactant. cAMP stimulates the synthesis of disaturated phospholipids and SP-A; in addition, it mediates the effect of a number of hormones.

Thyroid hormones

Thyroxine (T ₄ ) increases surfactant production and lung maturation. Infants who develop RDS have lower cord blood levels of T ₄ than those who do not. T ₄ does not easily cross the placenta, but triiodothyronine (T ₃ ) given to pregnant rats is associated with an increase in T ₃ in the fetal serum. T ₃ increases the type II cell receptors’ response to fibroblast pneumocyte factor, which is necessary for appropriate surfactant production. TRH, unlike T ₄ and T ₃ , readily crosses the placenta; it increases the amount of surfactant phospholipid. The effects of TRH are not entirely mediated by thyroid hormone. TRH stimulates prolactin production and functions as a neurotransmitter in the central nervous system.

Prolactin

Prolactin levels are lower in infants who develop RDS than in those who do not; they are also lower in immature than in mature infants and lower in males than in females ( ). The effect of prolactin both in vivo and in cultured lung systems, however, is variable and the role of prolactin in surfactant production regulation remains speculative.

Epidermal growth factor

EGF may be important in the development of the pulmonary epithelium. Infusion of this substance into lambs prevents the development of hyaline membrane disease ( ) and increases lung distensibility. There is a reduced amount of SP-A in the offspring of rats with EGF autoantibodies ( ). Müllerian-inhibiting substance inhibits lung maturation by blocking phosphorylation of EGF receptors ( ); this may be an explanation for the higher incidence of RDS in males. In non-human primate fetuses delivered at 78% of term, in utero treatment with EGF resulted in higher SP-A levels and L : S ratios in treated than in untreated fetuses ( ).

Fibroblast pneumocyte factor

Alveolar cells need the presence of fibroblasts and their pneumocyte factor to produce surfactant ( ). Glucocorticoids act on the fetal lung fibroblasts to induce the production of fibroblast pneumocyte factor, which in turn stimulates rapid surfactant synthesis by the alveolar type II cell.

Insulin

Insulin delays the maturation of alveolar type II cells and decreases the proportion of saturated PC ( ). In addition, infants of diabetic mothers have delayed appearance of PG ( ). Hyperglycaemia also plays a role in the delay in lung maturation seen in these babies ( ). Insulin inhibits SP-A gene expression ( ).

Testosterone

Premature male infants are more prone to RDS than are similarly immature female infants ( ). Male lungs are approximately 1 week more immature as determined by the disaturated PC content. These differences may be due to inhibition of surfactant production in males by androgens ( ); lipid concentration in the lung appears to be at least partly directly or indirectly regulated by androgens ( ). In addition, androgens delay lung maturation through their action on lung fibroblasts ( ).

Predisposing factors

Factors with equivocal effects on the incidence of RDS

Factors reducing the incidence of RDS (see prevention of RDS, pp. 473–475 )

Lung function

The lungs are stiff, with compliance values of approximately 0.3–0.5 ml/cmH ₂ O/kg, when the disease is at its worst ( ) ( Table 27.4 ). As surfactant begins to appear, the compliance improves and has usually returned to values of 1–2 ml/cmH ₂ O/kg ( ) by 6–7 days of age. In severe disease, the functional residual capacity (FRC) may be as low as 3 ml/kg ( ), whereas the FRC is at a normal level of 25–30 ml/kg in recovering babies ( ). Babies with RDS have a low tidal volume and a large physiological dead space. Minute ventilation, however, may be increased by an elevated respiratory rate in an attempt to sustain alveolar ventilation, but this is usually unsuccessful, resulting in alveolar underventilation and carbon dioxide retention. Pressure–volume loops on lungs excised at postmortem from babies dying of HMD have a characteristic pattern ( Fig. 27.12 ). During inflation, the volume change for a given increase in pressure is very small, and, during deflation, the change in volume follows a track almost similar to that seen during inflation, whereas, in the normal lung, air is retained until low pressures are reached (hysteresis). As the pressure drops to zero, very little or no air is retained within the surfactant-less alveoli, corresponding to the very small FRC measured in vivo. Inspiratory resistance is usually normal in RDS ( ) but expiratory resistance is increased, probably as a result of the closure of the airway prior to the expiratory grunt ( ). It is also increased by the presence of an endotracheal tube (ETT) ( ). An inevitable sequela of the abnormal lung mechanics is that the work of breathing is increased in neonates with RDS to twice that seen in those without RDS ( ; ).

Pressure–volume loops in excised lungs of neonates dying with and without hyaline membrane disease (HMD). In HMD, the deflation curve closely follows the inflation curve and little air is retained at zero pressure. In normal lungs, much more air is retained on the deflation limb of the loop (the phenomenon of hysteresis).

(Reproduced from .)

The time constant gives a measure of the time available for gas to leave the lung during expiration, which is normally accepted to take three time constants. The time constant is the compliance (l/cmH ₂ O) multiplied by the airways resistance (in cmH ₂ O/l/s). It is very short in neonates with severe RDS:

In babies with less stiff lungs, however, the time constant will be longer, and if the baby breathes rapidly (at 80/min), this will result in gas being retained in the lungs when the next inspiration starts ( ). Clinical studies ( ; ) have shown the respiratory rate of infants with RDS to be about 80–90/min, with an average inspiratory time of 0.25–0.35 seconds. This pattern of respiration may be adopted so that the neonate retains gas within the lungs and some level of FRC is maintained.

A characteristic feature of RDS is the expiratory grunt. This is the result of the baby attempting to sustain an FRC by delaying the escape of air from the lungs during expiration. The baby tries to do this in two ways: firstly, during expiration, the diaphragm continues to contract, trying to delay or brake the reduction in thoracic volume and thus retain gas within the alveoli ( ); secondly, by contracting the constrictor muscles of the larynx, an attempt is made to close the upper airway, as in the Valsalva manouevre. Since the abdominal muscles contract at the same time as the laryngeal muscles relax, there is an explosive exhalation of air, which is the characteristic ‘grunt’. Bypassing this laryngeal component of expiratory braking by putting an ETT through the cords results in a fall in the P a o ₂ in babies with RDS ( ).

Surfactant

The preterm baby is born with poor reserves of surfactant ( p. 459 ). Most babies, however, have some present in the first few hours after birth. The deterioration seen in babies with non-surfactant-treated RDS is due in part to the disappearance of these small quantities of surfactant, compounded by fatigue as the neonate struggles to sustain ventilation in stiff, surfactant-deficient lungs. The disappearance of surfactant is primarily due to the inhibitory effect of proteins on surfactant (see above) ( ), which leak on to the alveolar surface in the early oedematous stage of lung damage. The deleterious effect of hypoxia and acidaemia on surfactant synthesis ( p. 462 ) may also play a part, but patency of the ductus is not relevant ( ). The levels of surfactant proteins are also low in the first few hours in babies with RDS and rise as the babies recover. The lungs remain non-compliant and atelectatic until surfactant begins to reappear from 36 to 48 hours of age, as demonstrated by measurement of L : S ratios of pharyngeal aspirates ( ).

Pulmonary hypertension

Pulmonary artery pressure (PAP) remains high throughout the first week and even longer in some cases of RDS ( ; ). The more severe the RDS, the higher the PAP, which may remain close to systemic levels in fatal cases ( ). At least during systole, PAP can be higher than systemic pressure, at which time there is likely to be right-to-left ductal shunting. In diastole, the systemic pressure is likely to be higher than the pulmonary pressure and the overall effect is bidirectional ductal shunting, and this is frequently detected echocardiographically in RDS ( ; ).

Mechanisms of hypoxia: right-to-left shunt with ventilation–perfusion imbalance

Hypoxaemia in RDS is due to a large right-to-left shunt. There are four main sites of right-to-left shunts:

• 1
  

  Obligatory shunts present due to drainage of the veins of the myocardium directly into the left side of the heart and anastomoses between the bronchial and pulmonary circulation. These are small and of no haemodynamic or clinical significance.

  
  
• 2
  

  Shunting through the foramen ovale occurs if right atrial pressure is higher than left atrial pressure. Interatrial right-to-left shunting is rare in neonates with RDS ( ; ).

  
  
• 3
  

  Shunting through a patent ductus arteriosus (PDA): the ductus arteriosus is patent in most babies with RDS during the first 48–72 hours ( ; ). If the PAP exceeds the aortic pressure, there will be a significant right-to-left shunt. Right-to-left shunts at ductal level are common in persistent pulmonary hypertension of the newborn (PPHN; p. 495 ) but in uncomplicated RDS are small and constitute <10% of the total right-to-left shunt ( ). Right-to-left ductal shunting means that blood taken from an umbilical artery catheter (UAC) can have a much lower P a o ₂ than blood passing up the carotid arteries to the eyes. Colour Doppler studies in babies with RDS have demonstrated that intravascular shunting at the ductal or foramen ovale level is relatively unusual and the shunts through these channels are predominantly bidirectional or left-to-right in the first few days after birth. This has little effect on blood gas values, but increases the cardiac output and the load on the right ventricle ( ; ; ).

  
  
• 4
  

  The true intrapulmonary right-to-left shunt, when pulmonary capillary blood passes through the lung without coming into contact with a ventilated alveolus.

The combination of the above is the true right-to-left shunt. There is another right-to-left shunt which contributes to the total shunt or venous admixture seen in babies with RDS, and it is the result of pulmonary blood flow passing partially ventilated alveoli, that is, ventilation–perfusion imbalance. This large component of the right-to-left shunt in RDS can be eliminated by giving the baby 100% oxygen to breathe for 15 minutes (the hyperoxia or nitrogen washout test). This eliminates shunting resulting from partially oxygenated alveoli, and a shunt calculated at the end of a period breathing 100% oxygen is the true shunt outlined above. In most babies with RDS, the majority of the right-to-left shunt is the fourth component of the true shunt plus the shunt from ventilation–perfusion imbalance.

Carbon dioxide retention

The increased P a co ₂ in RDS is due to hypoventilation secondary to atelectasis, decreased tidal volume and increased dead space. Ventilation is also non-homogeneous, so whereas end-tidal P A co ₂ is a good measure of P a co ₂ in patients with normal lungs, in babies with RDS there is a risk that measurement of P A co ₂ will seriously underestimate P a co ₂ . Since the mixed venous P co ₂ (normally 6.13 kPa, 46 mmHg) is usually only a fraction of a kilopascal above arterial or alveolar P co ₂ (normally 5.33 kPa, 40 mmHg), the right-to-left shunt has to be enormous before the admixture of venous blood significally contributes to hypercapnia in RDS.

Prevention of prematurity

Tocolytic drugs to prevent preterm labour have proved disappointing ( ; ), prolonging pregnancy for not more than 48 hours ( ). Genital tract infection is associated with preterm labour, and in women with preterm rupture of the membranes (PROM) there is evidence that treatment with antibiotics reduces the prematurity rate ( ).

Antenatal steroid therapy

Not all steroids cross the placenta; cortisol is largely inactivated, but degradation is resisted by synthetic steroids such as betamethasone and dexamethasone. Antenatal administration of dexamethasone or betamethasone to pregnant women in preterm labour significantly reduces the incidence of RDS and neonatal death ( ). Several other serious complications of prematurity, including germinal matrix/intraventricular haemorrhage (GMH/IVH) and necrotising enterocolitis (NEC), are also reduced ( ; ; ). No long-term adverse effects were demonstrated from a single course of antenatal corticosteroids ( ). In a population-based cohort of 79 395 infants, antental steroid therapy was found to be an independent risk factor for asthma between 36 and 72 months of age (odds ratio 1.23) ( ), but antenatal exposure to a single course of betamethasone did not alter lung function or the prevalence of wheeze and asthma at age 30 ( ). Follow-up of antenatally steroid-treated babies shows no excess of handicap compared with controls ( ; ).

Some of the beneficial effects of corticosteroids are the consequence of reducing the incidence and severity of RDS, whereas others represent the maturing effect of steroids on many body systems. The interaction with the benefits of postnatal exogenous surfactant therapy is of particular importance. The effects of antenatal steroids ( Table 27.5 ) include inducing the enzymes for surfactant synthesis and the genes for the production of the surfactant proteins A, B, C and D ( ), and improving the quality of the surfactant produced ( ). Glucocorticoids, such as dexamethasone, can cause substantial stimulation of SP-B gene expression to two to three times adult levels in fetal lung explants ( ). They mature the non-surfactant-producing tissues of the lung ( ; ); the septa become longer, thinner and less cellular, with larger air spaces and increased numbers of alveolar divisions. In addition, antenatal steroids increase antioxidant enzyme activity and reduce oxidative stress ( ); the maximum effect was seen with steroids administered 2–4 days before delivery and females benefited more.

Thyroid preparations

Thyroid hormones are involved in the induction of surfactant synthesis ( ; ). There are reports of apparent success with intra-amniotic therapy ( ), as thyroid hormones and thyroid-stimulating hormone do not cross the placenta, but most researchers have studied the administration of thyrotrophin-releasing hormone (TRH) to the mother, usually in combination with dexamethasone. There is a consistent synergism between TRH and steroids in animal studies ( ; ). Although the results of early clinical studies were promising, in the ACTOBAT study ( ), the TRH group suffered increased morbidity, as they delivered at significantly earlier gestations. Meta-analysis of the results of 11 trials, which included 4500 women, has demonstrated that prenatal administration of TRH in addition to corticosteroids did not reduce the risk of neonatal respiratory distress or BPD. Indeed, the data showed there were adverse effects: an increase in requirement for ventilation and more likelihood of having a low Apgar score at 5 minutes ( ). Antenatally administered TRH can also produce transient suppression of the pituitary–thyroid axis and transient complications in the mother, including nausea, vomiting and increased blood pressure (BP) ( ).

Other antenatal drugs

Various drugs have been used in animal experiments to mature the surfactant synthetic pathways. These include opiates, aminophylline ( ) and ambroxol ( ). Benefit from ambroxol has been reported ( ), but this is not a consistent finding ( ). Some ( ) but not all ( ) animal experiments suggest that antenatal beta-mimetics may improve neonatal lung function. Their effect in the human neonate appears to be small ( ), although, in a randomised controlled trial ( ), infants whose mothers had received an infusion of terbutaline prior to elective delivery had significantly better lung function.

Prevention of intrapartum asphyxia

Asphyxia worsens RDS and predisposes to pulmonary haemorrhage. If asphyxia is absent and the preterm neonate is presenting by the vertex, there is no need to proceed to caesarean section on a routine basis ( ), but if fetal compromise develops, delivery by caesarean section should be considered even at early gestations.

Prevention of postnatal asphyxia

It is important to prevent postnatal hypoxic damage to lung capillaries and minimise the risk of haemorrhagic pulmonary oedema, by rapidly establishing normal blood gases and normal pulmonary perfusion and ensuring maximum surfactant release from the type II pneumocytes by adequate expansion of the lungs. Inadequate ventilation leads to poor surfactant release, resulting in hypoxia and acidaemia, leading to a vicious cycle ( Fig. 27.13 ). As a consequence, it had been argued that, unless a baby of <30 weeks of gestation is in excellent condition at 30 seconds of age, crying and vigorous, the baby should be actively resuscitated by intubation and intermittent positive-pressure ventilation (IPPV). The studies ( ; ) which demonstrated such an approach, reducing morbidity and mortality from RDS, however, were performed before the modern era of neonatal intensive care and a less aggressive approach using continuous positive airway pressure (CPAP) rather than IPPV is now preferred in many centres ( p. 231 ). Prevention of asphyxia, however, remains important, and appropriate resuscitation may require endotracheal intubation ( ).

Interrelationship of factors affecting surfactant and other components of lung function; solid lines indicate major effects.

(Reproduced from .)

Avoiding drug depression

Many drugs given to the mother in preterm labour – including opiate analgesics and anaesthetic agents – can result in marked hypotonia and respiratory depression in the infant. In general, as well as using the specific opiate antagonist naloxone (except in infants of drug-addicted mothers, in whom naloxone will precipitate drug withdrawal signs), affected babies may require ventilation from birth until the drugs are excreted or metabolised.

Avoidance of maternal fluid overload

Excessive fluid administration to the mother in labour may result in neonatal hyponatraemia ( ).

Prophylactic surfactant

All trials of surfactant therapy have shown a reduction in oxygen requirements and the ventilator pressures required. Problems with the measurement techniques resulted in confusion regarding the effect of surfactant on compliance, as the early improvements may not be detected by dynamic compliance measurements. Surfactant also results in elevation of lung volume ( ), in association with increased oxygenation ( ).

A large number of studies have been carried out assessing the impact of prophylactic surfactant, i.e. administering surfactant within the first few minutes after birth. Many varieties of surfactant have been used ( Table 27.6 ). Meta-analyses of the results have been performed ( ; ; ) demonstrating positive effects of both synthetic and natural surfactants. Prophylactic use of natural surfactant results in a significant reduction in pneumothorax, mortality, and the combined outcome of mortality and BPD, but not BPD alone ( ). In a randomised trial, Lucinactant, a synthetic surfactant containing a functional SP-B mimic that is leucine and lysine repeating units (KL4), was associated with significantly lower incidence of RDS at 24 hours than a non-protein-containing synthetic surfactant and lower RDS-related mortality at 14 days than either the non-protein-containing surfactant or a bovine-derived surfactant ( ). In another study ( ), however, Lucinactant was not more effective and meta-analysis of the results of the two randomised trials does not demonstrate that Lucinactant was associated with significant benefits at 36 weeks’ postmaturational age compared with an animal-derived surfactant ( ).

Meta-analyses of the results of trials comparing administering surfactant prophylactically or selectively, or early versus late, have demonstrated prophylactic/early administration is more effective. Prophylactic versus selective surfactant administration has been associated with a significant reduction in neonatal mortality, BPD/death and pneumothorax ( ) and early versus late administration a reduction in neonatal mortality and pneumothorax ( ). Early surfactant replacement with extubation to nasal CPAP (nCPAP), as compared with later, selective surfactant replacement and continued mechanical ventilation, was associated with an increased utilisation of exogenous surfactant replacement therapy ( ). In a subsequent trial ( ) prophylactic surfactant followed by extubation to nCPAP was not superior to early selective surfactant in terms of requirement for mechanical ventilation in the first 5 days after birth in infants born between 25 and 28 + 6 weeks’ gestation. In a study of 1316 infants ( ), infants randomised to intubation and surfactant treatment within 1 hour of birth compared with those randomised to CPAP in the delivery room had similar outcomes with respect to the primary outcome of death or BPD. Infants who received CPAP, however, less frequently required postnatal stertoids ( p < 0.001), required fewer days of mechanical ventilation ( p = 0.03) and were more likely to be alive and free from the need for mechanical ventilation by day 7 ( p = 0.01). Those results suggest that when nasal CPAP is used in the labour ward administration of surfactant can be delayed until the infant has displayed signs of respiratory distress.

Natural history

The disease is present within the first 4 hours after birth. In the absence of treatment with exogenous surfactant, over the next 24–36 hours the baby tires, dyspnoea worsens and the baby becomes oedematous. As surfactant synthesis commences, the severity of the disease begins to abate from 36–48 hours of age, and this is associated with a spontaneous diuresis ( ).

Respiratory signs

The more mature baby with RDS may breathe at a fast respiratory rate, exceeding 100/min. This faster rate is more efficient in terms of work of breathing. Some babies may alternate a breathing pattern of shallow tachypnoea up to 100–120/min with one in which they breathe comparatively slowly (40–60/min) with marked recession and grunting. The slow-breathing baby often has episodes of apnoea, and this is a sign that respiration is beginning to fail ( ). In addition to tachypnoea, there is marked intercostal and sternal recession, and flaring of the alae nasi. The main respiratory muscle is the diaphragm. In the presence of a compliant ribcage, diaphragmatic contraction results in a marked seesaw pattern, the chest moving inwards and the abdomen moving outwards during inspiration and vice versa on expiration. On auscultation there is a reduction in air entry. An expiratory grunt is a feature of most forms of neonatal respiratory disease and results from the baby trying to sustain FRC ( p. 457 ). In uncomplicated RDS, these clinical features gradually return to normal by 7 days at the latest.

Cardiovascular signs

The heart rate in mild to moderate cases of RDS is 140–160/min and shows normal variability. In infants with severe RDS, the heart rate tends to be slower (120/min) with little beat-to-beat variation. The heart sounds are normal. Murmurs are not normally present; if heard in the first 24–48 hours, they suggest congenital heart disease or ischaemic myocardial injury and require further investigation. A murmur appearing after 3–4 days is usually due to a PDA. Heart failure is not a feature of RDS; if present, it suggests cardiac disease.

Neonates with RDS are often hypotensive and this is associated with a worse prognosis ( ). Hypotension is less common in babies who receive antenatal steroids ( ). There are many causes for the hypotension, including hypoxia and acidaemia depressing the myocardium and reducing cardiac output, a low blood volume and high-pressure ventilation compromising venous return and reducing cardiac output. Hypotension predisposes to acidaemia, which increases pulmonary vascular resistance, GMH/IVH ( Ch. 40.5 ), renal failure ( Ch. 35.1 ) and NEC ( Ch. 29.3 ). It is essential, therefore, to measure the BP and correct symptomatic hypotension.

Central nervous system

The preterm baby even without RDS is hypotonic, inactive and lies in the frog position, spending most of the day asleep. Abnormal neurological signs are often subtle ( Ch. 40.1 ), but if present they are ominous, suggesting development of a GMH/IVH.

Abdominal examination

Examination of the abdomen is usually unremarkable; the liver, spleen and kidneys are often palpable but are rarely significantly enlarged. Hepatosplenomegaly suggests heart failure or sepsis and should be dealt with accordingly, and an easily felt liver in a baby with severe respiratory failure suggests a right tension pneumothorax ( p. 484 ).

Most babies with severe RDS have an ileus ( ), and do not pass meconium. Improvement in their general condition is often heralded by the appearance of bowel sounds and the passage of meconium, although gastric emptying may still be delayed. Jaundice is not uncommon; phototherapy and exchange transfusion are indicated in preterm infants at much lower bilirubin levels than in the full-term neonate ( Ch. 29.1 ).

Haematological

There are no unique haematological findings in RDS. The haemoglobin will vary with the local practice regarding cord clamping ( ). Anaemia may develop later due to GMH/IVH ( Ch. 40.5 ) or iatrogenic losses ( Ch. 30 ). Results of measurements of the coagulation system are often prolonged owing to prematurity in infants with RDS, although disseminated intravascular coagulation (DIC) is rare. The presence of a coagulopathy can be due to complications such as birth asphyxia, septicaemia or a GMH/IVH. Infants who have suffered intrauterine growth retardation are also at increased risk of coagulation abnormalities ( ). The white blood count is normal for the baby’s birthweight and gestation ( ). Thrombocytopenia is not a feature of RDS unless there is DIC ( Ch. 30 ).

Biochemical

The plasma electrolyte pattern is usually normal, although marked early hyponatraemia can be seen if the mother has been fluid-overloaded during labour ( ). The plasma calcium is frequently low (1.5–1.7 mmol/l) in the first 48–72 hours in ill LBW babies. Although infants of very-low-birthweight (VLBW) are prone to hypoglycaemia, when sick they are also susceptible to hyperglycaemia ( Ch. 34.1 ). Infection should be considered in a baby with hyperglycaemia. Babies with RDS may have impaired renal function, with a reduced glomerular filtration rate and renal plasma flow and a correspondingly raised urea and creatinine ( ); they are also poor at excreting hydrogen ions ( ). Fluid restriction has been advocated to improve lung function, but no such effect was seen in a randomised trial ( ).

Serum albumin levels are often below 25–30 g/l in preterm infants ( ) and are lower in the cord blood of babies who develop RDS than in controls ( ). The albumin may remain below 25 g/l for days or even weeks in critically ill babies; this is the result of albumin leaking into the subcutaneous tissues, poor protein intake and impaired albumin synthesis. Administration of albumin, however, does not improve lung function ( ) and may increase the risk of BPD development ( ); hence it should be avoided.

Blood gas measurements

Hypoxaemia occurs and can be used to assess the severity of the lung disease. A mixed metabolic and respiratory acidaemia is found in most cases of RDS, with the P a co ₂ being raised in all but the mildest cases; indeed, the absence of hypercapnia or the presence of a low P a co ₂ should suggest a diagnosis other than RDS in a dyspnoeic neonate ( p. 478 ).

Hormone levels

Cortisol levels of ill 26-week babies are lower than those of healthy preterm babies; they remain low for several days after birth and are further depressed by prenatal therapy with dexamethasone ( ). Levels of thyroid-stimulating hormone, thyroxine and triiodothyronine, although initially normal in cord blood ( ), drop below normal during the first week ( ).

Echocardiography

Echocardiographic studies in neonates with RDS confirm the presence of a PDA in most cases ( Ch. 28 ), but are otherwise normal in the absence of PPHN or severe depression of myocardial function. Doppler echocardiography is used to investigate the degree of pulmonary hypertension ( p. 495 ).

Measurement of surfactant status

This has limited applicability, as apparently typical RDS can develop in the presence of L : S ratios greater than 2.0, even when PG is present ( ), and surfactant-deficient RDS and congenital pneumonia due, in particular, to GBS can coexist. In addition, although assessment of surfactant proteins can be used to determine pulmonary maturity, the tests are expensive and time-consuming. There may, however, be a role for rapid early assessments of neonatal surfactant levels ( ; ) if supplies of surfactant are limited.

Chest X-ray

The CXR appearance contributes to the establishment of the diagnosis. In addition, thymic ( Fig. 27.14 ), cardiac and skeletal abnormalities can be identified and the positions of the ETT and indwelling cannulae checked. Classically, in RDS the CXR shows diffuse, fine granular opacification in both lung fields with an air bronchogram where the air-filled bronchi stand out against the atelectatic lungs. In reality, the appearance can be very variable, from a slight granularity to lungs that are so opaque that it is impossible to distinguish between the lung field and the cardiac silhouette. A ‘whiteout’ on an X-ray taken at 1 hour of age, however, may be due to retained fetal lung fluid. By 4 hours of age, as a result of clearance of the fluid, the CXR appearance may show marked improvement. The CXR appearance also depends on the phase of the respiratory cycle, the appearance being much worse on an expiratory rather than an inspiratory one. Positive-pressure support with both CPAP and IPPV can improve the CXR appearance in a baby who had marked X-ray changes while breathing spontaneously; surfactant treatment has the same effect ( ).

Severe respiratory distress syndrome. The lungs are totally opaque and cannot be separated from the heart border because of widespread atelectasis. An air bronchogram can be seen in the right lung.

Initial care

General management of the baby with RDS

Airleaks, pneumothorax, pulmonary interstitial emphysema ( p. 490 )

In the past, some form of airleak was reported in about 5% of babies with RDS who were breathing spontaneously; the incidence doubled with CPAP and rose to as high as 35–40% in babies treated with IPPV plus positive end-expiratory pressure (PEEP) and inspiratory times exceeding 1 second. Nowadays, with the use of synchronised IPPV ( p. 517 ) and surfactant ( p. 459 ), the overall incidence of airleaks is less than 10% in ventilated infants.

Patent ductus arteriosus

The incidence of symptomatic PDA is increased by fluid overload ( ). A clinically significant ductus in a ventilated preterm baby presents as signs of heart failure and a loud precordial murmur filling systole, frequently extending into diastole. The oxygen and ventilatory requirements increase and affected babies may develop massive pulmonary haemorrhange ( p. 509 ). Management is outlined on pages 511–512 .

Germinal matrix/intraventricular haemorrhage (see Ch. 41 , part 5 )

The development of a large GMH/IVH is usually associated with clinical deterioration characterised by anaemia, increased ventilatory requirements and abnormal neurological signs, which can be subtle ( Ch. 40.1 ). In many cases, smaller GMH/IVHs are asymptomatic and detected only on routine ultrasound. Many aspects of the management of respiratory failure in the neonate are directed towards preventing GMH/IVHs, for example avoiding procedures which might provoke surges in cerebral blood flow, including the avoidance of hypercarbia and wide swings in P a co ₂ and correcting coagulation disturbances.

Bronchopulmonary dysplasia

This is a most important complication of RDS in terms of morbidity, duration of therapy and associated costs. It is described in detail in Chapter 27, part 3 .

Renal failure

One of the purposes of attempting early correction and maintenance of BP, using dopamine to preserve renal perfusion and paying meticulous attention to the fluid balance in babies with RDS, is to sustain renal function. In some cases this is not successful, and in others an acute episode of collapse, such as may occur with bilateral tension pneumothoraces, results in acute tubular necrosis ( Ch. 35.1 ). If renal failure develops, it should be treated as outlined in Chapter 35, part 1 . If biochemical control cannot be achieved, then either peritoneal dialysis or haemofiltration may be used. Haemofiltration avoids the major problem with peritoneal dialysis, which is that the intraperitoneal fluid splints the diaphragm and makes oxygenation difficult in ventilated neonates.

Survival

Death from RDS in a baby weighing more than 1.5 kg is now exceptionally rare and the overall mortality from the condition has been reduced to between 5% and 10%.

Sequelae

Readmission to a general paediatric ward in the first 2 years after birth is common, but after that age readmissions are infrequent ( ). Amongst VLBW infants, infants with birthweight <750 g and gestational age of less than 28 weeks require the greatest number of admissions and longest duration of stay. In the first year, the duration of stay is inversely related to birthweight ( ). Readmissions are particularly likely in infants who developed BPD and subsequently suffered a respiratory syncytial virus infection ( ). Other causes of readmission include sequelae of surgery for NEC, failure to thrive and repair of an inguinal hernia, which is common in males with a birthweight of less than 1.00 kg.

Incidence

An early study ( ), which involved X-raying the chest of all newborns, demonstrated that 1% had airleaks, although only 10% of those with airleaks were symptomatic. The incidence was reported to be higher if there was associated lung disease or the neonate was receiving assisted ventilation; 4% of infants with lung disease developed airleaks, compared with 16% in infants receiving CPAP and 34% in those requiring mechanical ventilation ( ). In the last two decades, the incidence of pneumothorax has decreased in response to the use of surfactant therapy ( p. 459 ), pancuronium ( p. 488 ) and fast ventilator rates ( p. 519 ), with most units reporting airleak rates of less than 10% in ventilated babies.

Aetiology

Spontaneous pneumothoraces may occur immediately after birth owing to the high transpulmonary pressure swings generated by the newborn during his or her first breaths ( ) or because of active resuscitation. Familial spontaneous pneumothoraces occurring in neonates are very rare ( ). Pneumothoraces in one series ( ) were commoner following elective than emergency caesarean section or vaginal births. There was a significant progressive reduction in the incidence of pneumothorax when the elective caesarean sections were perfomed from 37 weeks onwards ( ). Pneumothorax is usually a complication of respiratory disease, for example RDS or meconium aspiration syndrome (MAS) or congenital malformations, in which there is uneven ventilation, alveolar overdistension and air trapping, made worse in many cases by IPPV. Pneumothorax may occasionally result from direct injury to the lung, for example direct perforation by suction catheters or introducers passed through the ETT ( ; ) or by central venous catheter placement ( ). Malposition of the ETT is associated with an increased risk of pneumothorax ( ).

Components of ventilatory support have been incriminated in increasing the incidence of airleak. These include high levels of PEEP ( ), but the data were not from a randomised study. A prolonged inflation time was also noted to be a risk factor ( ), perhaps because of provocation of active expiration against the ventilator ( ). The higher (50% versus 16%) incidence of airleak with an inspiratory : expiratory (I : E) ratio of >1.0 : 1 compared with an I : E ratio of <0.7 : 1 ( ) might also be explained by a similar mechanism. Both high peak inspiratory ( ; ) and mean airway pressures (MAPs) increased the incidence of airleaks ( ). Airleaks occur in babies who have started to exhale while the ventilator is still trying to inflate their lungs (active expiratory reflex) ( ).

Clinical features

Small pneumothoraces may be asymptomatic, but, when a large pneumothorax develops, all of the clinical features of respiratory distress may be present. In addition, with very large or tension pneumothoraces, the infant’s overall condition usually deteriorates, often dramatically, with pallor, shock and deterioration in oxygenation. An increased resonance on percussion may be detected and there is a decrease in air entry on the affected side. A tension pneumothorax will result in a shift of the mediastinum and the position of the cardiac impulse; there is also abdominal distension due to displacement of the diaphragm and, with a right-sided pneumothorax, downward displacement of the liver. At the time of a pneumothorax, there is a marked increase in cerebral blood flow velocity, which correlates closely with the systemic haemodynamic changes ( ). Pneumothorax is associated with haemorrhage into the germinal layer and ventricles of preterm infants. Increased levels of arginine vasopressin may also occur, resulting in fluid retention ( Ch. 35.1 ).

Diagnosis

Continuous monitoring of the heart rate, BP and P a co ₂ will give warning of the baby’s deterioration. Transillumination with an intense beam from a fibreoptic light is of considerable help in the preterm baby with a thin chest wall: abnormal air collections cause increased transmission of light on the involved side; however, PIE can give a similar appearance. The CXR remains the gold standard for diagnosing pneumothorax and should be done unless the infant’s clinical condition makes emergency drainage mandatory. The diagnosis of a pneumothorax on the CXR is usually obvious, but rarely the appearance of either lobar emphysema or cystic adenomatoid malformation of the lung may resemble a pneumothorax ( ). A small pneumothorax may only be recognised by a difference in radiolucency between the two lung fields ( Fig. 27.16 ). A large pneumothorax will be associated with absent lung markings and a collapsed lung on the ipsilateral side ( Fig. 27.17 ). A tension pneumothorax will be demonstrated by eversion of the diaphragm, bulging intercostal spaces and mediastinal shift ( Fig. 27.18 ).

Bilateral pneumothoraces. Note bulging at the intercostals’ margins. The difference in the translucency of the two sides indicates that there is more free air on the left.

Large left-sided tension pneumothorax. Note that the non-compliant lung has only partially collapsed.

Large right-sided tension pneumothorax with bulging over the midline and compression of the left lung.

Ill, ventilated infants are usually nursed in the supine position and intrapleural air rises to lie retrosternally. Retrosternal air is best demonstrated by a horizontal-beam, lateral-view CXR ( Fig. 27.19 ), which is also useful in demonstrating the position of the chest drain tip (see below; Fig. 27.20 ).

Lateral chest X-ray with anterior collection of air. Only one chest drain is positioned to lie anteriorly; the other tip lies posteriorly and the pneumothorax has been inadequately drained.

Lateral chest X-ray demonstrating a correctly anteriorly placed tip of a chest drain.

Prevention

The risk of pneumothorax can be reduced by administering surfactant ( p. 459 ), by using the minimum ventilator pressure required ( p. 517 ) and by abolishing the baby’s active expiratory efforts.

Treatment

Asymptomatic pneumothoraces need no treatment, other than careful observation of the infant. In term infants with mild symptoms, a pneumothorax may respond to increasing the inspired oxygen concentration to 100%, which will favour resorption of the extra-alveolar gas; but this strategy should not be used in prematurely born infants at risk of ROP. Expectant management can be successful in infants who have relatively mild disease, i.e. on lower ventilatory settings and better blood gases ( ). However, there is always a risk of the pneumothorax becoming a tension pneumothorax and there should be a low threshold for inserting a chest drain in a ventilated baby.

A pneumothorax must always be drained using a chest drain in symptomatic infants and those with tension pneumothoraces. If the infant is in extremis and there is no time for formal insertion of a chest drain, emergency drainage of a pneumothorax can be done by needle aspiration. A butterfly needle (18 G) should be used. This is then attached to a three-way tap, which is held under water in a small sterile container. The needle is inserted through the skin in the second intercostal space anteriorly, and then the skin and needle are moved sideways before advancing the needle through the underlying muscle; this reduces the likelihood of leaving an open needle track for entry of air once the needle has been removed. Care must be taken not to remove too much air by needle aspiration, as the needle might then tear the expanding lung. Following emergency drainage, a chest tube should be inserted ( Ch. 44 ).

Insertion of a chest tube (10–14 FG) should be performed under local anaesthesia through either the second intercostal space just lateral to the midclavicular line or the sixth space in the midaxillary line (see Ch. 44 ). The tip of the chest tube should lie retrosternally to achieve the most effective drainage. A retrospective review of 149 cases of chest drain placement ( ) revealed that inserting the chest drain through the anterior chest wall achieved retrosternal positioning in 85% of occasions compared with only 47% inserted through the lateral chest wall. The lateral site, however, is preferred for cosmetic reasons, as any resultant scar is less obvious. Retrosternal placement of the chest tube tip should be confirmed by CXR ( Chs. 43 , 44 ); a second drain is only infrequently required to ensure complete drainage if the first drain has been appropriately sited.

Complications of malpositioned chest tubes include traumatisation of the thoracic duct resulting in a chylothorax, cardiac tamponade due to a haemorrhagic pericardial effusion and phrenic nerve injury; the latter complication is more likely if the drainage tube is positioned deep in the chest ( ). Once inserted, the tube should be connected to an underwater seal drain with suction applied at a level of 5–10 cmH ₂ O. Heimlich valves are useful during transport, but can become blocked and so fail to operate if left in situ for any length of time. Once a chest drain has been inserted, it should be left in situ for at least a further 24 hours after it has ceased bubbling. The chest tube should then be clamped for a further few hours and only removed if no pleural air accumulates. Pneumothoraces persisting for an average of 10 days may respond to fibrin glue, but this treatment has been reported to have significant risks ( ).

After drainage of an uncomplicated pneumothorax, a baby not on IPPV usually improves rapidly. In a ventilated, very prematurely born baby, a pneumothorax often precipitates a serious deterioration in condition, with the development of a large intracerebral bleed.

Prognosis

The mortality, although not the incidence, varies with birthweight and is in general double that of babies who have RDS but no airleak. If a parenchymal haemorrhage occurs in association with a pneumothorax ( Ch. 40.5 ), this has a detrimental effect on neurological outcome.

Aetiology

PIE is gas trapped within the perivascular sheaths of the lung. In the surfactant-deficient lung of the preterm infant ( ), rupture of the small airways occurs distal to the termination of their fascial sheath, and air dissects into the interstitium. PIE occurs mainly in neonates with RDS ( ), but has been less frequently reported in infants with aspiration syndromes or sepsis. PIE is associated with positive-pressure ventilation, high peak inspiratory pressures and malpositioned ETTs ( ; ). It has rarely been described in spontaneously breathing infants ( ). PIE may be lobar in distribution, but more commonly involves both lungs. It frequently occurs with either a pneumothorax or pneumomediastinum.

Incidence

There is an inverse relationship between the incidence of PIE and birthweight ( ).

Pathophysiology

In infants with PIE, the trapped gas reduces pulmonary perfusion by compressing the vessels and interferes with ventilation. As a result, there is profound hypoxaemia combined with carbon dioxide retention.

Presentation

PIE is found on the CXR of a severely ill neonate carried out either on a routine basis or because the baby’s condition was deteriorating.

Diagnosis

Transillumination of the chest with diffuse PIE will give the same appearance as a large pneumothorax. The CXR, however, is diagnostic, demonstrating hyperinflation and a characteristic cystic appearance, which may be diffuse, multiple, small, non-confluent, cystic radiolucencies ( Figs 27.21 and 27.22 ), which may be unilateral ( Fig. 27.23 ); at a later stage, large bullae may appear ( Fig. 27.24 ). The appearance may be confused with lobar emphysema or with cystic adenomatoid malformation of the lung.

Bilateral pulmonary interstitial emphysema.

Gross pulmonary interstitial emphysema (PIE) of the right lung with overdistension and downward displacement of the diaphragm and moderately severe PIE of the left lung.

Severe pulmonary interstitial emphysema of the right lung with mediastinal shift and compression of the left lung.

Pulmonary interstitial emphysema of the right lung with gross cystic changes in the right middle lobe compressing the right lower lobe and left lung.

Treatment

Affected babies usually have severe RDS and/or sepsis; their ventilator management is particularly difficult. For both generalised and localised disease, ventilator pressures should be kept at the minimum compatible with acceptable gases ( P a o ₂ <6–7 kPa (45–52 mmHg), pH >7.25); the baby should be paralysed to minimise the risk of extension of the airleaks. Withdrawal of PEEP may result in disappearance of the PIE ( ).

Generalised PIE may respond to increasing the ventilator rate to 100–120/min ( ), in that the number of babies who progress to pneumothorax may be reduced, but there were no other advantages. Indeed, in one series ( ), the severity of the PIE increased, possibly because of the absence of a pneumothorax decompressing the interstitial emphysema. Transfer from conventional ventilators to high-frequency jet ventilation (HFJV) ( ; ), high-frequency flow interruption ( ) or oscillation ( ) has improved oxygenation in some infants with severe respiratory failure due to PIE, but a randomised controlled trial failed to show that HFO had benefit in PIE ( ). HFJV has been reported in a randomised trial to be more successful support than rapid-rate conventional ventilation ( ); survival and the incidence of BPD, GMH/IVH, PDA, airway obstruction and airleak, however, were similar in the two groups.

The conservative ventilatory management outlined above for generalised PIE should also be tried for localised disease and is often successful. In addition, in localised PIE, placing the infant with the hyperinflated lung dependent in the lateral decubitus position at all times can result in partial or complete atelectasis of the desired segments ( ; ). In this position, the upper ‘good’ lung receives a greater proportion of the ventilation ( ); the affected dependent lung is underventilated and hence decompresses. Selective bronchial intubation may also be useful. As soon as the affected lung is bypassed, it becomes atelectactic ( Fig. 27.25 ). If selective intubation is maintained for 24–48 hours, when the affected lung is reventilated the PIE does not usually recur ( ; ; ). This technique is more useful if the left lung is affected, as selective intubation of the right main bronchus is easier to perform. It may be necessary to support the infant on high-frequency oscillatory ventilation (HFOV) to maintain adequate blood gases during selective intubation ( ). The collections may persist and compress the adjacent normal lung parenchyma, causing a sudden deterioration in the infant’s condition. Resection of the affected area may be required to alleviate the respiratory distress.

Endotracheal tube inserted into the right main bronchus with resultant collapse of the left lung and right upper lobe.

Prognosis

The incidence of BPD is greatly increased following diffuse PIE ( p. 490 ) ( ; ) and radiologically the changes of PIE may merge imperceptibly into those of BPD. The mortality from diffuse PIE is high, but studies reporting outcome generally predate routine use of antenatal steroids and postnatal surfactant ( ; ; ).

Presentation

An isolated pneumomediastinum may be asymptomatic or the infant may have mild respiratory distress; it only rarely causes severe symptoms. The sternum may appear bowed and the heart sounds muffled. Mediastinal shift rarely occurs. Air may track up into the soft tissues of the neck, but this is uncommon. Pneumomediastinum often coexists with multiple airleaks, including PIE and pneumothorax, in severely ill, ventilated babies ( Fig. 27.26 ).

Left-sided pneumomediastinum (between the arrows and the heart border).

Diagnosis

This is made on the CXR ( Fig. 27.26 ), as a halo of air adjacent to the borders of the heart, and on lateral view it produces marked retrosternal hyperlucency. The mediastinal gas may elevate the thymus away from the pericardium, resulting in a cresentic configuration resembling a spinnaker sail ( ).

Treatment

An isolated pneumomediastinum is often asymptomatic and in general requires no treatment. It is very difficult to drain a pneumomediastinum, as the gas is collected in multiple independent lobules. Relatively successful attempts have been made, however, with multiple needling and tube drainage ( ). In term infants, use of a high inspired oxygen concentration will be associated with resorption of the extra-alveolar air, but this should not be attempted in preterm infants at risk from ROP.

Aetiology

Pneumopericardium rarely occurs spontaneously ( ) or in babies supported by CPAP ( ). The majority of cases occur in ventilated, prematurely born babies. Its frequent association with PIE and pneumomediastinum suggests that the gas enters the pericardium through a defect in the pericardial sac, probably at the pericardial reflection near the ostia of the pulmonary veins.

Diagnosis

The CXR demonstrates gas completely surrounding the heart ( Fig. 27.27 ), outlining the base of the great vessels and contained within the pericardium. Gas can be seen inferior to the diaphragmatic surface of the heart, differentiating this abnormality from a pneumomediastinum in which the mediastinal gas is limited inferiorly by the attachment of the mediastinal pleura to the central tendon of the diaphragm. In a haemodynamically significant pneumopericardium, the transverse diameter of the heart is significantly reduced.

Treatment

A conservative approach can be adopted for small asymptomatic lesions. All symptomatic pneumopericardia should be drained immediately by direct pericardial tap via the subxiphoid route. The BP should be monitored continuously, and the tap repeated if bradycardia or hypotension recurs. Catheter drainage may be necessary if the pericardial air reaccumulates.

Prognosis

The mortality rate for symptomatic pneumopericardium is between 80% and 90% ( ) and many survivors have neurological sequelae.

Diagnosis

If the pneumoperitoneum is large, the diagnosis can be made from the anteroposterior X-ray ( Fig. 27.29 ). For smaller leaks, a horizontal-beam lateral or right lateral X-ray is required ( Fig. 27.30 ). Rupture of the bowel, usually due to NEC, can generally be excluded by the absence of a history of gastrointestinal disease, in particular bloody stools or intestinal obstruction, and a normal gut gas pattern on erect abdominal X-ray. If there is still doubt, differentiating a pneumoperitoneum caused by transdiaphragmatic air dissection from one due to perforated bowel can be made by measuring the P o ₂ of aspirated intraperitoneal gas ( ). In ventilator-induced pneumoperitoneum, the intraperitoneal P o ₂ is very high, reflecting the P Ao ₂ , whereas the P o ₂ of a surgical pneumoperitoneum is similar to that of room air or lower.

Pneumoperitoneum due to gastrointestinal perforation. (A) Anteroposterior view shows the classic ‘football’ sign. (B) The lateral X-ray of the same infant shows a large collection of free air above the liver.

Pneumoperitoneum indicated on the anteroposterior view by a small amount of non-anatomical air to the right of the vertebral column.

Treatment

If the abdomen is not under sufficient tension to cause respiratory embarassment, then no treatment is necessary. If there is tension, the peritoneum should be drained either by needle aspiration or by inserting a drainage tube.

Pathogenesis

Gas embolism results from alveolar–capillary or bronchovenous fistulae, which have been demonstrated by barium studies at autopsy. Such communications are more likely to occur in airleak syndromes, but may also follow trauma to the lung. Laceration of lung tissue favours reversal of the intrabronchial pressure–pulmonary venous pressure gradient, thereby increasing the risk of pulmonary vascular air embolism.

Diagnosis

On the CXR, gas can be seen in the systemic and pulmonary arteries and veins ( Fig. 27.31 ). Gas can be withdrawn from the umbilical venous or arterial catheters, and this has been observed in over half the reported cases.

Postmortem X-ray of a baby who died from systemic air embolism. Gas can be seen (black arrows) within the heart and in the great vessels in the neck (white arrows).

Treatment

Early withdrawal of air from the UAC may be of benefit, particularly if the leak is small or has been introduced through an intravascular line.

Prognosis

This condition is usually fatal ( ).

Abnormal pulmonary vasculature

Infants with PPHN have abnormal pulmonary vascular reactivity, structure and/or growth. In postmortem studies on babies with PPHN, virtually all secondary to meconium inhalation, the muscularity of the pulmonary arteries is markedly increased ( ). Not only is the amount of muscle in the vessel wall increased, but also the muscle extends into vessels surrounding the alveoli, whereas in the normal baby muscular pulmonary arteries rarely extend past the terminal bronchiole. The exact intrauterine events that increase pulmonary vascular reactivity and impair structure are poorly understood. Impaired vascular epidermal growth factor (VEGF) signalling, however, can cause fetal pulmonary hypertension with structural remodelling, right ventricular hypertrophy and impaired pulmonary vasodilation in experimental models ( ). Chronic intrauterine pulmonary hypertension can markedly decrease lung VEGF expression; selective inhibition of VEGF mimics the structural and physiological changes of experimental PPHN ( ). Babies with PPHN have lower blood VEGF levels than controls ( ). Postnatally, sustained pulmonary hypertension rapidly accelerates pulmonary vascular injury, with aggressive smooth-muscle proliferation and remodelling. Initially the effects of hypertension are at least partially offset by release of endogenous vasodilators, but this may not be sustained ( ).

Vasoactive agents

NO is a potent pulmonary vasodilator, active in the transition of the circulation at birth ( p. 450 ). A significant rise in pulmonary blood flow at birth is related to the acute release of NO; vasodilation occurs through cGMP kinase-mediated stimulation of K ⁺ channels ( ). Other vasodilator products, including prostaglandin (PG) I ₂ , also modulate changes in pulmonary vascular tone at birth. NO modulates PGI ₂ activity in the perinatal lung ( ). Adenosine release may also contribute to the fall in pulmonary vascular resistance; this may be through enhanced production of NO ( ).

Endothelin-1 is a potent pulmonary vasoconstrictor; the plasma level is raised in neonates with hypoxia ( ) and severe PPHN ( ; ). Increased circulating levels of endothelin-1 mediate in part GBS-induced pulmonary hypertension ( ). Raised levels of the constrictor leukotrienes LTC4 and LTD4 have been found in the blood of some, but not all, neonates with PPHN when compared with ventilated neonates without this complication; the levels fall with successful therapy ( ; ; ; ). In the PPHN accompanying sepsis due to GBS or other organisms ( ; ; ), including viruses ( ), there is initial severe arterial spasm followed by increased vascular permeability and an increased lung fluid content and lymph flow ( ; ; ). In these babies it is thought that thromboxane A ₂ ( ; ; ) is responsible and that it has its effect without affecting the morphometry of the pulmonary vasculature ( ). In animal models, PPHN, but not the haematological features of GBS sepsis, can be prevented by treatment with drugs which inhibit thromboxane A ₂ synthesis, such as indometacin ( ), and reversed by intravenous infusion of the vasodilator prostaglandin PGE ₂ or isoprenaline ( ; ). The increased capillary permeability in sepsis-induced PPHN appears to be due to the action of bacterial endotoxins sequestering white cells in the lungs ( ; ), where they release vasoactive agents such as tumour necrosis factor. There is an additional effect of thromboxane A ₂ since, as with the short-term effects on the pulmonary vasculature, long-term effects can be mitigated by the use of indometacin.

Vascular hypoplasia

The PPHN of diaphragmatic hernia and other conditions associated with pulmonary hypoplasia is due to a reduction in the number of intralobar arteries and their increased muscularity ( ).

Blood gas changes/asphyxia

A fall in pH causes pulmonary vasoconstriction in experimental animals ( ; ), and hypoxia is a potent vasoconstrictor ( ). Neonatal pulmonary vasculature is extremely sensitive to changes in pH, P a o ₂ and P a co ₂ ( ). Therefore, perinatal and postnatal hypoxaemia and metabolic or respiratory acidaemia can cause marked pulmonary arterial spasm, pulmonary hypertension, a large right-to-left shunt and PPHN, particularly in babies with prenatal pulmonary arterial muscular hypertrophy.

Polycythaemia

A rise in haematocrit in experimental animals causes pulmonary hypertension. The factors involved, however, are not clear, since a rise in pulmonary vascular resistance is not seen if fetal blood as opposed to adult blood is used to raise the haematocrit ( ) and polycythaemia is not a consistent feature of neonates with PPHN ( ).

Heredity

Familial cases have been reported.

Haematological and biochemical

Thrombocytopenia has been reported in severe cases ( ); it may be a manifestation of abnormal prostaglandin activation.

Blood gases

In both primary and secondary PPHN, maximal P a o ₂ values of 6 kPa (45 mmHg) are characteristic, often with a difference of at least 1–2 kPa (7.5–15 mmHg) between preductal and postductal P a o ₂ ( Ch. 19 ). At diagnosis there may be a metabolic acidaemia, but respiratory acidaemia, by definition, is unusual. Metabolic acidaemia can be controlled by an initial infusion of base, followed by BP support and maintaining the haematocrit above 40%. A resistant acidosis is a feature of either the terminal stages of PPHN or some other underlying problem – in particular, overwhelming sepsis.

Chest X-ray

In secondary PPHN, the X-ray will be that of the underlying lung disease, although, by definition, the appearance will be less severe than anticipated for the severity of the hypoxaemia. In primary PPHN, the CXR changes are often minimal ( Fig. 27.33 ); there may be a mild non-specific increase in lung markings, but little else is noted.

Chest X-ray of an infant with primary persistent pulmonary hypertension of the newborn with absence of lung field markings.

Electrocardiogram

Various ECG changes have been reported in neonates with PPHN. The ECG may be normal, or more typically shows changes of right axis deviation, right atrial enlargement and right ventricular hypertrophy and overload ( ). In babies who develop PPHN following severe asphyxia, the ECG may show the changes of subendocardial ischaemia ( Appendix 3 ).

Echocardiography

Echocardiography is an essential investigation in suspected PPHN, and if the skill is not available a cyanosed baby requires transfer to a centre where this can be done. Firstly, and most importantly, it will exclude the various forms of cyanotic congenital heart disease by showing a normal cardiac anatomy. Secondly, pulmonary hypertension, right-to-left shunting at the ductal and foramen ovale level and ventricular function can be assessed ( ).

Bacteriology

PPHN can be secondary to sepsis; thus it is important that the infant is screened for infection ( Ch. 39.2 ).

Minimal handling

It is important to adhere to the ‘minimal handling’ maxim. Slight disturbance, for example turning the baby or taking the baby’s temperature, may precipitate severe hypoxaemia, and interventions such as ETT suctioning or physiotherapy can have devastating effects. Monitoring must therefore be continuous and interference with the baby reduced to an absolute minimum. ETT suctioning should be carried out only when essential to maintain ETT patency; chest physiotherapy is contraindicated.

Blood pressure and blood volume

The size of the right-to-left shunt is in part dependent on the systemic BP (see above); thus, in babies born at term, the systemic BP should be maintained at a mean of at least 40 mmHg, with a systolic of 50 mmHg. Aggressive therapy should be used to achieve an appropriate systemic BP, including volume challenges and, particularly, administration of inotropes. The haemoglobin level should be kept greater than 13 g/dl (PCV 40%) in order to maximise oxygen transport to the tissues. If polycythaemia (central PCV <70–75%) is present, the existence of PPHN is one of the situations in which a dilutional exchange transfusion is justified.

Coagulation disorders

If present, these should be corrected by appropriate factor replacement.

Fluid and electrolyte balance

Electrolyte abnormalities and hypoglycaemia must be corrected and pH and base deficit kept within normal limits by use of THAM or bicarbonate as appropriate. Urine output must be carefully monitored.

Antibiotics

Broad-spectrum antibiotic cover should be given to all babies with PPHN.

Respiratory support

Once a baby’s P a o ₂ falls below 5–6 kPa (37–45 mmHg) in 70% oxygen, the baby should be ventilated. Sufficient peak pressure should be used to achieve a P a co ₂ of not greater than 4.8–5.5 kPa (35–40 mmHg) and a pH <7.30. The inspired oxygen concentration should be increased as necessary to achieve a P a o ₂ of at least 8–9 kPa (56–63 mmHg). For the full-term baby prone to fight the ventilator, neuromuscular blocking agents should be used; in this situation there are theoretical reasons for preferring d -tubocurarine to pancuronium ( ).

PPHN unresponsive to conservative treatment

Meconium inhalation

To develop MAS, an infant must pass meconium, inhale it and the inhaled material must damage the lungs. All these factors are inextricably interlinked with the presence of fetal asphyxia.

Passage of meconium

An overall prevalence of 8–22% for the presence of meconium in liquor is quoted ( ; ; ). Meconium aspiration is a disease of term or postterm babies ( Ch. 12 ). Meconium staining of the liquor occurs in 5% or less of preterm pregnancies ( ), when it suggests chorioamnionitis, but the prevalence increases to 10% or more after 38 weeks, reaching 22% in patients at a gestational age of 42 weeks, and 44% in babies who deliver 1–2 weeks later.

The fetal passage of meconium may be due to a vagal reflex, but more convincing are the data showing that motilin, which is produced mainly by the jejunum and stimulates peristalsis, is very low in preterm infants and non-asphyxiated term infants, but is raised in asphyxiated term babies who pass meconium intrapartum ( ).

Inhalation of meconium

Meconium inhalation can occur before the onset of labour, as meconium has been found in the lungs of stillborn babies ( ) and in babies who die in the early neonatal period, who could not have inhaled meconium intrapartum ( ; ; ). Prolonged severe fetal hypoxia can stimulate fetal breathing, to the extent that amniotic fluid is inhaled ( ), and fetal gasping movements also draw intra-amniotic material into the alveoli ( ; ). Perinatally, meconium inhalation can occur if the baby breathes or gasps with the mouth, pharynx or larynx full of meconium-stained liquor. This may occur late in the second stage of labour, particularly if there is a severe mixed acidaemia with a fetal pH <7.0 ( ), when the raised P a co ₂ may have provoked intrapartum gasping. Postnatally, any meconium in the upper airway potentially can cause MAS. If meconium is inhaled, development of severe MAS depends in part on whether there is coexisting asphyxia ( ; ).

Effect of meconium on the lungs

Meconium is a sticky material composed of inspissated fetal intestinal secretions. When inhaled, it probably has at least four interacting deleterious effects on a neonatal lung ( Fig. 27.34 ):

• 1
  

  It creates a ball valve mechanism in the airways whereby air can be sucked in past the plug but cannot be exhaled. This increases airways resistance, mainly in expiration, causing gas trapping, lung overdistension and pneumothorax.

  
  
• 2
  

  It acts as a chemical irritant. Inflammatory cells and mediators are released, which affect vessel contractility, lead to capillary leakage and injure the lung parenchyma. The cytokines cause airway and alveolar epithelial necrosis ( ). Cell injury and apoptosis may also result from the high concentrations of phospholipase A ₂ found in meconium ( ). Thus, 24–48 hours after inhalation there is an exudative and inflammatory pneumonitis with alveolar collapse and cellular necrosis.

  
  
• 3
  

  The organic nature of inhaled material, although initially sterile, may predispose the baby to pulmonary infection, particularly with Escherichia coli . Meconium may inhibit phagocytosis and the neutrophil oxidative burst ( ), hence bacteria can grow in meconium-stained amniotic fluid. Meconium staining of the liquor may be a marker of chorioamnionitis, predisposing the baby to congenital pneumonia ( ; ) and meconium inhibits polymorph function ( ).

  
  
• 4
  

  Meconium inhibits surfactant function and production ( ; ; ); the inhibition is in a concentration-dependent manner ( ). The water/methanol-soluble phase (bilirubin and proteins) and, particularly, the chloroform-soluble phase (free fatty acids, triglycerides and cholesterol) of meconium inhibit surfactant ( ). In addition, phospholipase A ₂ degrades surfactant ( ) and lysophosphatidylcholine can inhibit surfactant secretion ( ). Meconium alters the morphological ultrastructure of surfactant and hence decreases its surface tension-lowering ability ( ). Infants with severe MAS, i.e. requiring ECMO, have been shown to have lower levels of phosphatidylcholine ( ).

Aetiology of meconium aspiration syndrome (MAS) and its associated clinical syndromes. PPHN, persistent pulmonary hypertension of the newborn.

These four factors combine to cause the severe airway and alveolar disease which is more likely to occur if there is coexisting asphyxial lung damage ( ; ; ).

Antenatal

Attempts to prevent MAS have largely proved unsuccessful. In a large randomised trial ( ) which included 1998 pregnant women in labour at 36 weeks or more of gestation who had thick meconium staining of the amniotic fluid, those randomised to amnioinfusion did not have a reduced risk of moderate or severe MAS, perinatal death or other major maternal or neonatal disorders. Suppression of fetal breathing movements by maternal narcotic administration, although successful in a baboon model ( ), did not reduce the incidence of MAS in two clinical series ( ; ).

Intrapartum/postpartum

Respiratory

The baby has tachypnoea, which may exceed 120/min. Intercostal and subcostal recession occurs and there is use of accessory muscles and flaring of the nostrils. An expiratory grunt may be heard. The meconium in the airways causes widespread sticky crepitations and occasional rhonchi, air trapping and an overdistended chest with an increased anteroposterior diameter. The baby may remain symptomatic for only 24 hours or be very dyspnoeic for 7–10 days before recovery. In patients who required ventilation, the respiratory disease has usually abated to a resting tachypnoea of 50–70/min in room air by 14 days of age.

Cardiovascular

In the absence of asphyxial damage to the myocardium, there are no specific cardiovascular features of MAS. Hypotension suggests myocardial damage, as do signs of congestive heart failure. In uncomplicated MAS, the heart rate tends to be around 110–125/min, and the BP is maintained within the normal range. If PPHN ( pp. 495–504 ) develops, S2 may remain single, and there may be the murmur of tricuspid incompetence ( Ch. 28 ).

Abdominal examination

The liver and spleen are often palpable because of downward displacement of the diaphragm caused by air trapping. In a severely affected infant, bowel sounds may be absent, with delayed passage of meconium. There may be urinary retention and bladder distension in babies with severe neurological problems or those who receive pancuronium.

Central nervous system

Depending on the severity of the coexisting neurological insult, the baby may behave normally or show features of HIE ( Ch. 40.4 ).

Haematological

The nucleated red blood cell ( ) and the white cell ( ; ) counts are often raised. White cell function is reduced ( ). Thrombocytopenia often occurs in neonates with meconium aspiration who have PPHN ( ), are ventilated ( ) or develop DIC secondary to severe asphyxia ( Ch. 30 ).

Biochemical

If coexisting asphyxia is severe, there may be inappropriate ADH production and hyponatraemia ( Ch. 35.2 ). Renal failure secondary to acute tubular necrosis may cause hyperkalaemia and a raised urea. Hypocalcaemia may also occur, as in any critically ill neonate ( Ch. 34.2 ).

Blood gases

Hypoxia is common, but in mature infants with mild to moderate disease and an efficient respiratory pump, ventilation is not a problem and the P a co ₂ may even be low, normal or only slightly raised. A P a co ₂ >8 kPa (60 mmHg) is unusual and is seen only in patients with severe lung disease who eventually need ventilation.

Changes in pH initially reflect the metabolic acidaemia of intrapartum asphyxia; mature babies commonly correct their acidaemia spontaneously from pH levels in the 7.10–7.15 range and base deficit values of 10–15 mmol/l ( ). After the first hour or two, persisting metabolic acidaemia indicates an underlying problem such as sepsis, hypotension and/or renal failure, which should be sought and remedied.

Urine analysis

Many babies with MAS, although not in overt renal failure, have a raised urinary β ₂ -microglobulin, indicating they have incurred some renal damage ( ). The urine may be greenish-brown in colour as a result of the absorption of meconium pigments across the pulmonary epithelium and their excretion in the urine ( ).

Echocardiography

In uncomplicated MAS, the ECG and echocardiogram will be normal. If there has been severe intrapartum asphyxia, there may be ECG changes suggesting subendocardial ischaemia, and the echocardiogram will show reduced cardiac contractility. In those with PPHN, echocardiography demonstrates right-to-left shunting at ductal and atrial levels and a jet of tricuspid insufficiency, indicating raised right ventricular pressures.

Chest X-ray

The common early changes are widespread patchy infiltration and, in 20–30% of patients, small pleural effusions. Overexpansion is also common in the early stage. In mild to moderate cases, the changes resolve within 48 hours. In severe cases, as the disease progresses, by 72 hours of age with or without ventilation the appearance is often changed to that of diffuse and homogeneous opacification of both lung fields, as a result of a pneumonitis and interstitial oedema secondary to the irritant effect of the inhaled meconium ( Fig. 27.35 ). These changes gradually resolve over the next week, but in severe cases the X-ray may still be abnormal at 14 days, and may merge into the pattern seen in BPD, although this is uncommon. Airleaks, in particular pneumothorax and pneumomediastinum, are very common in MAS ( p. 486 ).

Severe confluent pneumonitis in meconium aspiration syndrome.

Microbiology

All babies suffering from MAS should have an infection screen as soon as possible after admission to the NICU.

Oxygen therapy

Many babies with MAS can be managed by giving an appropriate concentration, up to 80–90%, of warmed humidified oxygen. The oxygen saturation should be maintained at 95% or the P a o ₂ greater than 10 kPa during the acute stage of the illness. In many mild cases, oxygen therapy at 40% or less for 24–48 hours is all that is required and P a o ₂ in room air is normal by 48 hours of age.

Acid–base homeostasis

Carbon dioxide retention is only a problem in severe cases. A P a co ₂ of 7.5–8 kPa (55–60 mmHg) is acceptable, providing the pH is sustained above 7.25. Intubation and ventilation are indicated if the P a co ₂ rises above 8 kPa (60 mmHg), particularly in the presence of a P a o ₂ <6 kPa (45 mmHg) early in the disease.

The first blood gas analysis taken after birth may show a marked metabolic acidaemia. Provided that the baby is otherwise stable, with a normal P a o ₂ and P a co ₂ , and is passing urine, base deficits of 10–15 can be left to correct spontaneously ( Ch. 35.2 ). The acidaemia should be corrected, however, if the base deficit is greater than 15 or the pH below 7.10.

In babies who show features of HIE, more rigid control of the blood gases is required ( Ch. 40.4 ); hypoxia, hypercapnia and acidaemia are all undesirable. This indication for intubation and ventilation takes priority over the more conservative management of the blood gases outlined for babies with uncomplicated lung disease.

Continuous positive airways pressure

CPAP can improve oxygenation, but is likely to increase the risk of pneumothorax. In addition, use of nasal prongs in term neonates usually makes them irritable and restless, with a fall in P aO ₂ .

Intermittent positive-pressure ventilation

Babies with MAS can be very difficult to ventilate; a long expiratory time and a low level of PEEP are theoretically best in MAS; elevation of PEEP can improve oxygenation, but increases the risk of pneumothorax. Administration of a neuromuscular blocking agent is virtually always required. When the blood gases start to improve, weaning can usually be rapid. Once the infant is in <50–60% oxygen and has peak pressures of 20 cmH ₂ O, neuromuscular blockade can be stopped. We then prefer to transfer infants to PTV and wean by a reduction in peak pressures, extubating infants into headbox oxygen without a period on CPAP.

High-frequency ventilation

HFJV used with surfactant, but not alone, has been reported to improve oxygenation in MAS ( ). A retrospective review, however, reported no significant difference in the outcome of infants with MAS supported by HFJV ( ). HFOV, particularly when used with NO, improved oxygenation and outcome in infants with PPHN and MAS ( ).

Extracorporeal membrane oxygenation

In a randomised trial, ECMO improved survival of MAS infants with an oxygenation index >40 by 50% ( ). Approximately 94% of babies with MAS who are managed with ECMO survive; this does not appear to be at an increased risk of disability or adverse neurological outcome ( ).

Pulmonary vasodilators ( p. 498 )

Drugs used to treat pulmonary hypertension can be effective in babies with MAS ( ; ; ; ; ). Inhaled NO improves oxygenation and decreases the need for ECMO ( ; ) but in these trials no other significant differences in major outcomes were noted.

Surfactant

Exogenous surfactant therapy has been used with anecdotal success ( ; ). In a randomised prospective study, babies who received surfactant within 6 hours of birth had fewer airleaks, were on IPPV and oxygen for a shorter period and were much less likely to require ECMO ( ). The maximum effect on oxygenation was after three doses or more, suggesting that larger doses are required in MAS. Once on ECMO, the use of surfactant speeds recovery and the rate of weaning from ECMO ( ). In a randomised trial, up to four doses of surfactant reduced the need for ECMO in term infants with respiratory failure, half of whom had MAS ( ); however, there were no other significant differences in outcome. Meta-analysis of the results of four randomised trials demonstrated that surfactant administration reduced the risk of requiring ECMO, but not mortality ( ).

Lavage with surfactant may be a particularly effective method of improving gas exchange by washing out meconium and the products of inflammation ( ), as well as diluting the meconium. Multiple small-volume dilute surfactant lavages have been reported to improve oxygenation ( ). Large aliquots (15 ml/kg) have also been used without adverse acute effects and a trend to improvement in oxygenation at 48 hours compared with controls ( ). In a randomised trial, no advantages of lavage compared with bolus were found with regard to length of hospitalisation or complications, but the sample size was small and the lavage group had improvements in oxygenation, decreases in MAP and A–a gradients ( ). In a randomised trial, lavage with the protein-containing synthetic surfactant Surfaxin (KL-4 surfactant) improved lung function ( ).

Antibiotics

The presence of organic and potentially infected material in the liquor and in the lung may predispose to pneumonia. Neonates with MAS should be put on broad-spectrum antibiotics, penicillin and gentamicin. The antibiotics should be discontinued when the culture results are known to be negative or after 7 days, when the baby is in the convalescent stage of the illness and requiring less than 30–40% oxygen.

Blood volume and blood pressure

If the haemoglobin falls below 13 g/dl or the PCV below 40%, the baby should be transfused. BP control is essential in all neonates with MAS, aiming to keep the pressure within the normal range ( Appendix 4 ). Hypotension is usually only a problem in babies who have suffered severe intrapartum asphyxia with coexisting myocardial injury or after vasodilators. If hypotension occurs, it is managed in the usual way with volume expansion and/or inotropes, depending on the neonate’s myocardial and renal function ( Ch. 35.2 ).

Physiotherapy

In neonates with mild to moderate disease who are not ventilated and require less than 60% inspired oxygen concentration, chest physiotherapy is rarely necessary. In the severely affected baby who is intubated and paralysed, chest percussion and ETT suction may be helpful, but should be continued only as long as this produces significant amounts of greenish material and abandoned if the neonate becomes hypoxaemic.

Steroids

In an animal model, although steroids reduced respiratory symptoms due to MAS, the mortality rate was higher ( ). In a randomised trial involving 35 infants ( ), steroid treatment in the first 6 hours after birth resulted in no significant differences in the duration of ventilation or survival and the steroid-treated group experienced an increased time to wean. In a subsequent small trial ( ), major outcomes (mortality and BPD) were not influenced by steroid therapy. More recently, steroid administration resulted in more rapid improvement in ventilated infants with MAS and PPHN ( ). Further studies are required to determine if steroid administration influences long-term outcomes.

Pneumothorax, airleaks

Pneumothorax, pneumomediastinum, pneumopericardium and pneumoperitoneum can all occur; approximately 50% of ventilated MAS babies suffer some form of airleak, but PIE is unusual.

Persistent pulmonary hypertension

This is a common complication of severe MAS, and appears to be particularly frequent in fatal cases ( ).

Bronchopulmonary dysplasia

This is a rare complication of MAS, although it may occur in any baby who survives after long-term high-pressure IPPV.

Mortality

Mortality rates are between 4% and 12% ( ). The majority of deaths are from respiratory failure, PPHN or airleaks ( ), but some die from the associated neurological or renal sequelae of severe asphyxia.

Morbidity

Pathophysiology

The anatomical structure of the pharynx and larynx protects the airway from inhalation ( Ch. 7.7 ) ( ) and there are defensive reflexes. The presence of any material in the pharynx initiates swallowing and reflex breath-holding ( ). If the airway remains threatened, additional reflexes, including more prolonged apnoea, choking, laryngospasm and coughing, are provoked ( ; ). These mechanisms provide a less effective shield over the airway in the neonatal period than they do in older children and adults. During sucking, the term neonate may have a reduction in ventilation ( ), P a o ₂ and heart rate ( ), progressing in some infants to apnoea ( ; ; ; ). This may be because of poor breathing/swallowing coordination or additional problems such as velopalatine insufficiency with reflux into the nasopharynx ( ). The preterm neonate additionally has immature sucking/swallowing coordination ( ), which may be overwhelmed by oral feeding, and a high incidence of GOR ( ). If there has been brain damage, the neurological control of swallowing may be compromised. Preterm babies can protect their airway as well as those born at term, but these frequent challenges mean that its integrity may eventually be breached ( ) and inhalation of stomach contents results. Even if the defence mechanisms are effective in preventing intrapulmonary inhalation, significant symptoms, especially apnoea ( ; ), may still result.

Coordinating sucking, swallowing and breathing becomes more difficult at all gestations if the neonate is sedated, for example by the transplacental passage of opiates, or if the neonate is tachypnoeic with RDS or TTN ( ).

Other common causes of breathing/swallowing incoordination in both preterm and term babies are structural malformations in the upper airway or gastrointestinal tract, or neurological problems interfering with normal swallowing. Biochemical problems such as hypoglycaemia or hyponatraemia may occasionally have the same effect. Most causes of dysphagia and sucking/swallowing incoordination are extremely rare and usually present with the primary disorder rather than with dysphagia.

Clinical features

The commonest manifestation of swallowing/breathing incoordination in the term baby is choking, spluttering and becoming transiently apnoeic and blue during a feed. The baby thereafter usually remains asymptomatic. Many of these babies are at the extreme end of the normal spectrum of the response to feeding ( ). More serious examples are seen in babies who have brain damage or have abnormalities such as a cleft palate. In these, even saliva may continually collect in the pharynx and the baby will be ‘mucousy’. In severe cases, babies have saliva dribbling from their mouths and may cough and splutter when trying to clear their airways: cyanosis and bradycardia can occur ( ; ). Persisting retention of secretions in the pharynx and larynx, in addition to causing noisy breathing and upper respiratory tract symptoms, may result in tachypnoea and retraction, and, on auscultation, widespread conducted sounds are heard. Affected babies can have reflex apnoea caused by the presence of foreign materials in the larynx ( ).

Investigation and differential diagnosis

On the basis of the history and clinical examination, it should be possible to distinguish babies who have had a single or at most two or three episodes due to immature mechanisms being overwhelmed, from those with GOR or a chronic neurological or structural problem ( Table 27.9 ). The clinical presentation of oesophageal atresia, with maternal polyhydramnios, followed by the baby having major problems with secretions in the first 2–3 hours, is sufficiently classical that it should not be missed. Other babies may have covert GOR, or may be refluxing into the nasopharynx during a feed, with subsequent reflex apnoea ( ). Appropriate oesophageal pH ( ; ) or contrast studies will demonstrate the abnormality.

Treatment

If no clinical abnormality is found (which is usually the case) in a term baby who has been admitted to the neonatal unit following such an episode on the postnatal ward, breast- or bottle-feeding can be continued under careful supervision, proceeding to further investigation only if choking persists. In convalescent LBW neonates, or those with recognised neurological or structural problems, all that is usually necessary in the absence of signs of aspiration pneumonia is to omit one or two feeds, before carefully restarting them, by nasogastric tube if necessary.

Babies with a tracheo-oesophageal fistula or laryngeal cleft should have surgical repair as soon as possible ( Ch. 29.4 ). Problems associated with palatal defects may be considerably improved by the use of a palatal prosthesis ( Ch. 27.7 ). In babies with Pierre Robin syndrome, laryngomalacia or other surgical problems in which there is not only tongue/palate incoordination but also a structural predisposition to inhalation, and, in addition, no prospect of immediate surgical correction, the airways should be meticulously suctioned and the baby nursed prone. It may, however, occasionally be necessary to resort to tracheostomy in order to protect the lungs.

A small group of babies, typically those with severe neurological damage secondary to HIE or with a primary problem such as dystrophia myotonica, may have prolonged difficulties. Frequent suctioning of the mouth and pharynx will be required and it may help to keep the baby lying prone or semiprone, allowing the baby’s mouth to empty by gravity. Persistence of problems is an ominous prognostic feature; despite suctioning and positioning and meticulous nursing care, inhalation of secretions will eventually result, progressing to aspiration pneumonia, which is a common terminal event in such cases.

Treatment

If episodes of apnoea or recurrent pulmonary disease in a neonate are confirmed to be due to reflux, small frequent feeds or continuous milk infusion are advocated; nasojejeunal feeds or thickened feeds may also be beneficial ( ). Antacids should be given if there is evidence of oesophagitis. Cisapride is no longer prescribed, because of the reports of toxicity and apparent lack of efficacy. Consequently, if the above measures fail, some clinicians prescribe another prokinetic agent, domperidone. Whether neonates benefit from any form of medical therapy for reflux has been questioned ( ) and fundoplication may be necessary if problems from GOR persist. In our experience, this is rarely necessary, except in babies with chronic severe reflux and BPD.

Prevention

Most cases of aspiration pneumonia can and should be prevented by prompt clinical recognition and appropriate management of the disorders in which they are likely to occur ( Table 27.8 ) and by careful attention to the feeding technique. Professional speech and language therapy input is essential for safe oral feeding in many of these babies.

Pathophysiology

The foreign material aspirated into the airway can have three effects: physical obstruction, chemical irritation and promotion of infection. All fluids, including water, are damaging, but gastric contents are particularly damaging because of their acidic pH ( ). In the first few days after birth, the pH of a neonate’s stomach contents can be 2.5 or less if the infant is unfed ( ) or fed only clear fluids with no buffering capacity. Inhaled curd is particulate and can obstruct airways, leading to lung collapse and/or consolidation, and may predispose to infection.

Clinical findings

In babies with sucking/swallowing incoordination, the features of their primary diagnosis will be present ( Table 27.9 ). In addition, if such infants have chronic pooling of secretions in their upper airway, they will be mucousy with rattling, noisy respiration, often coupled with respiratory distress due to obstruction of the airway by secretions. Widespread conducted sounds, therefore, are often heard on auscultation of the chest.

After a massive regurgitation or vomit which triggers an episode of apnoea, cyanosis and bradycardia, but which has been promptly and efficiently dealt with (see below), many neonates show no abnormal physical signs 10–15 minutes later. In these babies, the clinical features suggesting that inhalation pneumonia has actually occurred are the non-specific ones of respiratory distress ( p. 476 ). In a neonate with pre-existing lung disease, respiratory function deteriorates. In both groups, crepitations and rhonchi may be heard on auscultation.

Investigations

In the baby who rapidly reverts to normal and shows no signs of respiratory compromise 15–30 minutes after the episode, it is still advisable to do a CXR. A new area of consolidation, particularly in the right upper lobe, is very suggestive of inhalation, but more generalised and non-specific changes may occur. In either the chronic situation or following a single severe episode, if the baby has the signs of respiratory disease he or she should be investigated for infection ( Ch. 39.2 ). Measuring the electrolytes, blood sugar and calcium is indicated in all babies and may identify a cause for a convulsion.

Treatment

Morbidity and mortality of aspiration pneumonia

This is dependent on the underlying pathology, since the lung disease following inhalation per se is rarely, if ever, fatal. Babies with persistent failure to suck or swallow secretions after severe birth asphyxia and those with congenital neurological problems have a guarded prognosis on the basis of their underlying defects. Most babies with a structural defect do well with appropriate surgery, but there remains an appreciable mortality with laryngotracheo-oesophageal cleft ( p. 610 ) or Pierre Robin syndrome ( p. 605 ). For the baby whose problems are due to immaturity, the outlook is excellent, since it can be anticipated that the lung disease will respond to the therapy outlined, although some infants may develop BPD and have a prolonged convalescence.

Cardiac

The condition is commonly secondary to heart failure, hence the infant may have a tachycardia greater than 160/min and the murmur of a PDA is frequently heard ( ). Other signs of heart failure, including hepatosplenomegaly and a triple rhythm, can occur. The presence of peripheral oedema may indicate heart failure, hydrops, hypoalbuminaemia or fluid overload. Hypotension is virtually always present, because of a combination of blood and fluid loss, heart failure and coexisting hypoxaemia and acidaemia.

Respiratory

Infants are dyspnoeic and cyanotic and auscultation of the chest reveals widespread crepitations with a reduction in air entry.

Haematological

Although the haematocrit of the oedema fluid is usually <10%, considerable quantities of blood may be lost, and the haemoglobin may fall to 10 g/dl or even lower. found that coagulation disturbances were not a regular feature of their patients prior to the haemorrhage, but DIC is not uncommon afterwards.

Biochemical

Affected preterm babies usually have the same problems as those with severe RDS. In particular, hypoglycaemia, hypocalcaemia, hypoalbuminaemia and renal failure should be sought and remedied.

Chest X-ray

The CXR in the baby who has had a large MPH shows a virtual ‘whiteout’ ( Fig. 27.37 ) with just an air bronchogram visible. This appearance is indistinguishable from severe surfactant deficiency and may be a reflection of the secondary surfactant deficiency that occurs following pulmonary haemorrhage. As the condition improves on IPPV, the changes may clear or merge into those of BPD. Rarely, a lobar pattern of consolidation is found, suggesting that the haemorrhage has occurred in just a part of the lung.

Widespread homogeneous opacification of the lungs in a baby with massive pulmonary haemorrhage.

(Reproduced from .)

Bacteriology

The haemorrhage may be precipitated by sepsis. For this reason, an infection screen must always be taken immediately after the event. The baby’s condition, however, will usually preclude performing a lumbar puncture ( Ch. 39.2 ).

Blood gases

All components of arterial blood gas analysis deteriorate rapidly after the bleed. Hypoxia is severe, the P a co ₂ may increase to 10 kPa (75 mmHg) or more and there is usually a marked metabolic acidosis with a base deficit of at least 10 mmol/l. The combined respiratory and metabolic acidaemia may result in a pH of 7.10 or less.

Control of pulmonary oedema and heart failure